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Sample records for chemokines neuronal-glial interactions

  1. Interaction of chemokines with their receptors--from initial chemokine binding to receptor activating steps

    DEFF Research Database (Denmark)

    Thiele, Stefanie; Rosenkilde, Mette Marie

    2014-01-01

    interactions possibly occur, resulting in a multi-step process, as recently proposed for other 7TM receptors. Overall, the N-terminus of chemokine receptors is pivotal for binding of all chemokines. During receptor activation, differences between the two major chemokine subgroups occur, as CC-chemokines mainly......The human chemokine system comprises 19 seven-transmembrane helix (7TM) receptors and 45 endogenous chemokines that often interact with each other in a promiscuous manner. Due to the chemokine system's primary function in leukocyte migration, it has a central role in immune homeostasis...... and surveillance. Chemokines are a group of 8-12 kDa large peptides with a secondary structure consisting of a flexible N-terminus and a core-domain usually stabilized by two conserved disulfide bridges. They mainly interact with the extracellular domains of their cognate 7TM receptors. Affinityand activity...

  2. Neuronal Chemokines: Versatile Messengers In Central Nervous System Cell Interaction

    OpenAIRE

    de Haas, A. H.; van Weering, H. R. J.; Jong, E.K.; Boddeke, H. W. G. M.; Biber, K.P.H.

    2007-01-01

    Whereas chemokines are well known for their ability to induce cell migration, only recently it became evident that chemokines also control a variety of other cell functions and are versatile messengers in the interaction between a diversity of cell types. In the central nervous system (CNS), chemokines are generally found under both physiological and pathological conditions. Whereas many reports describe chemokine expression in astrocytes and microglia and their role in the migration of leuko...

  3. Chemokines

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    Richard Horuk

    2007-01-01

    Full Text Available Chemokines are a family of polypeptides that direct the migration of leukocytestoward a site of infection. They play a major role in autoimmune disease and chemokine receptors have recently been found to mediate HIV-1 fusion. In this short review we examine the role of chemokines in host defence and in the pathophysiology of autoimmune diseases. We conclude by discussing various therapeutic approaches that target chemokine receptors and that could be beneficial in disease.

  4. Profiling Heparin-Chemokine Interactions Using Synthetic Tools

    Science.gov (United States)

    de Paz, Jose L.; Moseman, E. Ashley; Noti, Christian; Polito, Laura; von Andrian, Ulrich H.; Seeberger, Peter H.

    2009-01-01

    Glycosaminoglycans (GAGs), such as heparin or heparan sulfate, are required for the in vivo function of chemokines. Chemokines play a crucial role in the recruitment of leukocyte subsets to sites of inflammation and lymphocytes trafficking. GAG-chemokine interactions mediate cell migration and determine which leukocyte subsets enter tissues. Identifying the exact GAC sequences that bind to particular chemokines is key to understand chemokine function at the molecular level and develop strategies to interfere with chemokine-mediated processes. Here, we characterize the heparin binding profiles of eight chemokines (CCL21, IL-8, CXCL12, CXCL13, CCL19, CCL25, CCL28, and CXCL16) by employing heparin microarrays containing a small library of synthetic heparin oligosaccharides. The chemokines differ significantly in their interactions with heparin oligosaccharides: While some chemokines, (e.g., CCL21) strongly bind to a hexasaccharide containing the GlcNSO3(6-OSO3)-IdoA(2-OSO3) repeating unit, CCL19 does not bind and CXCL12 binds only weakly. The carbohydrate microarray binding results were validated by surface plasmon resonance experiments. In vitro chemotaxis assays revealed that dendrimers coated with the fully sulfated heparin hexasaccharide inhibit lymphocyte migration toward CCL21. Migration toward CXCL12 or CCL19 was not affected. These in vitro homing assays indicate that multivalent synthetic heparin dendrimers inhibit the migration of lymphocytes toward certain chemokine gradients by blocking the formation of a chemokine concentration gradient on GAG endothelial chains. These findings are in agreement with preliminary in vivo measurements of circulating lymphocytes. The results presented here contribute to the understanding of GAG-chemokine interactions, a first step toward the design of novel drugs that modulate chemokine activity. PMID:18030990

  5. Neuronal chemokines : Versatile messengers in central nervous system cell interaction

    NARCIS (Netherlands)

    de Haas, A. H.; van Weering, H. R. J.; de Jong, E. K.; Boddeke, H. W. G. M.; Biber, K. P. H.

    2007-01-01

    Whereas chemokines are well known for their ability to induce cell migration, only recently it became evident that chemokines also control a variety of other cell functions and are versatile messengers in the interaction between a diversity of cell types. In the central nervous system (CNS), chemoki

  6. Neuronal-glial mechanisms of exercise-evoked stress robustness.

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    Fleshner, Monika; Greenwood, Benjamin N; Yirmiya, Raz

    2014-01-01

    Stress robustness by definition, incorporates both stress resistance (organisms endure greater stressor intensity or duration before suffering negative consequences) and stress resilience (organisms recover faster after suffering negative consequences). Factors that influence stress robustness include the nature of the stressor, (i.e., controllability, intensity, chronicity) and features of the organism (i.e., age, genetics, sex, and physical activity status). Here we present a novel hypothesis for how physically active versus sedentary living promotes stress robustness in the face of intense uncontrollable stress. Advances in neurobiology have established microglia as an active player in the regulation of synaptic activity, and recent work has revealed mechanisms for modulating glial function, including cross talk between neurons and glia. This chapter presents supporting evidence that the physical activity status of an organism may modulate stress-evoked neuronal-glial responses by changing the CX3CL1-CX3CR1 axis. Specifically, we propose that sedentary animals respond to an intense acute uncontrollable stressor with excessive serotonin (5-HT) and noradrenergic (NE) activity and/or prolonged down-regulation of the CX3CL1-CX3CR1 axis resulting in activation and proliferation of hippocampal microglia in the absence of pathogenic signals and consequent hippocampal-dependent memory deficits and reduced neurogenesis. In contrast, physically active animals respond to the same stressor with constrained 5-HT and NE activity and rapidly recovering CX3CL1-CX3CR1 axis responses resulting in the quieting of microglia, and protection from negative cognitive and neurobiological effects of stress. PMID:24481547

  7. Neuroprotective role of fibronectin in neuron-glial extrasynaptic transmission

    Institute of Scientific and Technical Information of China (English)

    Jintang Wang; Ling Yin; Zheng Chen

    2013-01-01

    Most hypotheses concerning the mechanisms underlying Parkinson's disease are based on altered synaptic transmission of the nigrostriatal system. However, extrasynaptic transmission was recently found to affect dopamine neurotransmitter delivery by anisotropic diffusion in the extracellular matrix, which is modulated by various extracellular matrix components such as fibronectin. The present study reviewed the neuroprotective effect of fibronectin in extrasynaptic transmission. Fibronectin can regulate neuroactive substance diffusion and receptor activation, and exert anti- neuroinflammatory, adhesive and neuroprotective roles. Fibronectin can bind to integrin and growth factor receptors to transactivate intracellular signaling events such as the phosphatidylinositol 3-kinase/protein kinase B pathway to regulate or amplify growth factor-like neuroprotective actions. Fibronectin is assembled into a fibrillar network around cells to facilitate cell migration, molecule and ion diffusion, and even drug delivery and treatment. In addition, the present study analyzed the neuroprotective mechanism of fibronectin in the pathogenesis of Parkinson's disease, involving integrin and growth factor receptor interactions, and discussed the possible therapeutic and diagnostic significance of fibronectin in Parkinson's disease.

  8. Inhibition of chemokine-glycosaminoglycan interactions in donor tissue reduces mouse allograft vasculopathy and transplant rejection.

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    Erbin Dai

    Full Text Available BACKGROUND: Binding of chemokines to glycosaminoglycans (GAGs is classically described as initiating inflammatory cell migration and creating tissue chemokine gradients that direct local leukocyte chemotaxis into damaged or transplanted tissues. While chemokine-receptor binding has been extensively studied during allograft transplantation, effects of glycosaminoglycan (GAG interactions with chemokines on transplant longevity are less well known. Here we examine the impact of interrupting chemokine-GAG interactions and chemokine-receptor interactions, both locally and systemically, on vascular disease in allografts. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of GAG or CC chemokine receptor 2 (CCR2 deficiency were coupled with the infusion of viral chemokine modulating proteins (CMPs in mouse aortic allograft transplants (n = 239 mice. Inflammatory cell invasion and neointimal hyperplasia were significantly reduced in N-deacetylase-N-sulfotransferase-1 (Ndst1(f/fTekCre(+ heparan sulfate (GAG-deficient (Ndst1(-/-, p<0.044 and CCR2-deficient (Ccr2(-/-, p<0.04 donor transplants. Donor tissue GAG or CCR2 deficiency markedly reduced inflammation and vasculopathy, whereas recipient deficiencies did not. Treatment with three CMPs was also investigated; Poxviral M-T1 blocks CC chemokine receptor binding, M-T7 blocks C, CC, and CXC GAG binding, and herpesviral M3 binds receptor and GAG binding for all classes. M-T7 reduced intimal hyperplasia in wild type (WT (Ccr2(+/+, p< or =0.003 and Ccr2(-/-, pchemokine-GAG interactions, even in the absence of chemokine

  9. Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide

    NARCIS (Netherlands)

    J. Zhao; R.W.H. Verwer; D.J. van Wamelen; X.R. Qi; S.F. Gao; P.J. Lucassen; D.F. Swaab

    2016-01-01

    There are indications for changes in glutamate metabolism in relation to depression or suicide. The glutamate-glutamine cycle and neuronal/glial glutamate transporters mediate the uptake of the glutamate and glutamine. The expression of various components of the glutamate-glutamine cycle and the neu

  10. CD26/dipeptidylpeptidase IV-chemokine interactions: double-edged regulation of inflammation and tumor biology.

    Science.gov (United States)

    Mortier, Anneleen; Gouwy, Mieke; Van Damme, Jo; Proost, Paul; Struyf, Sofie

    2016-06-01

    Post-translational modification of chemokines is an essential regulatory mechanism to enhance or dampen the inflammatory response. CD26/dipeptidylpeptidase IV, ubiquitously expressed in tissues and blood, removes NH2-terminal dipeptides from proteins with a penultimate Pro or Ala. A large number of human chemokines, including CXCL2, CXCL6, CXCL9, CXCL10, CXCL11, CXCL12, CCL3L1, CCL4, CCL5, CCL11, CCL14, and CCL22, are cleaved by CD26; however, the efficiency is clearly influenced by the amino acids surrounding the cleavage site and although not yet proven, potentially affected by the chemokine concentration and interactions with third molecules. NH2-terminal cleavage of chemokines by CD26 has prominent effects on their receptor binding, signaling, and hence, in vitro and in vivo biologic activities. However, rather than having a similar result, the outcome of NH2-terminal truncation is highly diverse. Either no difference in activity or drastic alterations in receptor recognition/specificity and hence, chemotactic activity are observed. Analogously, chemokine-dependent inhibition of HIV infection is enhanced (for CCL3L1 and CCL5) or decreased (for CXCL12) by CD26 cleavage. The occurrence of CD26-processed chemokine isoforms in plasma underscores the importance of the in vitro-observed CD26 cleavages. Through modulation of chemokine activity, CD26 regulates leukocyte/tumor cell migration and progenitor cell release from the bone marrow, as shown by use of mice treated with CD26 inhibitors or CD26 knockout mice. As chemokine processing by CD26 has a significant impact on physiologic and pathologic processes, application of CD26 inhibitors to affect chemokine function is currently explored, e.g., as add-on therapy in viral infection and cancer. PMID:26744452

  11. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice

    DEFF Research Database (Denmark)

    Koenen, RR; Hundelshausen, P; Nesmelova, IV;

    2009-01-01

    Atherosclerosis is characterized by chronic inflammation of the arterial wall due to chemokine-driven mononuclear cell recruitment. Activated platelets can synergize with chemokines to exacerbate atherogenesis; for example, by deposition of the chemokines platelet factor-4 (PF4, also known as CXCL4...... and by enhanced monocyte arrest resulting from CCL5-CXCL4 interactions. The CCL5 antagonist Met-RANTES reduces diet-induced atherosclerosis; however, CCL5 antagonism may not be therapeutically feasible, as suggested by studies using Ccl5-deficient mice which imply that direct CCL5 blockade would severely...... monocyte recruitment and reducing atherosclerosis without the aforementioned side effects. These results establish the in vivo relevance of chemokine heteromers and show the potential of targeting heteromer formation to achieve therapeutic effects...

  12. Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation

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    Gokhan Solen

    2010-02-01

    Full Text Available Abstract Background Long non-protein-coding RNAs (ncRNAs are emerging as important regulators of cellular differentiation and are widely expressed in the brain. Results Here we show that many long ncRNAs exhibit dynamic expression patterns during neuronal and oligodendrocyte (OL lineage specification, neuronal-glial fate transitions, and progressive stages of OL lineage elaboration including myelination. Consideration of the genomic context of these dynamically regulated ncRNAs showed they were part of complex transcriptional loci that encompass key neural developmental protein-coding genes, with which they exhibit concordant expression profiles as indicated by both microarray and in situ hybridization analyses. These included ncRNAs associated with differentiation-specific nuclear subdomains such as Gomafu and Neat1, and ncRNAs associated with developmental enhancers and genes encoding important transcription factors and homeotic proteins. We also observed changes in ncRNA expression profiles in response to treatment with trichostatin A, a histone deacetylase inhibitor that prevents the progression of OL progenitors into post-mitotic OLs by altering lineage-specific gene expression programs. Conclusion This is the first report of long ncRNA expression in neuronal and glial cell differentiation and of the modulation of ncRNA expression by modification of chromatin architecture. These observations explicitly link ncRNA dynamics to neural stem cell fate decisions, specification and epigenetic reprogramming and may have important implications for understanding and treating neuropsychiatric diseases.

  13. Approaches to studies on neuronal/glial relationships by 13C-MRS analysis.

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    Taylor, A; McLean, M; Morris, P; Bachelard, H

    1996-01-01

    The use of different 13C-labelled precursors alone or in combination ([1-13C]glucose, [2-13C]glucose, [1-13C]acetate, [2-13C]acetate and [1,2-13C2]acetate) to study neuronal/glial metabolic relationships by MRS is discussed. Glutamine and citrate resonances represent glial metabolism if a combination of [1-13C]glucose + [2-13C]acetate is used, but only for short time periods. A combination of [2-13C]glucose + [2-13C]acetate will label -COO- groups from glucose and -CH2 groups from acetate, respectively, which distinguish well in theory. However, this approach is severely limited by the long T1S of -COO- groups and low S/N. Contributions of the anaplerotic pathway can be assessed using [2-13C]glucose, but again can be limited by the long T1S of -COO- groups. Labelling of glycerol-3-phosphate (believed to be produced in glia) from [1-13C]glucose is difficult to see under normal conditions but has proved useful in, e.g., hypoxia. We believe the most promising approach is the use of [1-13C] glucose with [1,2-13C2]acetate, by analysis of the multiplets ('isotopomers') of the amino acid resonances.

  14. Indirect effects of TiO2 nanoparticle on neuron-glial cell interactions.

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    Hsiao, I-Lun; Chang, Chia-Cheng; Wu, Chung-Yi; Hsieh, Yi-Kong; Chuang, Chun-Yu; Wang, Chu-Fang; Huang, Yuh-Jeen

    2016-07-25

    Although, titanium dioxide nanoparticles (TiO2NPs) are nanomaterials commonly used in consumer products, little is known about their hazardous effects, especially on central nervous systems. To examine this issue, ALT astrocyte-like, BV-2 microglia and differentiated N2a neuroblastoma cells were exposed to 6 nm of 100% anatase TiO2NPs. A lipopolysaccharide (LPS) was pre-treated to activate glial cells before NP treatment for mimicking NP exposure under brain injury. We found that ALT and BV-2 cells took up more NPs than N2a cells and caused lower cell viability. TiO2NPs induced IL-1β in the three cell lines and IL-6 in N2a. LPS-activated BV-2 took up more TiO2NPs than normal BV-2 and released more intra/extracellular reactive oxygen species (ROS), IL-1β, IL-6 and MCP-1 than did activated BV-2. Involvement of clathrin- and caveolae-dependent endocytosis in ALT and clathrin-dependent endocytosis and phagocytosis in BV-2 both had a slow NP translocation rate to lysosome, which may cause slow ROS production (after 24 h). Although TiO2NPs did not directly cause N2a viability loss, by indirect NP exposure to the bottom chamber of LPS-activated BV-2 in the Transwell system, they caused late apoptosis and loss of cell viability in the upper N2a chamber due to H2O2 and/or TNF-α release from BV-2. However, none of the adverse effects in N2a or BV-2 cells was observed when TiO2NPs were exposed to ALT-N2a or ALT-BV-2 co-culture. These results demonstrate that neuron damage can result from TiO2NP-mediated ROS and/or cytokines release from microglia, but not from astrocytes. PMID:27216632

  15. Re: Chemokines in Cancer

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    Fehmi Narter

    2016-09-01

    Full Text Available Chemokines are chemotactic cytokines that regulate the trafficking and positioning of cells by activating the seven-transmembrane spanning G protein-coupled chemokine receptors (GPCR or non G protein-coupled seven-transmembrane spanning receptors called atypical chemokine receptors (ACKR. Chemokines are basic proteins that also bind to glycosaminoglycans which play important roles in their biology. Chemokines are divided into four subfamilies based on the position of the first two N-terminal cysteine residues, including the CC, CXC, CX3C and XC subfamilies. Nearly 50 chemokines and 20 signaling chemokine receptors and 4 AKCRs have been identified. Dysregulated expression of chemokines and their corresponding receptors is implicated in many diseases, such as autoimmune and inflammatory diseases and cancer. Chemokines are essential coordinators of cellular migration and cell-cell interactions and, therefore, have great impact on tumor development. In the tumor microenvironment, tumor-associated host cells and cancer cells release an array of different chemokines, resulting in the recruitment and activation of different cell types that mediate the balance between antitumor and pro-tumor responses. In addition to their primary role as chemoattractants, chemokines are also involved in other tumor-related processes, including tumor cell growth, angiogenesis and metastasis. Therefore, further studies of the distinctions between the pro-tumor and antitumor activities of chemokines are warranted in order to develop more effective therapies against cancer.

  16. Landmarks in the application of 13C-magnetic resonance spectroscopy to studies of neuronal/glial relationships.

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    Bachelard, H

    1998-01-01

    The development of the use of carbon isotopes as metabolic tracers is briefly described. 13C-labelled precursors (13CO2, 13CH4) first became available in 1940 and were studied in microorganisms, but their use was limited by very low enrichments and lack of suitable analytical equipment. More success was achieved with 11C and especially 14C, as these radioactive tracers did not need to be highly enriched. Although the stable 13C isotope can be used at a low percentage enrichment in mass spectrometry, its application to magnetic resonance spectroscopy (MRS) requires very highly enriched precursors, due to its low natural abundance and low sensitivity. Despite such limitations, however, the great advantage of 13C-MRS lies in its exquisite chemical specificity, in that labelling of different carbon atoms can be distinguished within the same molecule. Effective exploitation became feasible in the early 1970s with the advent of stable instruments, Fourier transform 13C-MRS, and the availability of highly enriched precursors. Reports of its use in brain research began to appear in the mid-1980s. The applications of 13C isotopomer analysis to research on neuronal/glial relationships are reviewed. The presence of neighbouring 13C-labelled atoms affects the appearance of the resonances (splitting due to C-C coupling), and so allows for unique quantification of rates through different and possibly competing pathways. Isotopomer patterns in resonances labelled from a combination of [1-13C]glucose and [1, 2-13C2]acetate have revealed aspects of neuronal/glial metabolic trafficking on depolarization and under hypoxic conditions in vitro. This approach has now been applied to in vivo studies on inhibition of glial metabolism using fluoroacetate. The results confirm the glial specificity of the toxin and demonstrate that it does not affect entry of acetate. When the glial TCA cycle is inhibited, the ability of the glia to participate in the glutamate/glutamine cycle remains

  17. Structural and functional characterization of the interactions of platelet derived chemokines CCL5, CXCL4 and CXCL4L1

    OpenAIRE

    Sarabi, Alisina

    2011-01-01

    Chemokines play an important role in the development of inflammation and in the recruitment of leukocytes from the vessel into the inflamed tissue. Activated platelets serve as a rich source of chemokines, e.g. CCL5, CXCL4 and its closely related variant CXCL4L1. The pro-inflammatory CCL5 is a known potent chemoattractant for monocytes and also responsible for its arrest on inflamed endothelium. Since this arrest is enhanced by the interaction of CCL5 with CXCL4, we aimed to determine the str...

  18. Staphylococcus via an interaction with the ELR+ CXC chemokine ENA-78 is associated with BOS.

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    Gregson, A L; Wang, X; Injean, P; Weigt, S S; Shino, M; Sayah, D; DerHovanessian, A; Lynch, J P; Ross, D J; Saggar, R; Ardehali, A; Li, G; Elashoff, R; Belperio, J A

    2015-03-01

    Staphylococcus aureus is the most commonly isolated gram-positive bacterium after lung transplantation (LT) and has been associated with poor posttransplant outcomes, but its effect on bronchiolitis obliterans syndrome (BOS) and death in the context of the allograft inflammatory environment has not been studied. A three-state Cox semi-Markovian model was used to determine the influence of allograft S. aureus and the ELR+ CXC chemokines on the survival rates and cause-specific hazards for movement from lung transplant (State 1) to BOS (State 2), from transplant (State 1) to death (State 3), and from BOS (State 2) to death (State 3). Acute rejection, pseudomonas pneumonia, bronchoalveolar lavage fluid (BALF) CXCL5 and its interaction with S. aureus all increased the likelihood of transition from transplant to BOS. Transition to death from transplant was facilitated by pseudomonas infection and single lung transplant. Movement from BOS to death was affected by the interaction between aspergillus, pseudomonas and CXCL5, but not S. aureus. S. aureus isolation had state specific effects after LT and only in concert with elevated BALF CXCL5 concentrations did it augment the risk of BOS. Pseudomonas and elevated BALF concentrations of CXCL5 continued as significant risk factors for BOS and death after BOS in lung transplantation.

  19. Role of IFN-gamma and LPS on Neuron/Glial Co-Cultures Infected by Neospora caninum

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    Erica Etelvina Viana De Jesus

    2014-10-01

    Full Text Available Neospora caninum causes cattle abortion and neurological symptoms in dogs. Although infection is usually asymptomatic, classical neurological symptoms of neosporosis may be associated with encephalitis. This parasite can grow in brain endothelial cells without markedly damages, but it can modulate the cellular environment to promote its survival in the brain. In previous studies, we described that IFN-γ decreased the parasite proliferation and down regulated nitric oxide production in astrocyte/microglia cultures. However, it remains unclear how glial cells respond to N. caninum in the presence of neurons. Therefore, we evaluated the effect of 300 IU/mL IFN-γ or 1.0 μg/mL of LPS on infected rat neuron/glial co-cultures. After 72 hours of infection, LPS did not affect the mitochondrial dehydrogenase activity. However, IFN-γ decreased this parameter by 15.5 and 12.0% in uninfected and infected cells, respectively. The number of tachyzoites decreased 54.1 and 44.3% in cells stimulated with IFN-γ and LPS, respectively. Infection or LPS treatment did not change NO production. On the other hand, IFN-γ induced increased nitrite release in 55.7%, but the infection reverted this induction. IL-10 levels increased only in infected cultures (treated or not, meanwhile PGE2 release was improved in IFN-γ/infected or LPS/infected cells. Although IFN-γ significantly reduced the neurite length in uninfected cultures (42.64%; p < 0.001, this inflammatory cytokine reverted the impairment of neurite outgrowth induced by the infection (81.39%. The results suggest a neuroprotective potential response of glia to N. caninum infection under IFN-γ stimulus. This observation contributes to understand the immune mediated mechanisms of neosporosis in CNS

  20. Extrasynaptic neurotransmission in the modulation of brain function. Focus on the striatal neuronal-glial networks

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    Kjell eFuxe

    2012-06-01

    Full Text Available Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT and histamine striatal afferents, the cholinergic interneurons and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal

  1. Diverse Physiological Roles of Calcitonin Gene-Related Peptide in Migraine Pathology: Modulation of Neuronal-Glial-Immune Cells to Promote Peripheral and Central Sensitization.

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    Durham, Paul L

    2016-08-01

    The neuropeptide calcitonin gene-related peptide (CGRP) is implicated in the underlying pathology of migraine by promoting the development of a sensitized state of primary and secondary nociceptive neurons. The ability of CGRP to initiate and maintain peripheral and central sensitization is mediated by modulation of neuronal, glial, and immune cells in the trigeminal nociceptive signaling pathway. There is accumulating evidence to support a key role of CGRP in promoting cross excitation within the trigeminal ganglion that may help to explain the high co-morbidity of migraine with rhinosinusitis and temporomandibular joint disorder. In addition, there is emerging evidence that CGRP facilitates and sustains a hyperresponsive neuronal state in migraineurs mediated by reported risk factors such as stress and anxiety. In this review, the significant role of CGRP as a modulator of the trigeminal system will be discussed to provide a better understanding of the underlying pathology associated with the migraine phenotype. PMID:27334137

  2. Suppressive effects of Bifidobacterium longum on the production of Th2-attracting chemokines induced with T cell-antigen-presenting cell interactions.

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    Iwabuchi, Noriyuki; Takahashi, Noritoshi; Xiao, Jin-Zhong; Yonezawa, Sumiko; Yaeshima, Tomoko; Iwatsuki, Keiji; Hachimura, Satoshi

    2009-04-01

    In human trials, Bifidobacterium longum BB536 alleviates subjective symptoms of Japanese cedar pollinosis, an IgE-mediated type I allergy caused by exposure to Japanese cedar, and significantly suppresses the increase of plasma thymus- and activation-regulated chemokine (TARC) associated with pollen dispersion. In the present study, we investigated the suppressive effects of BB536 on the production of T helper type 2 (Th2)-attracting chemokines, such as TARC and macrophage-derived chemokine (MDC), together with the mechanisms of their production. Murine splenocytes were cultured with heat-killed BB536, and the levels of Th2-attracting chemokines in the supernatants were measured. TARC and MDC were produced in cultures without stimulation, and the production was significantly suppressed by BB536. These chemokines were produced by antigen-presenting cells (APCs) of splenocytes stimulated with an anti-CD40 antibody. Furthermore, TARC production was induced with granulocyte macrophage colony-stimulating factor that was produced by T cells and dendritic cells. BB536 suppressed MDC production induced with the anti-CD40 antibody by APCs from the spleen, mesenteric lymph nodes (MLNs) and Peyer's patches, and it suppressed TARC production by APCs from the spleen and MLNs. These results indicate that BB536 suppresses the production of Th2-attracting chemokines induced by the T cell-APC interaction, suggesting a novel mechanism for alleviating symptoms of allergic disorders by probiotics.

  3. Analysis of Phosphorylation-dependent Protein Interactions of Adhesion and Degranulation Promoting Adaptor Protein (ADAP) Reveals Novel Interaction Partners Required for Chemokine-directed T cell Migration.

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    Kuropka, Benno; Witte, Amelie; Sticht, Jana; Waldt, Natalie; Majkut, Paul; Hackenberger, Christian P R; Schraven, Burkhart; Krause, Eberhard; Kliche, Stefanie; Freund, Christian

    2015-11-01

    Stimulation of T cells leads to distinct changes of their adhesive and migratory properties. Signal propagation from activated receptors to integrins depends on scaffolding proteins such as the adhesion and degranulation promoting adaptor protein (ADAP)(1). Here we have comprehensively investigated the phosphotyrosine interactome of ADAP in T cells and define known and novel interaction partners of functional relevance. While most phosphosites reside in unstructured regions of the protein, thereby defining classical SH2 domain interaction sites for master regulators of T cell signaling such as SLP76, Fyn-kinase, and NCK, other binding events depend on structural context. Interaction proteomics using different ADAP constructs comprising most of the known phosphotyrosine motifs as well as the structured domains confirm that a distinct set of proteins is attracted by pY571 of ADAP, including the ζ-chain-associated protein kinase of 70 kDa (ZAP70). The interaction of ADAP and ZAP70 is inducible upon stimulation either of the T cell receptor (TCR) or by chemokine. NMR spectroscopy reveals that the N-terminal SH2 domains within a ZAP70-tandem-SH2 construct is the major site of interaction with phosphorylated ADAP-hSH3(N) and microscale thermophoresis (MST) indicates an intermediate binding affinity (Kd = 2.3 μm). Interestingly, although T cell receptor dependent events such as T cell/antigen presenting cell (APC) conjugate formation and adhesion are not affected by mutation of Y571, migration of T cells along a chemokine gradient is compromised. Thus, although most phospho-sites in ADAP are linked to T cell receptor related functions we have identified a unique phosphotyrosine that is solely required for chemokine induced T cell behavior.

  4. Combinatorial signals by inflammatory cytokines and chemokines mediate leukocyte interactions with extracellular matrix.

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    Vaday, G G; Franitza, S; Schor, H; Hecht, I; Brill, A; Cahalon, L; Hershkoviz, R; Lider, O

    2001-06-01

    On their extravasation from the vascular system into inflamed tissues, leukocytes must maneuver through a complex insoluble network of molecules termed the extracellular matrix (ECM). Leukocytes navigate toward their target sites by adhering to ECM glycoproteins and secreting degradative enzymes, while constantly orienting themselves in response to specific signals in their surroundings. Cytokines and chemokines are key biological mediators that provide such signals for cell navigation. Although the individual effects of various cytokines have been well characterized, it is becoming increasingly evident that the mixture of cytokines encountered in the ECM provides important combinatorial signals that influence cell behavior. Herein, we present an overview of previous and ongoing studies that have examined how leukocytes integrate signals from different combinations of cytokines that they encounter either simultaneously or sequentially within the ECM, to dynamically alter their navigational activities. For example, we describe our findings that tumor necrosis factor (TNF)-alpha acts as an adhesion-strengthening and stop signal for T cells migrating toward stromal cell-derived factor-1alpha, while transforming growth factor-beta down-regulates TNF-alpha-induced matrix metalloproteinase-9 secretion by monocytes. These findings indicate the importance of how one cytokine, such as TNF-alpha, can transmit diverse signals to different subsets of leukocytes, depending on its combination with other cytokines, its concentration, and its time and sequence of exposure. The combinatorial effects of multiple cytokines thus affect leukocytes in a step-by-step manner, whereby cells react to cytokine signals in their immediate vicinity by altering their adhesiveness, directional movement, and remodeling of the ECM. PMID:11404372

  5. Regulation of neurotropic signaling by the inducible, NF-kB-sensitive miRNA-125b in Alzheimer’s disease (AD) and in primary human neuronal-glial (HNG) cells

    OpenAIRE

    Zhao, Yuhai; Bhattacharjee, Surjyadipta; Jones, Brandon M.; Hill, Jim; Dua, Prerna; Lukiw, Walter J.

    2013-01-01

    Inducible micro RNAs (miRNAs) perform critical regulatory roles in central nervous system (CNS) development, aging, health and disease. Using miRNA arrays, RNA-sequencing, enhanced Northern dot blot hybridization technologies, Western immunoblot and bioinformatics analysis we have studied miRNA abundance and complexity in Alzheimer’s disease (AD) brain tissues compared to age-matched controls. In both short post-mortem AD and in stressed primary human neuronal-glial (HNG) cells we observe a c...

  6. SOX1 links the function of neural patterning and Notch signalling in the ventral spinal cord during the neuron-glial fate switch

    Energy Technology Data Exchange (ETDEWEB)

    Genethliou, Nicholas; Panayiotou, Elena [The Cyprus Institute of Neurology and Genetics, Airport Avenue, No. 6, Agios Dometios, 2370 Nicosia (Cyprus); Department of Biological Sciences, University of Cyprus, P.O. Box 20537, 1678 Nicosia (Cyprus); Panayi, Helen; Orford, Michael; Mean, Richard; Lapathitis, George; Gill, Herman; Raoof, Sahir [The Cyprus Institute of Neurology and Genetics, Airport Avenue, No. 6, Agios Dometios, 2370 Nicosia (Cyprus); Gasperi, Rita De; Elder, Gregory [James J. Peters VA Medical Center, Research and Development (3F22), 130 West Kingsbridge Road, Bronx, NY 10468 (United States); Kessaris, Nicoletta; Richardson, William D. [Wolfson Institute for Biomedical Research and Research Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT (United Kingdom); Malas, Stavros, E-mail: smalas@cing.ac.cy [The Cyprus Institute of Neurology and Genetics, Airport Avenue, No. 6, Agios Dometios, 2370 Nicosia (Cyprus); Department of Biological Sciences, University of Cyprus, P.O. Box 20537, 1678 Nicosia (Cyprus)

    2009-12-25

    During neural development the transition from neurogenesis to gliogenesis, known as the neuron-glial ({Nu}/G) fate switch, requires the coordinated function of patterning factors, pro-glial factors and Notch signalling. How this process is coordinated in the embryonic spinal cord is poorly understood. Here, we demonstrate that during the N/G fate switch in the ventral spinal cord (vSC) SOX1 links the function of neural patterning and Notch signalling. We show that, SOX1 expression in the vSC is regulated by PAX6, NKX2.2 and Notch signalling in a domain-specific manner. We further show that SOX1 regulates the expression of Hes1 and that loss of Sox1 leads to enhanced production of oligodendrocyte precursors from the pMN. Finally, we show that Notch signalling functions upstream of SOX1 during this fate switch and is independently required for the acquisition of the glial fate perse by regulating Nuclear Factor I A expression in a PAX6/SOX1/HES1/HES5-independent manner. These data integrate functional roles of neural patterning factors, Notch signalling and SOX1 during gliogenesis.

  7. Functional interaction between angiotensin II receptor type 1 and chemokine (C-C Motif) receptor 2 with implications for chronic kidney disease

    OpenAIRE

    Mohammed Akli Ayoub; Yuan Zhang; Kelly, Robyn S.; Heng B See; Johnstone, Elizabeth K.M.; McCall, Elizabeth A.; Williams, James H; Kelly, Darren J.; Pfleger, Kevin D.G.

    2015-01-01

    Understanding functional interactions between G protein-coupled receptors is of great physiological and pathophysiological importance. Heteromerization provides one important potential mechanism for such interaction between different signalling pathways via macromolecular complex formation. Previous studies suggested a functional interplay between angiotensin II receptor type 1 (AT1) and Chemokine (C-C motif) Receptor 2 (CCR2). However the molecular mechanisms are not understood. We investiga...

  8. 13C-Labeled Heparan Sulfate Analogue as a Tool To Study Protein/Heparan Sulfate Interactions by NMR Spectroscopy: Application to the CXCL12α Chemokine

    International Nuclear Information System (INIS)

    Heparan sulfate (HS), a polysaccharide of the glycosaminoglycan family characterized by a unique level of complexity, has emerged as a key regulator of many fundamental biological processes. Although it has become clear that this class of molecules exert their functions by interacting with proteins, the exact modes of interaction still remain largely unknown. Here we report the engineering of a 13C-labeled HS-like oligosaccharide with a defined oligo-saccharidic sequence that was used to investigate the structural determinants involved in protein/HS recognition by multidimensional NMR spectroscopy. Using the chemokine CXCL12α as a model system, we obtained experimental NMR data on both the oligosaccharide and the chemokine that was used to obtain a structural model of a protein/HS complex. This new approach provides a foundation for further investigations of protein/HS interactions and should find wide application. (authors)

  9. Nerve growth factor injected into the gastric ulcer base incorporates into endothelial, neuronal, glial and epithelial cells: implications for angiogenesis, mucosal regeneration and ulcer healing.

    Science.gov (United States)

    Tanigawa, T; Ahluwalia, A; Watanabe, T; Arakawa, T; Tarnawski, A S

    2015-08-01

    A previous study has demonstrated that locally administered growth factors such as epidermal growth factor, basic fibroblast growth factor and hepatocyte growth factor can accelerate healing of experimental gastric ulcers in rats. That study indicates that locally administered growth factors can exert potent biological effects resulting in enhanced gastric ulcers healing. However, the fate of injected growth factors, their retention and localization to specific cellular compartments have not been examined. In our preliminary study, we demonstrated that local injection of nerve growth factor to the base of experimental gastric ulcers dramatically accelerates ulcer healing, increases angiogenesis - new blood vessel formation, and improves the quality of vascular and epithelial regeneration. Before embarking on larger, definitive and time sequence studies, we wished to determine whether locally injected nerve growth factor is retained in gastric ulcer's tissues and taken up by specific cells during gastric ulcer healing. Gastric ulcers were induced in anesthetized rats by local application of acetic acid using standard methods; and, 60 min later fluorescein isothiocyanate-labeled nerve growth factor was injected locally to the ulcer base. Rats were euthanized 2, 5 and 10 days later. Gastric specimens were obtained and processed for histology. Unstained paraffin sections were examined under a fluorescence microscope, and the incorporation of fluorescein isothiocyanate-labeled nerve growth factor into various gastric tissue cells was determined and quantified. In addition, we performed immunostaining for S100β protein that is expressed in neural components. Five and ten days after ulcer induction labeled nerve growth factor (injected to the gastric ulcer base) was incorporated into endothelial cells of blood vessels, neuronal, glial and epithelial cells, myofibroblasts and muscle cells. This study demonstrates for the first time that during gastric ulcer healing

  10. Regulation of neurotropic signaling by the inducible, NF-kB-sensitive miRNA-125b in Alzheimer's disease (AD) and in primary human neuronal-glial (HNG) cells.

    Science.gov (United States)

    Zhao, Yuhai; Bhattacharjee, Surjyadipta; Jones, Brandon M; Hill, Jim; Dua, Prerna; Lukiw, Walter J

    2014-08-01

    Inducible microRNAs (miRNAs) perform critical regulatory roles in central nervous system (CNS) development, aging, health, and disease. Using miRNA arrays, RNA sequencing, enhanced Northern dot blot hybridization technologies, Western immunoblot, and bioinformatics analysis, we have studied miRNA abundance and complexity in Alzheimer's disease (AD) brain tissues compared to age-matched controls. In both short post-mortem AD and in stressed primary human neuronal-glial (HNG) cells, we observe a consistent up-regulation of several brain-enriched miRNAs that are under transcriptional control by the pro-inflammatory transcription factor NF-kB. These include miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155. Of the inducible miRNAs in this subfamily, miRNA-125b is among the most abundant and significantly induced miRNA species in human brain cells and tissues. Bioinformatics analysis indicated that an up-regulated miRNA-125b could potentially target the 3'untranslated region (3'-UTR) of the messenger RNA (mRNA) encoding (a) a 15-lipoxygenase (15-LOX; ALOX15; chr 17p13.3), utilized in the conversion of docosahexaneoic acid into neuroprotectin D1 (NPD1), and (b) the vitamin D3 receptor (VDR; VD3R; chr12q13.11) of the nuclear hormone receptor superfamily. 15-LOX and VDR are key neuromolecular factors essential in lipid-mediated signaling, neurotrophic support, defense against reactive oxygen and nitrogen species (reactive oxygen and nitrogen species), and neuroprotection in the CNS. Pathogenic effects appear to be mediated via specific interaction of miRNA-125b with the 3'-UTR region of the 15-LOX and VDR messenger RNAs (mRNAs). In AD hippocampal CA1 and in stressed HNG cells, 15-LOX and VDR down-regulation and a deficiency in neurotrophic support may therefore be explained by the actions of a single inducible, pro-inflammatory miRNA-125b. We will review the recent data on the pathogenic actions of this up-regulated miRNA-125b in AD and discuss potential

  11. Interaction of the selectin ligand PSGL-1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs.

    Science.gov (United States)

    Veerman, Krystle M; Williams, Michael J; Uchimura, Kenji; Singer, Mark S; Merzaban, Jasmeen S; Naus, Silvia; Carlow, Douglas A; Owen, Philip; Rivera-Nieves, Jesús; Rosen, Steven D; Ziltener, Hermann J

    2007-05-01

    P-selectin glycoprotein ligand 1 (PSGL-1) is central to the trafficking of immune effector cells to areas of inflammation through direct interactions with P-selectin, E-selectin and L-selectin. Here we show that PSGL-1 was also required for efficient homing of resting T cells to secondary lymphoid organs but functioned independently of selectin binding. PSGL-1 mediated an enhanced chemotactic T cell response to the secondary lymphoid organ chemokines CCL21 and CCL19 but not to CXCL12 or to inflammatory chemokines. Our data show involvement of PSGL-1 in facilitating the entry of T cells into secondary lymphoid organs, thereby demonstrating the bifunctional nature of this molecule.

  12. Chemokines and Chemokine Receptors in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Wenjing Cheng

    2014-01-01

    Full Text Available Multiple sclerosis is an autoimmune disease with classical traits of demyelination, axonal damage, and neurodegeneration. The migration of autoimmune T cells and macrophages from blood to central nervous system as well as the destruction of blood brain barrier are thought to be the major processes in the development of this disease. Chemokines, which are small peptide mediators, can attract pathogenic cells to the sites of inflammation. Each helper T cell subset expresses different chemokine receptors so as to exert their different functions in the pathogenesis of MS. Recently published results have shown that the levels of some chemokines and chemokine receptors are increased in blood and cerebrospinal fluid of MS patients. This review describes the advanced researches on the role of chemokines and chemokine receptors in the development of MS and discusses the potential therapy of this disease targeting the chemokine network.

  13. Re: Chemokines in Cancer

    OpenAIRE

    Fehmi Narter

    2016-01-01

    Chemokines are chemotactic cytokines that regulate the trafficking and positioning of cells by activating the seven-transmembrane spanning G protein-coupled chemokine receptors (GPCR) or non G protein-coupled seven-transmembrane spanning receptors called atypical chemokine receptors (ACKR). Chemokines are basic proteins that also bind to glycosaminoglycans which play important roles in their biology. Chemokines are divided into four subfamilies based on the position of the first two N-termina...

  14. CXCL12 chemokine and its receptors as major players in the interactions between immune and nervous systems

    Directory of Open Access Journals (Sweden)

    Alice eGuyon

    2014-03-01

    Full Text Available The chemokine CXCL12/SDF1a has first been described in the immune system where it functions include chemotaxis for lymphocytes and macrophages, migration of hematopoietic cells from fetal liver to bone marrow and the formation of large blood vessels. Among other chemokines, CXCL12 has recently attracted much attention in the brain as it has been shown that it can be produced not only by glial cells but also by neurons. In addition, its receptors CXCR4 and CXCR7, which are belonging to the G-protein coupled receptors family, are abundantly expressed in diverse brain area, CXCR4 being a major co-receptor for human immunodeficiency virus (HIV-1 entry. This chemokine system has been shown to play important roles in brain plasticity processes occurring during development but also in the physiology of the brain in normal and pathological conditions. For example, in neurons, CXCR4 stimulation has been shown regulate the synaptic release of glutamate and GABA. It can also act post-synaptically by activating a G-protein Inward Rectifier K+ (GIRK, a voltage-gated K channel Kv2.1 associated to neuronal survival, and by increasing high voltage activated (HVA Ca2+ currents. In addition, it has been recently evidenced that there are several crosstalks between the CXCL12/CXCR4-7 system and other neurotransmitter systems in the brain (such as GABA, glutamate, opioids ans cannabinoids. Overall, this chemokine system could be one of the key players of the neuro-immune interface that participates in shaping the brain in response to changes in the environment.

  15. Opiate addiction therapies and HIV-1 Tat: interactive effects on glial [Ca²⁺]i, oxyradical and neuroinflammatory chemokine production and correlative neurotoxicity.

    Science.gov (United States)

    Fitting, Sylvia; Zou, Shiping; El-Hage, Nazira; Suzuki, Masami; Paris, Jason J; Schier, Christina J; Rodríguez, José W; Rodriguez, Myosotys; Knapp, Pamela E; Hauser, Kurt F

    2014-01-01

    Few preclinical studies have compared the relative therapeutic efficacy of medications used to treat opiate addiction in relation to neuroAIDS. Here we compare the ability of methadone and buprenorphine, and the prototypic opiate morphine, to potentiate the neurotoxic and proinflammatory ([Ca²⁺]i, ROS, H₂O₂, chemokines) effects of HIV-1 Tat in neuronal and/or mixed-glial co-cultures. Repeated observations of neurons during 48 h exposure to combinations of Tat, equimolar concentrations (500 nM) of morphine, methadone, or buprenorphine exacerbated neurotoxicity significantly above levels seen with Tat alone. Buprenorphine alone displayed marked neurotoxicity at 500 nM, prompting additional studies of its neurotoxic effects at 5 nM and 50 nM concentrations ± Tat. In combination with Tat, buprenorphine displayed paradoxical, concentration-dependent, neurotoxic and neuroprotective actions. Buprenorphine neurotoxicity coincided with marked elevations in [Ca²⁺]i, but not increases in glial ROS or chemokine release. Tat by itself elevated the production of CCL5/RANTES, CCL4/MIP-1β, and CCL2/MCP-1. Methadone and buprenorphine alone had no effect, but methadone interacted with Tat to further increase production of CCL5/RANTES. In combination with Tat, all drugs significantly increased glial [Ca²⁺]i, but ROS was only significantly increased by co-exposure with morphine. Taken together, the increases in glial [Ca²⁺]i, ROS, and neuroinflammatory chemokines were not especially accurate predictors of neurotoxicity. Despite similarities, opiates displayed differences in their neurotoxic and neuroinflammatory interactions with Tat. Buprenorphine, in particular, was partially neuroprotective at a low concentration, which may result from its unique pharmacological profile at multiple opioid receptors. Overall, the results reveal differences among addiction medications that may impact neuroAIDS.

  16. Roles of Chemokines in Thymopoiesis: Redundancy and Regulation

    Institute of Scientific and Technical Information of China (English)

    Wenxian Fu; Weifeng Chen

    2004-01-01

    Thymus is the primary lymphoid organ involved in the development of thymocytes. Maturation related events of thymocytes within thymus, especially the widely discussed directional migration of thymocytes, is regulated by chemokines via chemokine receptors mediated signaling pathway. Multiple types of chemokines and chemokine receptors, as components of the network-interaction within thymic microenvironment, are involved in the thymopoiesis. It appears that these chemokines are functionally redundant and such phenomenon may be explained not only by the promiscuous, non-one-to-one matching between ligands-receptors within CXC or CC chemokine subfamily, but also by the various spatio-temporal expression patterns within different cell types and developmental stages. The redundancy and regulation of thymus expressed chemokines and chemokine receptors during thymocyte development are herein discussed.

  17. Roles of Chemokines in Thymopoiesis: Redundancy and Regulation

    Institute of Scientific and Technical Information of China (English)

    WenxianFu; WeifengChen

    2004-01-01

    Thymus is the primary lymphoid organ involved in the development of thymocytes. Maturation related events of thymocytes within thymus, especially the widely discussed directional migration of thymocytes, is regulated by chemokines via chemokine receptors mediated signaling pathway. Multiple types of chemokines and chemokine receptors, as components of the network-interaction within thymic microenvironment, are involved in the thymopoiesis. It appears that these chemokines are functionally redundant and such phenomenon may be explained not only by the promiscuous, non-one-to-one matching between ligands-receptors within CXC or CC chemokine subfamily, but also by the various spatio-temporal expression patterns within different cell types and developmental stages. The redundancy and regulation of thymus expressed chemokines and chemokine receptors during thymocyte development are herein discussed. Cellular & Molecular Immunology.

  18. In silico analysis reveals sequential interactions and protein conformational changes during the binding of chemokine CXCL-8 to its receptor CXCR1.

    Directory of Open Access Journals (Sweden)

    Je-Wen Liou

    Full Text Available Chemokine CXCL-8 plays a central role in human immune response by binding to and activate its cognate receptor CXCR1, a member of the G-protein coupled receptor (GPCR family. The full-length structure of CXCR1 is modeled by combining the structures of previous NMR experiments with those from homology modeling. Molecular docking is performed to search favorable binding sites of monomeric and dimeric CXCL-8 with CXCR1 and a mutated form of it. The receptor-ligand complex is embedded into a lipid bilayer and used in multi ns molecular dynamics (MD simulations. A multi-steps binding mode is proposed: (i the N-loop of CXCL-8 initially binds to the N-terminal domain of receptor CXCR1 driven predominantly by electrostatic interactions; (ii hydrophobic interactions allow the N-terminal Glu-Leu-Arg (ELR motif of CXCL-8 to move closer to the extracellular loops of CXCR1; (iii electrostatic interactions finally dominate the interaction between the N-terminal ELR motif of CXCL-8 and the EC-loops of CXCR1. Mutation of CXCR1 abrogates this mode of binding. The detailed binding process may help to facilitate the discovery of agonists and antagonists for rational drug design.

  19. Functional interaction between angiotensin II receptor type 1 and chemokine (C-C motif receptor 2 with implications for chronic kidney disease.

    Directory of Open Access Journals (Sweden)

    Mohammed Akli Ayoub

    Full Text Available Understanding functional interactions between G protein-coupled receptors is of great physiological and pathophysiological importance. Heteromerization provides one important potential mechanism for such interaction between different signalling pathways via macromolecular complex formation. Previous studies suggested a functional interplay between angiotensin II receptor type 1 (AT1 and Chemokine (C-C motif Receptor 2 (CCR2. However the molecular mechanisms are not understood. We investigated AT1-CCR2 functional interaction in vitro using bioluminescence resonance energy transfer in HEK293 cells and in vivo using subtotal-nephrectomized rats as a well-established model for chronic kidney disease. Our data revealed functional heteromers of these receptors resulting in CCR2-Gαi1 coupling being sensitive to AT1 activation, as well as apparent enhanced β-arrestin2 recruitment with agonist co-stimulation that is synergistically reversed by combined antagonist treatment. Moreover, we present in vivo findings where combined treatment with AT1- and CCR2-selective inhibitors was synergistically beneficial in terms of decreasing proteinuria, reducing podocyte loss and preventing renal injury independent of blood pressure in the subtotal-nephrectomized rat model. Our findings further support a role for G protein-coupled receptor functional heteromerization in pathophysiology and provide insights into previous observations indicating the importance of AT1-CCR2 functional interaction in inflammation, renal and hypertensive disorders.

  20. In Vivo Models to Study Chemokine Biology.

    Science.gov (United States)

    Amaral, F A; Boff, D; Teixeira, M M

    2016-01-01

    Chemokines are essential mediators of leukocyte movement in vivo. In vitro assays of leukocyte migration cannot mimic the complex interactions with other cell types and matrix needed for cells to extravasate and migrate into tissues. Therefore, in vivo strategies to study the effects and potential relevance of chemokines for the migration of particular leukocyte subsets are necessary. Here, we describe methods to study the effects and endogenous role of chemokine in mice. Advantages and pitfalls of particular models are discussed and we focus on description in model's joint and pleural cavity inflammation and the effects and relevance of CXCR2 and CCR2 ligands on cell migration.

  1. Chemokines, lymphocytes, and HIV

    Directory of Open Access Journals (Sweden)

    Farber J.M.

    1998-01-01

    Full Text Available Chemokines are members of a family of more than 30 human cytokines whose best-described activities are as chemotactic factors for leukocytes and that are presumed to be important in leukocyte recruitment and trafficking. While many chemokines can act on lymphocytes, the roles of chemokines and their receptors in lymphocyte biology are poorly understood. The recent discoveries that chemokines can suppress infection by HIV-1 and that chemokine receptors serve, along with CD4, as obligate co-receptors for HIV-1 entry have lent urgency to studies on the relationships between chemokines and lymphocytes. My laboratory has characterized Mig and Crg-2/IP-10, chemokines that are induced by IFN-g and that specifically target lymphocytes, particularly activated T cells. We have demonstrated that the genes for these chemokines are widely expressed during experimental infections in mice with protozoan and viral pathogens, but that the patterns of mig and crg-2 expression differed, suggesting non-redundant roles in vivo. Our related studies to identify new chemokine receptors from activated lymphocytes resulted in the cloning of STRL22 and STRL33. We and others have shown that STRL22 is a receptor for the CC chemokine MIP-3a, and STRL22 has been re-named CCR6. Although STRL33 remains an orphan receptor, we have shown that it can function as a co-receptor for HIV-1 envelope glycoproteins, and that it is active with a broader range of HIV-1 envelope glycoproteins than the major co-receptors described to date. The ability of STRL33 to function with a wide variety of envelope glycoproteins may become particularly important if therapies are instituted to block other specific co-receptors. We presume that investigations into the roles of chemokines and their receptors in lymphocyte biology will provide information important for understanding the pathogenesis of AIDS and for manipulating immune and inflammatory responses for clinical benefit

  2. Chemokines and their receptors in Atherosclerosis.

    Science.gov (United States)

    van der Vorst, Emiel P C; Döring, Yvonne; Weber, Christian

    2015-09-01

    Atherosclerosis, a chronic inflammatory disease of the medium- and large-sized arteries, is the main underlying cause of cardiovascular diseases (CVDs) most often leading to a myocardial infarction or stroke. However, atherosclerosis can also develop without this clinical manifestation. The pathophysiology of atherosclerosis is very complex and consists of many cells and molecules interacting with each other. Over the last years, chemokines (small 8-12 kDa cytokines with chemotactic properties) have been identified as key players in atherogenesis. However, this remains a very active and dynamic field of research. Here, we will give an overview of the current knowledge about the involvement of chemokines in all phases of atherosclerotic lesion development. Furthermore, we will focus on two chemokines that recently have been associated with atherogenesis, CXCL12, and macrophage migration inhibitory factor (MIF). Both chemokines play a crucial role in leukocyte recruitment and arrest, a critical step in atherosclerosis development. MIF has shown to be a more pro-inflammatory and thus pro-atherogenic chemokine, instead CXCL12 seems to have a more protective function. However, results about this protective role are still quite debatable. Future research will further elucidate the precise role of these chemokines in atherosclerosis and determine the potential of chemokine-based therapies. PMID:26175090

  3. Solution NMR characterization of chemokine CXCL8/IL-8 monomer and dimer binding to glycosaminoglycans: structural plasticity mediates differential binding interactions.

    Science.gov (United States)

    Joseph, Prem Raj B; Mosier, Philip D; Desai, Umesh R; Rajarathnam, Krishna

    2015-11-15

    Chemokine CXCL8/interleukin-8 (IL-8) plays a crucial role in directing neutrophils and oligodendrocytes to combat infection/injury and tumour cells in metastasis development. CXCL8 exists as monomers and dimers and interaction of both forms with glycosaminoglycans (GAGs) mediate these diverse cellular processes. However, very little is known regarding the structural basis underlying CXCL8-GAG interactions. There are conflicting reports on the affinities, geometry and whether the monomer or dimer is the high-affinity GAG ligand. To resolve these issues, we characterized the binding of a series of heparin-derived oligosaccharides [heparin disaccharide (dp2), heparin tetrasaccharide (dp4), heparin octasaccharide (dp8) and heparin 14-mer (dp14)] to the wild-type (WT) dimer and a designed monomer using solution NMR spectroscopy. The pattern and extent of binding-induced chemical shift perturbation (CSP) varied between dimer and monomer and between longer and shorter oligosaccharides. NMR-based structural models show that different interaction modes coexist and that the nature of interactions varied between monomer and dimer and oligosaccharide length. MD simulations indicate that the binding interface is structurally plastic and provided residue-specific details of the dynamic nature of the binding interface. Binding studies carried out under conditions at which WT CXCL8 exists as monomers and dimers provide unambiguous evidence that the dimer is the high-affinity GAG ligand. Together, our data indicate that a set of core residues function as the major recognition/binding site, a set of peripheral residues define the various binding geometries and that the structural plasticity of the binding interface allows multiplicity of binding interactions. We conclude that structural plasticity most probably regulates in vivo CXCL8 monomer/dimer-GAG interactions and function.

  4. Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis.

    Science.gov (United States)

    Sasaki, Soichiro; Baba, Tomohisa; Nishimura, Tatsunori; Hayakawa, Yoshihiro; Hashimoto, Shin-Ichi; Gotoh, Noriko; Mukaida, Naofumi

    2016-08-01

    From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone upon its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3 clone displayed an enhanced expression of a chemokine, CCL4, but not its specific receptor, CCR5. CCL4 shRNA-transfection of 4T1.3 clone had few effects on its in vitro properties, but reduced the tumorigenicity arising from the intra-bone injection. Moreover, intra-bone injection of 4T1.3 clone caused smaller tumors in mice deficient in CCR5 or those receiving CCR5 antagonist than in wild-type mice. The reduced tumor formation was associated with attenuated accumulation of CCR5-positive fibroblasts expressing connective tissue growth factor (CTGF)/CCN2. Tumor cell-derived CCL4 could induce fibroblasts to express CTGF/CCN2, which could support 4T1.3 clone proliferation under hypoxic culture conditions. Thus, the CCL4-CCR5 axis can contribute to breast cancer metastasis to bone by mediating the interaction between cancer cells and fibroblasts in bone cavity.

  5. Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis.

    Science.gov (United States)

    Sasaki, Soichiro; Baba, Tomohisa; Nishimura, Tatsunori; Hayakawa, Yoshihiro; Hashimoto, Shin-Ichi; Gotoh, Noriko; Mukaida, Naofumi

    2016-08-01

    From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone upon its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3 clone displayed an enhanced expression of a chemokine, CCL4, but not its specific receptor, CCR5. CCL4 shRNA-transfection of 4T1.3 clone had few effects on its in vitro properties, but reduced the tumorigenicity arising from the intra-bone injection. Moreover, intra-bone injection of 4T1.3 clone caused smaller tumors in mice deficient in CCR5 or those receiving CCR5 antagonist than in wild-type mice. The reduced tumor formation was associated with attenuated accumulation of CCR5-positive fibroblasts expressing connective tissue growth factor (CTGF)/CCN2. Tumor cell-derived CCL4 could induce fibroblasts to express CTGF/CCN2, which could support 4T1.3 clone proliferation under hypoxic culture conditions. Thus, the CCL4-CCR5 axis can contribute to breast cancer metastasis to bone by mediating the interaction between cancer cells and fibroblasts in bone cavity. PMID:27177471

  6. Chemokines and Chemokine Receptors as Novel Therapeutic Targets in Rheumatoid Arthritis (RA): Inhibitory Effects of Traditional Chinese Medicinal Components

    Institute of Scientific and Technical Information of China (English)

    Xin Chen; Joost J. Oppenheim; O.M.Zack Howard

    2004-01-01

    Chemokines belong to a large family of inflammatory cytokines responsible for migration and accumulation of leukocytes at inflammatory sites. Over the past decade, accumulating evidence indicated a crucial role for chemokines and chemokine receptors in the pathophysiology of rheumatoid arthritis (RA). RA is a chronic autoimmune disease in which the synovial tissue is heavily infiltrated by leukocytes. Chemokines play an important role in the infiltration, localization, retention of infiltrating leukocytes and generation of ectopic germinal centers in the inflamed synovium. Recent evidence also suggests that identification of inhibitors directly targeting chemokines or their receptors may provide a novel therapeutic strategy in RA. Traditional Chinese medicinals (TCMs) have a long history in the treatment of inflammatory joint disease. The basis for the clinical benefits of TCM remains largely unclear. Our studies have led to the identification of numerous novel chemokine/chemokine receptor inhibitors present in anti-inflammatory TCMs. All of these inhibitors were previously reported by other researchers to have anti-arthritic effect, which may be attributable, at least in part, to their inhibitory effect on chemokine and/or chemokine receptor. Therefore, identification of agents capable of targeting chemokine/chemokine receptor interactions has suggested a mechanism of action for several TCM components and provided a means of identifying additional anti-RA TCM. Thus, this approach may lead to the discovery of new inhibitors of chemokines or chemokine receptors that can be used to treat diseases associated with inappropriately overactive chemokine mediated inflammatory reactions. Cellular & Molecular Immunology. 2004;1(5):336-342.

  7. 关注神经元和混合性神经元-胶质肿瘤的临床病理研究%Clinicopathologic study of neuronal and mixed neuronal-glial tumors

    Institute of Scientific and Technical Information of China (English)

    卢德宏; 滕梁红; 徐庆中

    2008-01-01

    神经元和混合性神经元-胶质肿瘤(neuronal and mixed neuronal-glial tumours)是一组有不同程度神经元分化和胶质分化的肿瘤,近些年来该类肿瘤得到了越来越多的重视。在最新出皈的WHO中枢神经系统肿瘤分类(2007版,简称WHO2007年分类)中,变化最大的就属神经元和混合性神经元胶质肿瘤这一章节。在WHO2007年分类中共新增了八个新的肿瘤类型,而有关神经元和混合性神经元胶质肿瘤这一章节中就增加了三种新肿瘤,使其包括了12种肿瘤类型;小脑发育不良性神经节细胞瘤(Lhermitte-Duelos)、婴儿促纤维增生性星形细胞瘤/节细胞胶质瘤(desmoplastic infantile astrocytoma/ganglioglioma)、胚胎发育不良性神经上皮肿瘤(dysembryoplastic neuroepithelial tumour,DNT),

  8. Chemokines and Chemokine Receptors as Novel Therapeutic Targets in Rheumatoid Arthritis (RA): Inhibitory Effects of Traditional Chinese Medicinal Components

    Institute of Scientific and Technical Information of China (English)

    XinChen; JoostJ.Oppenheim; O.M.ZackHoward

    2004-01-01

    Chemokines belong to a large family of inflammatory cytokines responsible for migration and accumulation of leukocytes at inflammatory sites. Over the past decade, accumulating evidence indicated a crucial role for chemokines and chemokine receptors in the pathophysiology of rheumatoid arthritis (RA). RA is a chronic autoimmune disease in which the synovial tissue is heavily infiltrated by leukocytes. Chemokines play an important role in the infiltration, localization, retention of infiltrating leukocytes and generation of ectopic germinal centers in the inflamed synovium. Recent evidence also suggests that identification of inhibitors directly targeting chemokines or their receptors may provide a novel therapeutic strategy in RA. Traditional Chinese medicinals (TCMs) have a long history in the treatment of inflammatory joint disease. The basis forthe clinical benefits of TCM remains largely unclear. Our studies have led to the identification of numerousnovel chemokine/chemokine receptor inhibitors present in anti,inflammatory TCMs. All of these inhibitors were previously reported by other researchers to have anti-arthritic effect, which may be attributable, at leastin part, to their inhibitory effect on chemokine and/or chemokine receptor. Therefore, identification of agents capable of targeting chemokine/chemokine receptor interactions has suggested a mechanism of action for several TCM components and provided a means of identifying additional anti-RA TCM. Thus, this approach may lead to the discovery of new inhibitors of chemokines or chemokine receptors that can be used to treat diseases associated with inappropriately overactive chemokine mediated inflammatory reactions. Cellular & Molecular Immunology. 2004;1(5):336-342.

  9. Biased and g protein-independent signaling of chemokine receptors

    DEFF Research Database (Denmark)

    Steen, Anne; Larsen, Olav; Thiele, Stefanie;

    2014-01-01

    not be absolute, i.e., full versus no activation. Here we discuss biased signaling in the chemokine system, including the structural basis for biased signaling in chemokine receptors, as well as in class A 7TM receptors in general. This includes overall helical movements and the contributions of micro......-switches based on recently published 7TM crystals and molecular dynamics studies. All three forms of biased signaling are abundant in the chemokine system. This challenges our understanding of "classic" redundancy inevitably ascribed to this system, where multiple chemokines bind to the same receptor and where...... a single chemokine may bind to several receptors - in both cases with the same functional outcome. The ubiquitous biased signaling confers a hitherto unknown specificity to the chemokine system with a complex interaction pattern that is better described as promiscuous with context-defined roles...

  10. Functional interaction between herpes simplex virus type 2 gD and HVEM transiently dampens local chemokine production after murine mucosal infection.

    Directory of Open Access Journals (Sweden)

    Miri Yoon

    Full Text Available Herpes virus entry mediator (HVEM is one of two principal receptors mediating herpes simplex virus (HSV entry into murine and human cells. It functions naturally as an immune signaling co-receptor, and may participate in enhancing or repressing immune responses depending on the natural ligand used. To investigate whether engagement of HVEM by HSV affects the in vivo response to HSV infection, we generated recombinants of HSV-2(333 that expressed wild-type gD (HSV-2/gD or mutant gD able to bind to nectin-1 (the other principal entry receptor but not HVEM. Replication kinetics and yields of the recombinant strains on Vero cells were indistinguishable from those of wild-type HSV-2(333. After intravaginal inoculation with mutant or wild-type virus, adult female C57BL/6 mice developed vaginal lesions and mortality in similar proportions, and mucosal viral titers were similar or lower for mutant strains at different times. Relative to HSV-2/gD, percentages of HSV-specific CD8(+ T-cells were similar or only slightly reduced after infection with the mutant strain HSV-2/gD-Δ7-15, in all tissues up to 9 days after infection. Levels of HSV-specific CD4(+ T-cells five days after infection also did not differ after infection with either strain. Levels of the cytokine IL-6 and of the chemokines CXCL9, CXCL10, and CCL4 were significantly lower in vaginal washes one day after infection with HSV-2/gD compared with HSV-2/gD-Δ7-15. We conclude that the interaction of HSV gD with HVEM may alter early innate events in the murine immune response to infection, without significantly affecting acute mortality, morbidity, or initial T-cell responses after lethal challenge.

  11. Chemokine Signaling Specificity: Essential Role for the N-Terminal Domain of Chemokine Receptors†

    Science.gov (United States)

    N. Prado, Gregory; Suetomi, Katsutoshi; Shumate, David; Maxwell, Carrie; Ravindran, Aishwarya; Rajarathnam, Krishna; Navarro, Javier

    2009-01-01

    Chemokine IL-8 (CXCL8) binds to its cognate receptors CXCR1 and CXCR2 to induce inflammatory responses, wound healing, tumorogenesis, and neuronal survival. Here we identify the N-loop residues in IL-8 (H18 and F21) and the receptor N-termini as the major structural determinants regulating the rate of receptor internalization, which in turn controlled the activation profile of ERK1/2, a central component of the receptor/ERK signaling pathway that dictates signal specificity. Our data further support the idea that the chemokine receptor core acts as a plastic scaffold. Thus, the diversity and intensity of inflammatory and noninflammatory responses mediated by chemokine receptors appear to be primarily determined by the initial interaction between the receptor N-terminus and the N-loop of chemokines. PMID:17630697

  12. Chemokine Receptors and Transplantation

    Institute of Scientific and Technical Information of China (English)

    Jinquan Tan; Gang Zhou

    2005-01-01

    A complex process including both the innate and acquired immune responses results in allograft rejection. Some chemokine receptors and their ligands play essential roles not only for leukocyte migration into the graft but also in facilitating dendritic and T cell trafficking between lymph nodes and the transplant in the early and late stage of the allogeneic response. This review focuses on the impact of these chemoattractant proteins on transplant outcome and novel diagnostic and therapeutic approaches for antirejection therapy based on targeting of chemokine receptors and/or their ligands. Cellular & Molecular Immunology.

  13. IL-1β produced by aggressive breast cancer cells is one of the factors that dictate their interactions with mesenchymal stem cells through chemokine production.

    Science.gov (United States)

    Escobar, Pauline; Bouclier, Céline; Serret, Julien; Bièche, Ivan; Brigitte, Madly; Caicedo, Andres; Sanchez, Elodie; Vacher, Sophie; Vignais, Marie-Luce; Bourin, Philippe; Geneviève, David; Molina, Franck; Jorgensen, Christian; Lazennec, Gwendal

    2015-10-01

    The aim of this work was to understand whether the nature of breast cancer cells could modify the nature of the dialog of mesenchymal stem cells (MSCs) with cancer cells. By treating MSCs with the conditioned medium of metastatic Estrogen-receptor (ER)-negative MDA-MB-231, or non-metastatic ER-positive MCF-7 breast cancer cells, we observed that a number of chemokines were produced at higher levels by MSCs treated with MDA-MB-231 conditioned medium (CM). MDA-MB-231 cells were able to induce NF-κB signaling in MSC cells. This was shown by the use of a NF-kB chemical inhibitor or an IκB dominant negative mutant, nuclear translocation of p65 and induction of NF-κB signature. Our results suggest that MDA-MB-231 cells exert their effects on MSCs through the secretion of IL-1β, that activates MSCs and induces the same chemokines as the MDA-MB-231CM. In addition, inhibition of IL-1β secretion in the MDA-MB-231 cells reduces the induced production of a panel of chemokines by MSCs, as well the motility of MDA-MB-231 cells. Our data suggest that aggressive breast cancer cells secrete IL-1β, which increases the production of chemokines by MSCs.

  14. Chemokines and Chemokine Receptors in the Development of Lupus Nephritis

    Directory of Open Access Journals (Sweden)

    Xiaofeng Liao

    2016-01-01

    Full Text Available Lupus nephritis (LN is a major cause of morbidity and mortality in the patients with systemic lupus erythematosus (SLE, an autoimmune disease with damage to multiple organs. Leukocyte recruitment into the inflamed kidney is a critical step to promote LN progression, and the chemokine/chemokine receptor system is necessary for leukocyte recruitment. In this review, we summarize recent studies on the roles of chemokines and chemokine receptors in the development of LN and discuss the potential and hurdles of developing novel, chemokine-based drugs to treat LN.

  15. Chemokines and Chemokine Receptors in the Development of Lupus Nephritis.

    Science.gov (United States)

    Liao, Xiaofeng; Pirapakaran, Tharshikha; Luo, Xin M

    2016-01-01

    Lupus nephritis (LN) is a major cause of morbidity and mortality in the patients with systemic lupus erythematosus (SLE), an autoimmune disease with damage to multiple organs. Leukocyte recruitment into the inflamed kidney is a critical step to promote LN progression, and the chemokine/chemokine receptor system is necessary for leukocyte recruitment. In this review, we summarize recent studies on the roles of chemokines and chemokine receptors in the development of LN and discuss the potential and hurdles of developing novel, chemokine-based drugs to treat LN. PMID:27403037

  16. The emerging role of CXC chemokines and their receptors in cancer.

    Science.gov (United States)

    Vinader, Victoria; Afarinkia, Kamyar

    2012-05-01

    Chemokines and their receptors have a multifaceted role in tumor biology and are implicated in nearly all aspects of cancer growth, survival and dissemination. Modulation of the interaction between chemokines and their cell surface receptor is, therefore, a promising area for the development of new cancer medicines. In this review, we look at the compelling evidence that is emerging to support targeting CXC chemokines, also known as family α chemokines, as novel therapeutic strategies in the treatment of cancer. PMID:22571611

  17. Dual GPCR and GAG mimicry by the M3 chemokine decoy receptor

    Energy Technology Data Exchange (ETDEWEB)

    Alexander-Brett, Jennifer M.; Fremont, Daved H. (WU-MED)

    2008-09-23

    Viruses have evolved a myriad of evasion strategies focused on undermining chemokine-mediated immune surveillance, exemplified by the mouse {gamma}-herpesvirus 68 M3 decoy receptor. Crystal structures of M3 in complex with C chemokine ligand 1/lymphotactin and CC chemokine ligand 2/monocyte chemoattractant protein 1 reveal that invariant chemokine features associated with G protein-coupled receptor binding are primarily recognized by the decoy C-terminal domain, whereas the N-terminal domain (NTD) reconfigures to engage divergent basic residue clusters on the surface of chemokines. Favorable electrostatic forces dramatically enhance the association kinetics of chemokine binding by M3, with a primary role ascribed to acidic NTD regions that effectively mimic glycosaminoglycan interactions. Thus, M3 employs two distinct mechanisms of chemical imitation to potently sequester chemokines, thereby inhibiting chemokine receptor binding events as well as the formation of chemotactic gradients necessary for directed leukocyte trafficking.

  18. 'Reverse gear' cellular movement mediated by chemokines.

    Science.gov (United States)

    Zlatopolskiy, A; Laurence, J

    2001-08-01

    We sought to model the mechanism by which leucocytes may be actively repulsed by a beta-chemokine signal. This model is used to interpret an apparent paradox in chemokine biology, whereby high levels of a T-cell chemoattractant, stromal cell derived factor-1 (SDF-1), are present in bone marrow and thymic tissues despite a paucity of mature T lymphocytes in these areas. We postulate the differential involvement in cell migration of the two binding sites on SDF-1 for its sole receptor, CXCR4, depending on whether high or low concentrations of SDF-1 are encountered by the cell. Site choice would be mediated by divergent affinities of the two binding interactions. We also propose differential signalling following SDF-1/CXCR4 interactions on the plasma membrane versus ligand/receptor complexes in endocytic vesicles. Preliminary data showing divergent susceptibility to kinase inhibitors depending on whether a cell is attracted to or repulsed by SDF-1, are consistent with this model. In terms of physical movement toward or away from a chemokine gradient, we compare the cycling of surface receptors during migration to the caterpillar drive of a tractor, which can change direction simply by altering the direction of rotation of its threads. Finally, the potential clinical implications of concentration-dependent, chemokine-based cell attraction and repulsion are discussed. PMID:11488980

  19. Teleost Chemokines and Their Receptors

    Directory of Open Access Journals (Sweden)

    Steve Bird

    2015-11-01

    Full Text Available Chemokines are a superfamily of cytokines that appeared about 650 million years ago, at the emergence of vertebrates, and are responsible for regulating cell migration under both inflammatory and physiological conditions. The first teleost chemokine gene was reported in rainbow trout in 1998. Since then, numerous chemokine genes have been identified in diverse fish species evidencing the great differences that exist among fish and mammalian chemokines, and within the different fish species, as a consequence of extensive intrachromosomal gene duplications and different infectious experiences. Subsequently, it has only been possible to establish clear homologies with mammalian chemokines in the case of some chemokines with well-conserved homeostatic roles, whereas the functionality of other chemokine genes will have to be independently addressed in each species. Despite this, functional studies have only been undertaken for a few of these chemokine genes. In this review, we describe the current state of knowledge of chemokine biology in teleost fish. We have mainly focused on those species for which more research efforts have been made in this subject, specially zebrafish (Danio rerio, rainbow trout (Oncorhynchus mykiss and catfish (Ictalurus punctatus, outlining which genes have been identified thus far, highlighting the most important aspects of their expression regulation and addressing any known aspects of their biological role in immunity. Finally, we summarise what is known about the chemokine receptors in teleosts and provide some analysis using recently available data to help characterise them more clearly.

  20. IL-1β produced by aggressive breast cancer cells is one of the factors that dictate their interactions with mesenchymal stem cells through chemokine production

    OpenAIRE

    Escobar, Pauline; Bouclier, Céline; Serret, Julien; Bièche, Ivan; Brigitte, Madly; Caicedo, Andres; Sanchez, Elodie; Vacher, Sophie; Vignais, Marie-Luce; Bourin, Philippe; Geneviève, David; Molina, Franck; Jorgensen, Christian; Lazennec, Gwendal

    2015-01-01

    The aim of this work was to understand whether the nature of breast cancer cells could modify the nature of the dialog of mesenchymal stem cells (MSCs) with cancer cells. By treating MSCs with the conditioned medium of metastatic Estrogen-receptor (ER)-negative MDA-MB-231, or non-metastatic ER-positive MCF-7 breast cancer cells, we observed that a number of chemokines were produced at higher levels by MSCs treated with MDA-MB-231 conditioned medium (CM). MDA-MB-231 cells were able to induce N...

  1. A beginner's guide to chemokines.

    Science.gov (United States)

    Vinader, Victoria; Afarinkia, Kamyar

    2012-05-01

    This review provides an overview of chemokines and their receptors, with an emphasis on general features and nomenclature along with a short summary of their properties and functions. It is intended as an introduction to the subject and a reference point for those wishing to learn key facts about chemokines and their role in biology. PMID:22571610

  2. Chemokine genetic polymorphism in human health and disease.

    Science.gov (United States)

    Qidwai, Tabish

    2016-08-01

    Chemokine receptor-ligand interaction regulates transmigration of lymphocytes and monocytes from circulation to the inflammatory sites. CC chemokine receptors, chemokine receptor 2(CCR2) and 5 (CCR5) are important in recruitment of immune cells as well as non-immune cells under pathological condition. CCR2, CCR5 and their ligands (CCL2 and CCL5) are major contributor to the autoimmune and inflammatory diseases and cancer. Currently studies are being done to explore genetic variations in chemokine genes and their involvement in diseases that could make clear disease severity and deaths. Conflicting results of studies in different populations and diseases promoted to investigate chemokines genetic polymorphisms in miscellaneous diseases. This study is aimed to evaluate the influence of chemokines genetic polymorphisms in pathogenesis and outcome of prevalent non infectious diseases. Present study demonstrates the likely role played by genetic variations in drug response and evolution. Moreover this study highlights chemokine as therapeutic target and diagnostic biomarker in pathological condition. PMID:27262929

  3. Duffy antigen receptor for chemokines mediates chemokine endocytosis through a macropinocytosis-like process in endothelial cells.

    Directory of Open Access Journals (Sweden)

    Yani Zhao

    Full Text Available The Duffy antigen receptor for chemokines (DARC shows high affinity binding to multiple inflammatory CC and CXC chemokines and is expressed by erythrocytes and endothelial cells. Recent evidence suggests that endothelial DARC facilitates chemokine transcytosis to promote neutrophil recruitment. However, the mechanism of chemokine endocytosis by DARC remains unclear.We investigated the role of several endocytic pathways in DARC-mediated ligand internalization. Here we report that, although DARC co-localizes with caveolin-1 in endothelial cells, caveolin-1 is dispensable for DARC-mediated (125I-CXCL1 endocytosis as knockdown of caveolin-1 failed to inhibit ligand internalization. (125I-CXCL1 endocytosis by DARC was also independent of clathrin and flotillin-1 but required cholesterol and was, in part, inhibited by silencing Dynamin II expression.(125I-CXCL1 endocytosis was inhibited by amiloride, cytochalasin D, and the PKC inhibitor Gö6976 whereas Platelet Derived Growth Factor (PDGF enhanced ligand internalization through DARC. The majority of DARC-ligand interactions occurred on the endothelial surface, with DARC identified along plasma membrane extensions with the appearance of ruffles, supporting the concept that DARC provides a high affinity scaffolding function for surface retention of chemokines on endothelial cells.These results show DARC-mediated chemokine endocytosis occurs through a macropinocytosis-like process in endothelial cells and caveolin-1 is dispensable for CXCL1 internalization.

  4. Chemokines and chemokine receptors in inflammation of the nervous system

    DEFF Research Database (Denmark)

    Huang, D; Han, Yong-Chang; Rani, M R;

    2000-01-01

    This article focuses on the production of chemokines by resident glial cells of the nervous system. We describe studies in two distinct categories of inflammation within the nervous system: immune-mediated inflammation as seen in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis...

  5. Differential expression of chemokines, chemokine receptors and proteinases by foreign body giant cells (FBGCs) and osteoclasts.

    Science.gov (United States)

    Khan, Usman A; Hashimi, Saeed M; Khan, Shershah; Quan, Jingjing; Bakr, Mahmoud M; Forwood, Mark R; Morrison, Nigel M

    2014-07-01

    Osteoclasts and foreign body giant cells (FBGCs) are both derived from the fusion of macropahges. These cells are seen in close proximity during foreign body reactions, therefore it was assumed that they might interact with each other. The aim was to identify important genes that are expressed by osteoclasts and FBGCs which can be used to understand peri-implantitis and predict the relationship of these cells during foreign body reactions. Bone marrow macrophages (BMM) were treated with receptor activator of nuclear factor kappa B ligand (RANKL) to produce osteoclasts. Quantitative PCR (qPCR) was used to identify the genes that were expressed by osteoclasts and FBGCs compared to macrophage controls. TRAP staining was used to visualise the cells while gelatine zymography and western blots were used for protein expression. Tartrate-resistant acid phosphatase (TRAP), matrix metallo proteinase 9 (MMP9), nuclear factor of activated T cells 1 (NFATc1), cathepsin K (CTSK) and RANK were significantly lower in FBGCs compared to osteoclasts. Inflammation specific chemokines such as monocyte chemotactic protein (MCP1 also called CCL2), macrophage inflammatory protein 1 alpha (MIP1α), MIP1β and MIP1γ, and their receptors CCR1, CCR3 and CCR5, were highly expressed by FBGCs. FBGCs were negative for osteoclast specific markers (RANK, NFATc1, CTSK). FBGCs expressed chemokines such as CCL2, 3, 5 and 9 while osteoclasts expressed the receptors for these chemokines i.e. CCR1, 2 and 3. Our findings show that osteoclast specific genes are not expressed by FBGCs and that FBGCs interact with osteoclasts during foreign body reaction through chemokines.

  6. Biased and G protein-independent signaling of chemokine receptors

    Directory of Open Access Journals (Sweden)

    Anne eSteen

    2014-06-01

    Full Text Available Biased signaling or functional selectivity occurs when a 7TM receptor preferentially activates one of several available pathways. It can be divided into three distinct forms: ligand bias, receptor bias, and tissue or cell bias, where it is mediated by different ligands (on the same receptor, different receptors (with the same ligand or different tissues or cells (for the same ligand-receptor pair. Most often biased signaling is differentiated into G protein-dependent and β-arrestin-dependent signaling. Yet, it may also cover signaling differences within these groups. Moreover, it may not be absolute, i.e. full versus no activation. Here we discuss biased signaling in the chemokine system, including the structural basis for biased signaling in chemokine receptors, as well as in class A 7TM receptors in general. This includes overall helical movements and the contributions of micro-switches based on recently published 7TM crystals and molecular dynamics studies. All three forms of biased signaling are abundant in the chemokine system. This challenges our understanding of classic redundancy inevitably ascribed to this system, where multiple chemokines bind to the same receptor and where a single chemokine may bind to several receptors – in both cases with the same functional outcome. The ubiquitous biased signaling confer a hitherto unknown specificity to the chemokine system with a complex interaction pattern that is better described as promiscuous with context-defined roles and different functional outcomes in a ligand-, receptor- or cell/tissue-defined manner. As the low number of successful drug development plans implies, there are great difficulties in targeting chemokine receptors; in particular with regard to receptor antagonists as anti-inflammatory drugs. Un-defined and putative non-selective targeting of the complete cellular signaling system could be the underlying cause of lack of success. Therefore, biased ligands could be the

  7. Chemokines in Cancer Development and Progression and Their Potential as Targeting Molecules for Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Naofumi Mukaida

    2014-01-01

    Full Text Available Chemokines were initially identified as bioactive substances, which control the trafficking of inflammatory cells including granulocytes and monocytes/macrophages. Moreover, chemokines have profound impacts on other types of cells associated with inflammatory responses, such as endothelial cells and fibroblasts. These observations would implicate chemokines as master regulators in various inflammatory responses. Subsequent studies have further revealed that chemokines can regulate the movement of a wide variety of immune cells including lymphocytes, natural killer cells, and dendritic cells in both physiological and pathological conditions. These features endow chemokines with crucial roles in immune responses. Furthermore, increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of cancer cells. It is widely acknowledged that cancer develops and progresses to invade and metastasize in continuous interaction with noncancerous cells present in cancer tissues, such as macrophages, lymphocytes, fibroblasts, and endothelial cells. The capacity of chemokines to regulate both cancerous and noncancerous cells highlights their crucial roles in cancer development and progression. Here, we will discuss the roles of chemokines in carcinogenesis and the possibility of chemokine targeting therapy for the treatment of cancer.

  8. Chemokine Receptor 7 Knockout Attenuates Atherosclerotic Plaque Development

    NARCIS (Netherlands)

    Luchtefeld, Maren; Grothusen, Christina; Gagalick, Andreas; Jagavelu, Kumaravelu; Schuett, Harald; Tietge, Uwe J. F.; Pabst, Oliver; Grote, Karsten; Drexler, Helmut; Foerster, Reinhold; Schieffer, Bernhard

    2010-01-01

    Background-Atherosclerosis is a systemic inflammatory disease characterized by the formation of atherosclerotic plaques. Both innate immunity and adaptive immunity contribute to atherogenesis, but the mode of interaction is poorly understood. Chemokine receptor 7 (CCR7) is critically involved in the

  9. Chemokines in the corpus luteum: Implications of leukocyte chemotaxis

    Directory of Open Access Journals (Sweden)

    Liptak Amy R

    2003-11-01

    Full Text Available Abstract Chemokines are small molecular weight peptides responsible for adhesion, activation, and recruitment of leukocytes into tissues. Leukocytes are thought to influence follicular atresia, ovulation, and luteal function. Many studies in recent years have focused attention on the characterization of leukocyte populations within the ovary, the importance of leukocyte-ovarian cell interactions, and more recently, the mechanisms of ovarian leukocyte recruitment. Information about the role of chemokines and leukocyte trafficking (chemotaxis during ovarian function is important to understanding paracrine-autocrine relationships shared between reproductive and immune systems. Recent advances regarding chemokine expression and leukocyte accumulation within the ovulatory follicle and the corpus luteum are the subject of this mini-review.

  10. Chemokines in tumor development and progression

    Energy Technology Data Exchange (ETDEWEB)

    Mukaida, Naofumi, E-mail: naofumim@kenroku.kanazawa-u.ac.jp [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Chiyoda-ku, Tokyo 102-0075 (Japan); Baba, Tomohisa [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan)

    2012-01-15

    Chemokines were originally identified as mediators of the inflammatory process and regulators of leukocyte trafficking. Subsequent studies revealed their essential roles in leukocyte physiology and pathology. Moreover, chemokines have profound effects on other types of cells associated with the inflammatory response, such as endothelial cells and fibroblasts. Thus, chemokines are crucial for cancer-related inflammation, which can promote tumor development and progression. Increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of tumor cells. The wide range of activities of chemokines in tumorigenesis highlights their roles in tumor development and progression.

  11. Virus-encoded chemokine receptors--putative novel antiviral drug targets

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M

    2005-01-01

    Large DNA viruses, in particular herpes- and poxviruses, have evolved proteins that serve as mimics or decoys for endogenous proteins in the host. The chemokines and their receptors serve key functions in both innate and adaptive immunity through control of leukocyte trafficking, and have...... to their closest endogenous homologs, are interactions with a wider range of chemokines, which can act as agonists, antagonists and inverse agonists, and the exploitation of many signal transduction pathways. High constitutive activity is another key property of some--but not all--of these receptors. The chemokine...... receptors belong to the superfamily of G-protein coupled 7TM receptors that per se are excellent drug targets. At present, non-peptide antagonists have been developed against many chemokine receptors. The potentials of the virus-encoded chemokine receptors as drug targets--ie. as novel antiviral strategies...

  12. Erythrocyte Duffy antigen receptor for chemokines (DARC):diagnostic and therapeutic implications in atherosclerotic Cardiovascular disease

    Institute of Scientific and Technical Information of China (English)

    Stavros APOSTOLAKIS; Georgios K CHALIKIAS; Dimitrios N TZIAKAS; Stavros KONSTANTINIDES

    2011-01-01

    Atherosclerosis is an inflammatory disease.The last three decades efforts have been made to elucidate the biochemical pathways that are implicated in the process of atherogenesis and plaque development.Chemokines are crucial mediators in every step of this process.Additionally.cellular components of the peripheral blood have been proved important mediators in the formation and progression of atherosclerotic lesions.However,until recently data were mostly focusing on leukocytes and platelets.Erythrocytes were considered unreceptive bystanders and limited data supported their importance in the progression and destabilization of the atherosclerotic plaque.Recently erythrocytes, through their Duffy antigen receptor for chemokines(DARC),have been proposed as appealing regulators of chemokine-induced pathways.Dissimilar to every other chemokine receptor DARC possesses high affinity for severalligands from both CC and CXC chemokine sub-families.Moreover,DARC is not coupled to a G-protein or any other intracellular signalling system;thus it is incapable of generating second messages.The exact biochemical role of erythrocyte DARC remains to be determined.It is however challenging the fact that DARC is a regulator of almost every CC and CXC chemokine ligand and therefore DARC antagonism could efiectively block the complex pre-inflammatory chemokine network.In the present review we intent to provid recent evidence supporting the role of erythrocytes in atherosclerosis focusing on the erythrocyte-chemokine interaction through the Duffy antigen system.

  13. Chemokine Systems Link Obesity to Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Tsuguhito Ota

    2013-06-01

    Full Text Available Obesity is a state of chronic low-grade systemic inflammation. This chronic inflammation is deeply involved in insulin resistance, which is the underlying condition of type 2 diabetes and metabolic syndrome. A significant advance in our understanding of obesity-associated inflammation and insulin resistance has been recognition of the critical role of adipose tissue macrophages (ATMs. Chemokines are small proteins that direct the trafficking of immune cells to sites of inflammation. In addition, chemokines activate the production and secretion of inflammatory cytokines through specific G protein-coupled receptors. ATM accumulation through C-C motif chemokine receptor 2 and its ligand monocyte chemoattractant protein-1 is considered pivotal in the development of insulin resistance. However, chemokine systems appear to exhibit a high degree of functional redundancy. Currently, more than 50 chemokines and 18 chemokine receptors exhibiting various physiological and pathological properties have been discovered. Therefore, additional, unidentified chemokine/chemokine receptor pathways that may play significant roles in ATM recruitment and insulin sensitivity remain to be fully identified. This review focuses on some of the latest findings on chemokine systems linking obesity to inflammation and subsequent development of insulin resistance.

  14. Atypical chemokine receptors in cancer: friends or foes?

    Science.gov (United States)

    Massara, Matteo; Bonavita, Ornella; Mantovani, Alberto; Locati, Massimo; Bonecchi, Raffaella

    2016-06-01

    The chemokine system is a fundamental component of cancer-related inflammation involved in all stages of cancer development. It controls not only leukocyte infiltration in primary tumors but also angiogenesis, cancer cell proliferation, and migration to metastatic sites. Atypical chemokine receptors are a new, emerging class of regulators of the chemokine system. They control chemokine bioavailability by scavenging, transporting, or storing chemokines. They can also regulate the activity of canonical chemokine receptors with which they share the ligands by forming heterodimers or by modulating their expression levels or signaling activity. Here, we summarize recent results about the role of these receptors (atypical chemokine receptor 1/Duffy antigen receptor for chemokine, atypical chemokine receptor 2/D6, atypical chemokine receptor 3/CXC-chemokine receptor 7, and atypical chemokine receptor 4/CC-chemokine receptor-like 1) on the tumorigenesis process, indicating that their effects are strictly dependent on the cell type on which they are expressed and on their coexpression with other chemokine receptors. Indeed, atypical chemokine receptors inhibit tumor growth and progression through their activity as negative regulators of chemokine bioavailability, whereas, on the contrary, they can promote tumorigenesis when they regulate the signaling of other chemokine receptors, such as CXC-chemokine receptor 4. Thus, atypical chemokine receptors are key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti-inflammatory and immunotherapeutic strategies. PMID:26908826

  15. Microbiological exploitation of the chemokine system

    DEFF Research Database (Denmark)

    Holst, Peter J; Rosenkilde, Mette M

    2003-01-01

    Several viruses encode chemokine elements in their genome. This review focuses on the roles of such elements in the ongoing battle between the virus and the host. The biological and pharmacological characterizations of several of these chemokine elements have highlighted their importance in the m...

  16. Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers

    Directory of Open Access Journals (Sweden)

    Jessica L Williams

    2014-05-01

    Full Text Available In the adult central nervous system (CNS, chemokines and their receptors are involved in developmental, physiological and pathological processes. Although most lines of investigation focus on their ability to induce the migration of cells, recent studies indicate that chemokines also promote cellular interactions and activate signaling pathways that maintain CNS homeostatic functions. Many homeostatic chemokines are expressed on the vasculature of the blood brain barrier including CXCL12, CCL19, CCL20, and CCL21. While endothelial cell expression of these chemokines is known to regulate the entry of leukocytes into the CNS during immunosurveillance, new data indicate that CXCL12 is also involved in diverse cellular activities including adult neurogenesis and neuronal survival, having an opposing role to the homeostatic chemokine, CXCL14, which appears to regulate synaptic inputs to neural precursors. Neuronal expression of CX3CL1, yet another homeostatic chemokine that promotes neuronal survival and communication with microglia, is partly regulated by CXCL12. Regulation of CXCL12 is unique in that it may regulate its own expression levels via binding to its scavenger receptor CXCR7/ACKR3. In this review, we explore the diverse roles of these and other homeostatic chemokines expressed within the CNS, including the possible implications of their dysfunction as a cause of neurologic disease.

  17. Increased type 1 chemokine expression in experimental Chagas disease correlates with cardiac pathology in beagle dogs.

    Science.gov (United States)

    Guedes, Paulo M M; Veloso, Vanja M; Talvani, André; Diniz, Livia F; Caldas, Ivo S; Do-Valle-Matta, Maria A; Santiago-Silva, Juliana; Chiari, Egler; Galvão, Lucia M C; Silva, João S; Bahia, Maria T

    2010-11-15

    Chemokines and chemokine receptors interaction have presented important role in leukocyte migration to specific immune reaction sites. Recently, it has been reported that chemokine receptors CXC (CXCR3) and CC (CCR5) were preferentially expressed on Th1 cells while CCR3 and CCR4 were preferentially expressed on Th2 cells. This study evaluated the mRNA expression of type 1 and type 2 chemokine and chemokine receptors in the cardiac tissue of Beagle dogs infected with distinct genetic groups of Trypanosoma cruzi (Y, Berenice-78 and ABC strains) during acute and chronic phases. To analyze the correlation between chemokine and chemokine receptors expression and the development of heart pathology, the chronic infected animals were divided into groups, according to the parasite strain and based on the degree of heart damage: cardiac and indeterminate form of Chagas disease. Our results indicated that cardiac type1/2 chemokines and their receptors were partially dependent on the genetic diversity of parasites as well as the polarization of clinical forms. Also, dogs presenting cardiac form showed lower heart tissue mRNA expression of CCL24 (type 2) and higher expression of CCL5, CCL4 and CXCR3 (type 1) when compared with those with indeterminate form of disease. Together, these data reinforce a close-relation between T. cruzi genetic population and the host specific type 1 immune response and, for the first time, we show the distribution of type 1/2 chemokines associated with the development of cardiac pathology using dogs, a well similar model to study human Chagas disease.

  18. Chemokine Function in Periodontal Disease and Oral Cavity Cancer

    Directory of Open Access Journals (Sweden)

    Sinem Esra Sahingur

    2015-05-01

    Full Text Available The chemotactic cytokines, or chemokines, comprise a superfamily of polypeptides with a wide range of activities that include recruitment of immune cells to sites of infection and inflammation, as well as stimulation of cell proliferation. As such, they function as antimicrobial molecules and play a central role in host defenses against pathogen challenge. However, their ability to recruit leukocytes and potentiate or prolong the inflammatory response may have profound implications for the progression of oral diseases such as chronic periodontitis, where tissue destruction may be widespread. Moreover, it is increasingly recognized that chronic inflammation is a key component of tumor progression. Interaction between cancer cells and their microenvironment is mediated in large part by secreted factors such as chemokines, and serves to enhance the malignant phenotype in oral and other cancers. In this article, we will outline the biological and biochemical mechanisms of chemokine action in host-microbiome interactions in periodontal disease and in oral cancer, and how these may overlap and contribute to pathogenesis.

  19. Chemokines and chemokine receptors in mucosal homeostasis at the intestinal epithelial barrier in inflammatory bowel disease

    OpenAIRE

    Noah P Zimmerman; Vongsa, Rebecca A.; Wendt, Michael K; Michael B Dwinell

    2008-01-01

    Chemokines, a large family of small chemoattractive cytokines, and their receptors play an integral role in the regulation of the immune response and homeostasis. The ability of chemokines to attract specific populations of immune cells sets them apart from other chemoattractants. Chemokines produced within the gastrointestinal mucosa, are critical players in directing the balance between physiological and pathophysiological inflammation in health, inflammatory bowel disease and the progressi...

  20. Viral leads for chemokine-modulatory drugs

    DEFF Research Database (Denmark)

    Lindow, Morten; Lüttichau, Hans Rudolf; Schwartz, Thue W

    2003-01-01

    The chemokine system, which controls leukocyte trafficking, provides several potentially very attractive anti-inflammatory drug targets. However, the complexity and redundancy of this system makes it very difficult to exploit through classical drug discovery. Despite this, viruses have millions...

  1. Chemokines and chemokine receptors in mucosal homeostasis at the intestinal epithelial barrier in inflammatory bowel disease.

    Science.gov (United States)

    Zimmerman, Noah P; Vongsa, Rebecca A; Wendt, Michael K; Dwinell, Michael B

    2008-07-01

    Chemokines, a large family of small chemoattractive cytokines, and their receptors play an integral role in the regulation of the immune response and homeostasis. The ability of chemokines to attract specific populations of immune cells sets them apart from other chemoattractants. Chemokines produced within the gastrointestinal mucosa are critical players in directing the balance between physiological and pathophysiological inflammation in health, inflammatory bowel disease (IBD), and the progression to colon cancer. In addition to the well-characterized role of chemokines in directed trafficking of immune cells to the gut mucosa, the expression of chemokine receptors on the cells of the epithelium makes them active participants in the chemokine signaling network. Recent findings demonstrate an important role for chemokines and chemokine receptors in epithelial barrier repair and maintenance as well as an intricate involvement in limiting metastasis of colonic carcinoma. Increased recognition of the association between barrier defects and inflammation and the subsequent progression to cancer in IBD thus implicates chemokines as key regulators of mucosal homeostasis and disease pathogenesis. PMID:18452220

  2. Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response.

    Science.gov (United States)

    Koizumi, Keiichi; Hojo, Shozo; Akashi, Takuya; Yasumoto, Kazuo; Saiki, Ikuo

    2007-11-01

    The chemotactic cytokines called chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC chemokine receptor 4 (CXCR4) was first investigated as a chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell-derived chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the chemokine CCL9-induced infiltration of immature myeloid cells into cancer, high-level expression of cancer cell-derived chemokine CXCL16 increases infiltrating CD8(+) and CD4(+) T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell-derived chemokines on cancer progression, using CCL9 and CXCL16 as examples. PMID:17894551

  3. Involvement of chemokine receptors in breast cancer metastasis

    Science.gov (United States)

    Müller, Anja; Homey, Bernhard; Soto, Hortensia; Ge, Nianfeng; Catron, Daniel; Buchanan, Matthew E.; McClanahan, Terri; Murphy, Erin; Yuan, Wei; Wagner, Stephan N.; Barrera, Jose Luis; Mohar, Alejandro; Verástegui, Emma; Zlotnik, Albert

    2001-03-01

    Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1α and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.

  4. Allosteric and orthosteric sites in CC chemokine receptor (CCR5), a chimeric receptor approach

    DEFF Research Database (Denmark)

    Thiele, Stefanie; Steen, Anne; Jensen, Pia C;

    2011-01-01

    molecules often act more deeply in an allosteric mode. However, opposed to the well described molecular interaction of allosteric modulators in class C 7-transmembrane helix (7TM) receptors, the interaction in class A, to which the chemokine receptors belong, is more sparsely described. Using the CCR5...... chemokine receptor as a model system, we studied the molecular interaction and conformational interchange required for proper action of various orthosteric chemokines and allosteric small molecules, including the well known CCR5 antagonists TAK-779, SCH-C, and aplaviroc, and four novel CCR5 ago......-allosteric molecules. A chimera was successfully constructed between CCR5 and the closely related CCR2 by transferring all extracellular regions of CCR2 to CCR5, i.e. a Trojan horse that resembles CCR2 extracellularly but signals through a CCR5 transmembrane unit. The chimera bound CCR2 (CCL2 and CCL7), but not CCR5...

  5. Rapid method for culturing embryonic neuron-glial cell cocultures

    DEFF Research Database (Denmark)

    Svenningsen, Åsa Fex; Shan, Wei-Song; Colman, David R;

    2003-01-01

    A streamlined, simple technique for primary cell culture from E17 rat tissue is presented. In an attempt to standardize culturing methods for all neuronal cell types in the embryo, we evaluated a commercial medium without serum and used similar times for trypsinization and tested different surfaces...... for plating. In 1 day, using one method and a single medium, it is possible to produce robust E17 cultures of dorsal root ganglia (DRG), cerebellum, and enteric plexi. Allowing the endogenous glial cells to repopulate the cultures saves time compared with existing techniques, in which glial cells are added...... to cultures first treated with antimitotic agents. It also ensures that all the cells present in vivo will be present in the culture. Myelination commences after approximately 2 weeks in culture for dissociated DRG and 3-4 weeks in cerebellar cultures. In enteric cultures, glial wrapping of the enteric...

  6. Polymorphisms in chemokine and chemokine receptor genes and the development of coal workers' pneumoconiosis

    Energy Technology Data Exchange (ETDEWEB)

    Nadif, R.; Mintz, M.; Rivas-Fuentes, S.; Jedlicka, A.; Lavergne, E.; Rodero, M.; Kauffmann, F.; Combadiere, C.; Kleeberger, S.R. [INSERM, Villejuif (France)

    2006-02-07

    Chemokines and their receptors are key regulators of inflammation and may participate in the lung fibrotic process. Associations of polymorphisms in CCL5 (G-403A) and its receptor CCR5 {Delta}32), CCL2 (A-2578G) and CCR2 (V641), and CX3CR1 V2491 and T280M with coal worker's pneumoconiosis (CWP) were investigated in 209 miners examined in 1990, 1994 and 1999. Coal dust exposure was assessed by job history and ambient measures. The main health outcome was lung computed tomography (CT) score in 1990. Internal coherence was assessed by studying CT score in 1994, 4-year change in CT score, and CWP prevalence in 1999. CCR5 {Delta}32 carriers had significantly higher CT score in 1990 and 1994 (2.15 vs. 1.28, p = 0.01; 3.04 vs. 1.80, p = 0.04). The CX3CR1 1249 allele was significantly associated with lower 1990 CT score and lower progression in 4-year change in CT score in CCR5{Delta}32 carriers only (p for interaction = 0.03 and 0.02). CX3CR1 V2491 was associated with lower 1999 CWP prevalence (16.7%, 13.2%, 0.0% for VV, VI and II); the effect was most evident in miners with high dust exposure (31.6%, 21.7%, 0.0%). Our findings indicate that chemokine receptors CCR5 and CX3CR1 may be involved in the development of pneumoconiosis.

  7. Solution structure of the complex between poxvirus-encoded CC chemokine inhibitor vCCI and human MIP-1β

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Li; DeRider, Michele; McCornack, Milissa A.; Jao, Chris; Isern, Nancy G.; Ness, Traci; Moyer, Richard; Liwang, Patricia J.

    2006-09-19

    Chemokines (chemotactic cytokines) comprise a large family of proteins that recruit and activate leukocytes, giving chemokines a major role in both the immune response and inflammation-related diseases. The poxvirus-encoded viral CC chemokine inhibitor (vCCI) binds to many CC chemokines with high affinity, acting as a potent inhibitor of chemokine action. We have used heteronuclear multidimensional NMR to determine the first structure of an orthopoxvirus vCCI in complex with a human CC chemokine MIP-1β. vCCI binds to the chemokine with 1:1 stoichiometry, using residues from its β-sheet II to interact with the a surface of MIP-1β that includes the N-terminus, the following residues in the so-called N-loop20’s region, and the 40’s loop. This structure reveals a general strategy of vCCI for selective chemokine binding, as vCCI appears to interact most stronglyinteracts most directly with residues that are conserved among a subset of CC chemokines, but are not conservednot among the other chemokine subfamilies. This structure reveals a general strategy of vCCI for selective chemokine binding. Chemokines play critical roles in the immune system, causing chemotaxis of a variety of cells to sites of infection and inflammation, as well as mediating cell homing and immune system development 1(Baggiolini 2001). To date, about 50 chemokines have been identified, and these small proteins (7-14 kDa) are believed to function by binding with endothelial or matrix glycosaminoglycans to form a concentration gradient that is then sensed by high affinity, 7-transmembrane domain G-protein coupled chemokine receptors on the surface of immune cells surface. The chemokine system is critical for host defense in healthy individuals, butand can also lead to diseases including asthma, arthritis, and atherosclerosis in the case of malfunction, often due to inappropriate inflammation and subsequent tissue damage 2(Gerard and Rollins 2001). There are four subfamilies of chemokines, CC

  8. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Tani, M; Jensen, J;

    1999-01-01

    Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether...

  9. Heterologous Quaternary Structure of CXCL12 and its Relationship to the CC Chemokine Family

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, J.; Yuan, H; Kong, Y; Xiong, Y; Lolis, E

    2010-01-01

    X-ray crystallographic studies reveal that CXCL12 is able to form multiple dimer types, a traditional CXC dimer and a 'CC-like' form. Phylogenetic analysis of all known human chemokines demonstrates CXCL12 is more closely related to the CC chemokine class than other CXC chemokines. These observations indicate that CXCL12 contains genomic and structural elements characteristic of both CXC and CC chemokines.Chemokines are members of a superfamily of proteins involved in the migration of cells to the proper anatomical position during embryonic development or in response to infection or stress during an immune response. There are two major (CC and CXC) and two minor (CX3C and XC) families based on the sequence around the first conserved cysteine. The topology of all structures is essentially identical with a flexible N-terminal region of 3-8 amino acids, a 10-20 residue N-terminal loop, a short 3{sub 10}-helix, three {beta}-strands, and a {alpha}-helix. The major consequence of the subtle difference between the families occurs at the oligomeric level. Monomers of the CC, CXC, and CX3C families form dimers in a family-specific manner. The XCL1 chemokine is a monomer that can interconvert between two folded states. All chemokines activate GPCRs according to family-specificity, however there are a few examples of chemokines crossing the family boundary to function as antagonists. A two-stage mechanism for chemokine activation of GPCRs has been proposed. The N-terminal region of the receptor interacts with the chemokine, followed by receptor activation by the chemokine N-terminal region. Monomeric chemokines have been demonstrated to be the active form for receptor function. There are numerous examples of both chemokines and their receptors forming dimers. While family-specific dimerization may be an attractive explanation for why specific chemokines only activate GPCRs within their own family, the role of dimers in the function of chemokines has not been

  10. Molecular determinants of receptor binding and signaling by the CX3C chemokine fractalkine

    DEFF Research Database (Denmark)

    Mizoue, L S; Sullivan, S K; King, D S;

    2001-01-01

    Fractalkine/CX3CL1 is a membrane-tethered chemokine that functions as a chemoattractant and adhesion protein by interacting with the receptor CX3CR1. To understand the molecular basis for the interaction, an extensive mutagenesis study of fractalkine's chemokine domain was undertaken. The results...... reveal a cluster of basic residues (Lys-8, Lys-15, Lys-37, Arg-45, and Arg-48) and one aromatic (Phe-50) that are critical for binding and/or signaling. The mutant R48A could bind but not induce chemotaxis, demonstrating that Arg-48 is a signaling trigger. This result also shows that signaling residues......, but not all, pathways required for migration. Fractalkine also binds the human cytomegalovirus receptor US28, and analysis of the mutants indicates that US28 recognizes many of the same epitopes of fractalkine as CX3CR1. Comparison of the binding surfaces of fractalkine and the CC chemokine MCP-1 reveals...

  11. Chemokines in CSF of Alzheimer's disease patients

    Directory of Open Access Journals (Sweden)

    Jôice Dias Corrêa

    2011-06-01

    Full Text Available Some studies have linked the presence of chemokines to the early stages of Alzheimer's disease (AD. Then, the identification of these mediators may contribute to diagnosis. Our objective was to evaluate the levels of beta-amyloid (BA, tau, phospho-tau (p-tau and chemokines (CCL2, CXCL8 and CXCL10 in the cerebrospinal fluid (CSF of patients with AD and healthy controls. The correlation of these markers with clinical parameters was also evaluated. The levels of p-tau were higher in AD compared to controls, while the tau/p-tau ratio was decreased. The expression of CCL2 was increased in AD. A positive correlation was observed between BA levels and all chemokines studied, and between CCL2 and p-tau levels. Our results suggest that levels of CCL2 in CSF are involved in the pathogenesis of AD and it may be an additional useful biomarker for monitoring disease progression.

  12. Chemokines and chemokine receptors expression in the lesions of patients with American cutaneous leishmaniasis

    Directory of Open Access Journals (Sweden)

    Nilka Luisa Diaz

    2013-06-01

    Full Text Available American cutaneous leishmaniasis (ACL presents distinct active clinical forms with different grades of severity, known as localised (LCL, intermediate (ICL and diffuse (DCL cutaneous leishmaniasis. LCL and DCL are associated with a polarised T-helper (Th1 and Th2 immune response, respectively, whereas ICL, or chronic cutaneous leishmaniasis, is associated with an exacerbated immune response and a mixed cytokine expression profile. Chemokines and chemokine receptors are involved in cellular migration and are critical in the inflammatory response. Therefore, we evaluated the expression of the chemokines CXCL10, CCL4, CCL8, CCL11 and CXCL8 and the chemokine receptors CCR3, CXCR3, CCR5 and CCR7 in the lesions of patients with different clinical forms of ACL using immunohistochemistry. LCL patients exhibited a high density of CXCL10+, CCL4+ and CCL8+ cells, indicating an important role for these chemokines in the local Th1 immune response and the migration of CXCR3+ cells. LCL patients showed a higher density of CCR7+ cells than ICL or DCL patients, suggesting major dendritic cell (DC migration to lymph nodes. Furthermore, DCL was associated with low expression levels of Th1-associated chemokines and CCL11+ epidermal DCs, which contribute to the recruitment of CCR3+ cells. Our findings also suggest an important role for epidermal cells in the induction of skin immune responses through the production of chemokines, such as CXCL10, by keratinocytes.

  13. Chemokines and Chemokine Receptors: Their Manifold Roles in Homeostasis and Disease

    Institute of Scientific and Technical Information of China (English)

    Yingying Le; Ye Zhou; Pablo Iribarren; Ji Ming Wang

    2004-01-01

    Chemokines are a superfamily of small proteins that bind to G protein-coupled receptors on target cells and were originally discovered as mediators of directional migration of immune cells to sites of inflammation and injury. In recent years, it has become clear that the function of chemokines extends well beyond the role in leukocyte chemotaxis. They participate in organ development, angiogenesis/angiostasis, leukocyte trafficking and homing, tumorigenesis and metastasis, as well as in immune responses to microbial infection. Therefore,chemokines and their receptors are important targets for modulation of host responses in pathophysiological conditions and for therapeutic intervention of human diseases.

  14. Chemokines and Chemokine Receptors: Their Manifold Roles in Homeostasis and Disease

    Institute of Scientific and Technical Information of China (English)

    YingyingLe; YeZhou; PabloIribarren; JiMingWang

    2004-01-01

    Chemokines are a superfamily of small proteins that bind to G protein-coupled receptors on target cells and were originally discovered as mediators of directional migration of immune cells to sites of inflammation and injury. In recent years, it has become clear that the function of chemokines extends well beyond the role in leukocyte chemotaxis. They participate in organ development, angiogenesis/angiostasis, leukocyte trafficking and homing, tumorigenesis and metastasis, as well as in immune responses to microbial infection. Therefore, chemokines and their receptors are important targets for modulation of host responses in pathophysiological conditions and for therapeutic intervention of human diseases. Cellular & Molecular Immunology. 2004;1(2):95-104.

  15. Positive Relationship between Total Antioxidant Status and Chemokines Observed in Adults

    Directory of Open Access Journals (Sweden)

    Yanli Li

    2014-01-01

    Full Text Available Objective. Human evidence is limited regarding the interaction between oxidative stress biomarkers and chemokines, especially in a population of adults without overt clinical disease. The current study aims to examine the possible relationships of antioxidant and lipid peroxidation markers with several chemokines in adults. Methods. We assessed cross-sectional associations of total antioxidant status (TAS and two lipid peroxidation markers malondialdehyde (MDA and thiobarbituric acid reactive substances (TBARS with a suite of serum chemokines, including CXCL-1 (GRO-α, CXCL-8 (IL-8, CXCL-10 (IP-10, CCL-2 (MCP-1, CCL-5 (RANTES, CCL-8 (MCP-2, CCL-11 (Eotaxin-1, and CCL-17 (TARC, among 104 Chinese adults without serious preexisting clinical conditions in Beijing before 2008 Olympics. Results. TAS showed significantly positive correlations with MCP-1 (r=0.15751, P=0.0014, MCP-2 (r=0.3721, P=0.0001, Eotaxin-1 (r=0.39598, P<0.0001, and TARC (r=0.27149, P=0.0053. The positive correlations remained unchanged after controlling for age, sex, body mass index, smoking, and alcohol drinking status. No associations were found between any of the chemokines measured in this study and MDA or TBARS. Similar patterns were observed when the analyses were limited to nonsmokers. Conclusion. Total antioxidant status is positively associated with several chemokines in this adult population.

  16. Chapter 8. Activation mechanisms of chemokine receptors

    DEFF Research Database (Denmark)

    Jensen, Pia C; Rosenkilde, Mette M

    2009-01-01

    Chemokine receptors belong to the large family of 7-transmembrane (7TM) G-protein-coupled receptors. These receptors are targeted and activated by a variety of different ligands, indicating that activation is a result of similar molecular mechanisms but not necessarily similar modes of ligand bin...

  17. Cytokines and Chemokines in Irritant Contact Dermatitis

    OpenAIRE

    Haur Yueh Lee; Marco Stieger; Nikhil Yawalkar; Masato Kakeda

    2013-01-01

    Irritant contact dermatitis is a result of activated innate immune response to various external stimuli and consists of complex interplay which involves skin barrier disruption, cellular changes, and release of proinflammatory mediators. In this review, we will focus on key cytokines and chemokines involved in the pathogenesis of irritant contact dermatitis and also contrast the differences between allergic contact dermatitis and irritant contact dermatitis.

  18. Chemokine cooperativity is caused by competitive glycosaminoglycan binding

    NARCIS (Netherlands)

    Verkaar, F.; Offenbeek, J. van; Lee, M. van der; Lith, L.H. van; Watts, A.O.; Rops, A.L.; Aguilar, D.C.; Ziarek, J.J.; Vlag, J. van der; Handel, T.M.; Volkman, B.F.; Proudfoot, A.E.; Vischer, H.F.; Zaman, G.J.; Smit, M.J.

    2014-01-01

    Chemokines comprise a family of secreted proteins that activate G protein-coupled chemokine receptors and thereby control the migration of leukocytes during inflammation or immune surveillance. The positional information required for such migratory behavior is governed by the binding of chemokines t

  19. Chemokines and their receptors in central nervous system disease

    NARCIS (Netherlands)

    Biber, K; de Jong, EK; van Weering, HRJ; Boddeke, HWGM

    2006-01-01

    Almost a decade ago, it was discovered that the human deficiency virus (HIV) makes use of chemokine receptors to infect blood cells. This appreciation of the clinical relevance of specific chemokine receptors has initiated a considerable boost in the field of chemokine research. It is clear today th

  20. A Combinatorial Approach to Biophysically Characterise Chemokine-Glycan Binding Affinities for Drug Development

    Directory of Open Access Journals (Sweden)

    Tanja Gerlza

    2014-07-01

    Full Text Available Chemokine binding to glycosaminoglycans (GAGs is recognised to be an important step in inflammation and other pathological disorders like tumor growth and metastasis. Although different ways and strategies to interfere with these interactions are being pursued, no major breakthrough in the development of glycan-targeting drugs has been reported so far. We have engineered CXCL8 towards a dominant-negative form of this chemokine (dnCXCL8 which was shown to be highly active in various inflammatory animal models due to its inability to bind/activate the cognate CXCL8 GPC receptors on neutrophils in combination with its significantly increased GAG-binding affinity [1]. For the development of GAG-targeting chemokine-based biopharmaceuticals, we have established a repertoire of methods which allow the quantification of protein-GAG interactions. Isothermal fluorescence titration (IFT, surface plasmon resonance (SPR, isothermal titration calorimetry (ITC, and a novel ELISA-like competition assay (ELICO have been used to determine Kd and IC50 values for CXCL8 and dnCXCL8 interacting with heparin and heparan sulfate (HS, the proto-typical members of the GAG family. Although the different methods gave different absolute affinities for the four protein-ligand pairs, the relative increase in GAG-binding affinity of dnCXCL8 compared to the wild type chemokine was found by all methods. In combination, these biophysical methods allow to discriminate between unspecific and specific protein-GAG interactions.

  1. The Role of Chemokines in Promoting Colorectal Cancer Invasion/Metastasis

    Directory of Open Access Journals (Sweden)

    Yoshiro Itatani

    2016-04-01

    Full Text Available Colorectal cancer (CRC is one of the leading causes of cancer-related death worldwide. Although most of the primary CRC can be removed by surgical resection, advanced tumors sometimes show recurrences in distant organs such as the liver, lung, lymph node, bone or peritoneum even after complete resection of the primary tumors. In these advanced and metastatic CRC, it is the tumor-stroma interaction in the tumor microenvironment that often promotes cancer invasion and/or metastasis through chemokine signaling. The tumor microenvironment contains numerous host cells that may suppress or promote cancer aggressiveness. Several types of host-derived myeloid cells reside in the tumor microenvironment, and the recruitment of them is under the control of chemokine signaling. In this review, we focus on the functions of chemokine signaling that may affect tumor immunity by recruiting several types of bone marrow-derived cells (BMDC to the tumor microenvironment of CRC.

  2. The role of chemokines and chemokine receptors in eosinophil activation during inflammatory allergic reactions

    Directory of Open Access Journals (Sweden)

    Oliveira S.H.P.

    2003-01-01

    Full Text Available Chemokines are important chemotactic cytokines that play a fundamental role in the trafficking of leukocytes to sites of inflammation. They are also potent cell-activating factors, inducing cytokine and histamine release and free radical production, a fact that makes them particularly important in the pathogenesis of allergic inflammation. The action of chemokines is regulated at the level of agonist production and processing as well as at the level of receptor expression and coupling. Therefore, an analysis of the ligands must necessarily consider receptors. Eosinophils are target cells involved in the allergic inflammatory response since they are able to release a wide variety of mediators including CC and CXC chemokines and express their receptors. These mediators could damage the airway epithelial cells and might be important to stimulate other cells inducing an amplification of the allergic response. This review focuses on recently emerging data pertaining to the importance of chemokines and chemokine receptors in promoting eosinophil activation and migration during the allergic inflammatory process. The analysis of the function of eosinophils and their chemokine receptors during allergic inflammation might be a good approach to understanding the determinants of asthma severity and to developing novel therapies.

  3. Genetic variants in the chemokines and chemokine receptors in Chagas disease.

    Science.gov (United States)

    Flórez, Oscar; Martín, Javier; González, Clara Isabel

    2012-08-01

    Clinical symptoms of Chagas' disease occur in 30% of the individuals infected with Trypanosoma cruzi and are characterised by heart inflammation and dysfunction. Chemokines and chemokine receptors control the migration of leukocytes during the inflammatory process and are involved in the modulation of Th1 or Th2 responses. To determine their influence, we investigated the possible role of CCL5/RANTES and CXCL8/IL8 chemokines, and CCR2 and CCR5 chemokines receptors cluster gene polymorphisms with the development of chagasic cardiomyopathy. Our study included 260 Chagas seropositive individuals (asymptomatic, n=130; cardiomyopathic, n=130) from an endemic area of Colombia. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and TaqMan SNP genotyping assay. We found statistically significant differences in the distribution of the CCR5 human haplogroup (HH)-A (p=0.027; OR=3.78, 95% CI=1.04-13.72). Moreover, we found that the CCR5-2733 G and CCR5-2554 T alleles are associated, respectively, with a reduced risk of susceptibility and severity to develop chagasic cardiomyopathy. No other associations were found to be significant for the other polymorphisms analysed in the CCR5, CCR2, CCL5/RANTES and CXCL8/IL8 genes. Our data suggest that the analysed chemokines and chemokine receptor genetic variants have a weak but important association with the development of chagasic cardiomyopathy in the population under study.

  4. Chemokines CXCL10 and CCL2

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Sellebjerg, F; Jensen, C V;

    2001-01-01

    Studies of chemokines in cerebrospinal fluid (CSF) of patients with active multiple sclerosis (MS) have indicated that specific chemokines may have important roles in disease pathogenesis. We previously reported that CSF concentrations of CXCL10 (previously known as IP-10) were elevated in MS...... patients in relapse, whilst levels of CCL2 (MCP-1) were reduced. Here, we report a serial analysis of CSF CXCL10 and CCL2 concentrations in 22 patients with attacks of MS or acute optic neuritis (ON) treated with methylprednisolone, and 26 patients treated with placebo in two randomized controlled trials....... The levels of CXCL10 were higher in the patient group than in controls but two outliers in the control group also had high CSF concentrations of CXCL10. The CSF concentrations of CXCL10 did not change over time or after treatment. The CSF concentration of CXCL10 was positively correlated with the CSF...

  5. CXC and CC Chemokines as Angiogenic Modulators in Nonhaematological Tumors

    Science.gov (United States)

    Bracarda, Sergio; Nabissi, Massimo; Massari, Francesco; Bria, Emilio; Tortora, Giampaolo; Santoni, Giorgio; Cascinu, Stefano

    2014-01-01

    Chemokines are a superfamily of structurally homologous heparin-binding proteins that includes potent inducers and inhibitors of angiogenesis. The imbalance between angiogenic and angiostatic chemokine activities can lead to abnormalities, such as chronic inflammation, dysplastic transformation, and even tumor development and spreading. In this review, we summarize the current literature regarding the role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in patients with nonhaematological tumors. PMID:24971349

  6. CXC and CC Chemokines as Angiogenic Modulators in Nonhaematological Tumors

    Directory of Open Access Journals (Sweden)

    Matteo Santoni

    2014-01-01

    Full Text Available Chemokines are a superfamily of structurally homologous heparin-binding proteins that includes potent inducers and inhibitors of angiogenesis. The imbalance between angiogenic and angiostatic chemokine activities can lead to abnormalities, such as chronic inflammation, dysplastic transformation, and even tumor development and spreading. In this review, we summarize the current literature regarding the role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in patients with nonhaematological tumors.

  7. Pouncing on the chemokine receptor Chimera.

    Science.gov (United States)

    Mascolini, M

    1997-08-01

    Scientists are seeking to unravel the mystery of chemokine receptors in an attempt to develop treatments for HIV infection; however, receptor experts are realizing that the picture is more complicated than they first imagined. Scientists want to know, among other things, what parts of each coreceptor are essential for viral fusion with target cells, what makes macrophage-tropic viruses switch their preference to T-lymphocytes, why HIV goes after chemokine receptors in the first place, and how fusion and entry occur. Other issues discussed include whether blocking coreceptors for HIV will actually curb this disease, virus turnover in monkey studies showing that SIV may go through the cycle as many as 100 times per day, and studies showing that the first days of infection may predict the course of disease. Final comments concern the use of ritonavir plus indinavir in treatment combinations for children with HIV and the latest progress toward vaccine development. Understanding these and other puzzles might help scientists to develop drugs to block receptors active in HIV infection and perhaps curb HIV. More than 14 biotechnology and pharmaceutical firms are working to design coreceptor blockers, despite the opinions of several leading researchers that the drugs are not terribly promising. Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Disease (NIAID), notes that a famous attempt to block HIV's primary receptor failed, and David Ho, the man who demonstrated why CD4 would not work as therapy, is similarly cautious. According to Ho, drug makers will have no trouble developing compounds that keep HIV off chemokine receptors, such as CCR5 or CXCR4, but whether those compounds will slow disease progression is another question. PMID:11364629

  8. T-cells in the cerebrospinal fluid express a similar repertoire of inflammatory chemokine receptors in the absence or presence of CNS inflammation

    DEFF Research Database (Denmark)

    Kivisäkk, P; Trebst, C; Liu, Z;

    2002-01-01

    It is believed that chemokines and their receptors are involved in trafficking of T-cells to the central nervous system (CNS). The aim of the current study was to define the expression on cerebrospinal fluid (CSF) T-cells of six chemokine receptors associated with trafficking to sites...... is not sufficient for the trafficking of CD3+T-cells to the CSF. We hypothesize that CXCR3 is the principal inflammatory chemokine receptor involved in intrathecal accumulation of T-cells in MS. Through interactions with its ligands, CXCR3 is proposed to mediate retention of T-cells in the inflamed CNS....

  9. Genomic organization, annotation, and ligand-receptor inferences of chicken chemokines and chemokine receptor genes based on comparative genomics

    Directory of Open Access Journals (Sweden)

    Sze Sing-Hoi

    2005-03-01

    Full Text Available Abstract Background Chemokines and their receptors play important roles in host defense, organogenesis, hematopoiesis, and neuronal communication. Forty-two chemokines and 19 cognate receptors have been found in the human genome. Prior to this report, only 11 chicken chemokines and 7 receptors had been reported. The objectives of this study were to systematically identify chicken chemokines and their cognate receptor genes in the chicken genome and to annotate these genes and ligand-receptor binding by a comparative genomics approach. Results Twenty-three chemokine and 14 chemokine receptor genes were identified in the chicken genome. All of the chicken chemokines contained a conserved CC, CXC, CX3C, or XC motif, whereas all the chemokine receptors had seven conserved transmembrane helices, four extracellular domains with a conserved cysteine, and a conserved DRYLAIV sequence in the second intracellular domain. The number of coding exons in these genes and the syntenies are highly conserved between human, mouse, and chicken although the amino acid sequence homologies are generally low between mammalian and chicken chemokines. Chicken genes were named with the systematic nomenclature used in humans and mice based on phylogeny, synteny, and sequence homology. Conclusion The independent nomenclature of chicken chemokines and chemokine receptors suggests that the chicken may have ligand-receptor pairings similar to mammals. All identified chicken chemokines and their cognate receptors were identified in the chicken genome except CCR9, whose ligand was not identified in this study. The organization of these genes suggests that there were a substantial number of these genes present before divergence between aves and mammals and more gene duplications of CC, CXC, CCR, and CXCR subfamilies in mammals than in aves after the divergence.

  10. Chemokine signaling involving chemokine (C-C motif) ligand 2 plays a role in descending pain facilitation

    Institute of Scientific and Technical Information of China (English)

    Wei Guo; Hu Wang; Shiping Zou; Ronald Dubner; Ke Ren

    2012-01-01

    Objective Despite accumulating evidence on a role of immune cells and their associated chemicals in mechanisms of pain,few studies have addressed the potential role of chemokines in the descending facilitation of persistent pain.The present study was undertaken to test the hypothesis that the chemokine (C-C motif) ligand 2 (CCL2) (commonly known as monocyte chemoattractant protein-1) signaling in the rostral ventromedial medulla (RVM),a pivotal structure in brainstem pain modulatory circuitry,is involved in descending pain facilitation in rats.Methods An L5 spinal nerve ligation (SNL) was produced in rats under pentobarbital anesthesia.Western blot and immunohistochemistry were used to detect the expression levels of CCL2 and CCL2 receptor (CCR2),and examine their distributions compared with the neuronal marker NeuN as well as glial markers glial fibrillary acidic protein (GFAP,astroglial) and CD11b (microglial),respectively.Results SNL induced an increase in CCL2 expression in the RVM,and this returned to the control level at 4 weeks after injury.The induced CCL2 colocalized with NeuN,but not with GFAP and CD11b.CCR2 was also upregulated by SNL in the RVM,and this increase lasted for at least 4 weeks.CCR2 was colocalized with CD1 1b but not GFAP.Few RVM neurons also exhibited CCR2 staining.Neutralizing CCL2 with an anti-CCL2 antibody (0.2-20 ng) or injecting RS-102895 (0.1-10 pmol),a CCR2b chemokine receptor antagonist,into the RVM on day 1 after SNL,significantly attenuated the established thermal and mechanical hypersensitivity.In addition,injection of recombinant rat CCL2 (0.03-3pmol) into the RVM induced dose-dependent hyperalgesia,which was prevented by pretreatment with RS-102895 (10pmol).Interleukin-1β (IL-1β),a potent inducer of neuronal CCL2,was also selectively upregulated in RVM reactive astrocytes.Injection of IL-1β (120 fmol) into the RVM induced behavioral hyperalgesia,which was blocked by RS-102895(10 pmol).However,an IL-1 receptor antagonist (3

  11. Distinct chemokine receptor and cytokine expression profile in secondary progressive MS

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Sellebjerg, F

    2001-01-01

    Chemokines, small chemotactic cytokines, have been implicated in active relapsing-remitting MS (RRMS). However, the role of chemokines and chemokine receptors has not been specifically studied in secondary progressive MS (SPMS)....

  12. Berberine suppresses migration of MCF-7 breast cancer cells through down-regulation of chemokine receptors

    OpenAIRE

    Naghmeh Ahmadiankia; Hamid Kalalian Moghaddam; Mohammad Amir Mishan; Ahmad Reza Bahrami; Hojjat Naderi-Meshkin; Hamid Reza Bidkhori; Maryam Moghaddam; Seyed Jamal Aldin Mirfeyzi

    2016-01-01

    Objective(s): Berberine is one of the main alkaloids and it has been proven to have different pharmacological effects including inhibition of cell cycle and progression of apoptosis in various cancerous cells; however, its effects on cancer metastasis are not well known. Cancer cells obtain the ability to change their chemokine system and convert into metastatic cells. In this study, we examined the effect of berberine on breast cancer cell migration and its probable interaction with the chem...

  13. Neonatal chemokine levels and risk of autism spectrum disorders

    DEFF Research Database (Denmark)

    Abdallah, Morsi; Larsen, Nanna; Grove, Jakob;

    2013-01-01

    A potential role of chemokines in the pathophysiology of Autism Spectrum Disorders (ASDs) has been previously suggested. In a recent study we examined levels of three inflammatory chemokines (MCP-1, MIP-1a and RANTES) in samples of amniotic fluid of children diagnosed later in life with ASD...

  14. Chemokine receptor CCR5 in interferon-treated multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F; Kristiansen, T B; Wittenhagen, P;

    2007-01-01

    To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta).......To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta)....

  15. Chemokine-Derived Peptides: Novel Antimicrobial and Antineoplasic Agents

    Science.gov (United States)

    Valdivia-Silva, Julio; Medina-Tamayo, Jaciel; Garcia-Zepeda, Eduardo A.

    2015-01-01

    Chemokines are a burgeoning family of chemotactic cytokines displaying a broad array of functions such as regulation of homeostatic leukocyte traffic and development, as well as activating the innate immune system. Their role in controlling early and late inflammatory stages is now well recognized. An improper balance either in chemokine synthesis or chemokine receptor expression contributes to various pathological disorders making chemokines and their receptors a useful therapeutic target. Research in this area is progressing rapidly, and development of novel agents based on chemokine/chemokine receptors antagonist functions are emerging as attractive alternative drugs. Some of these novel agents include generation of chemokine-derived peptides (CDP) with potential agonist and antagonist effects on inflammation, cancer and against bacterial infections. CDP have been generated mainly from N- and C-terminus chemokine sequences with subsequent modifications such as truncations or elongations. In this review, we present a glimpse of the different pharmacological actions reported for CDP and our current understanding regarding the potential use of CDP alone or as part of the novel therapies proposed in the treatment of microbial infections and cancer. PMID:26062132

  16. Chemokine-Derived Peptides: Novel Antimicrobial and Antineoplasic Agents

    Directory of Open Access Journals (Sweden)

    Julio Valdivia-Silva

    2015-06-01

    Full Text Available Chemokines are a burgeoning family of chemotactic cytokines displaying a broad array of functions such as regulation of homeostatic leukocyte traffic and development, as well as activating the innate immune system. Their role in controlling early and late inflammatory stages is now well recognized. An improper balance either in chemokine synthesis or chemokine receptor expression contributes to various pathological disorders making chemokines and their receptors a useful therapeutic target. Research in this area is progressing rapidly, and development of novel agents based on chemokine/ chemokine receptors antagonist functions are emerging as attractive alternative drugs. Some of these novel agents include generation of chemokine-derived peptides (CDP with potential agonist and antagonist effects on inflammation, cancer and against bacterial infections. CDP have been generated mainly from N- and C-terminus chemokine sequences with subsequent modifications such as truncations or elongations. In this review, we present a glimpse of the different pharmacological actions reported for CDP and our current understanding regarding the potential use of CDP alone or as part of the novel therapies proposed in the treatment of microbial infections and cancer.

  17. The atypical chemokine receptor D6 contributes to the development of experimental colitis1

    OpenAIRE

    Bordon, Yvonne; Hansell, Chris A H; Sester, David P; Clarke, Mairi; Mowat, Allan McI; Nibbs, Robert J B

    2009-01-01

    Pro-inflammatory CC chemokines control leukocyte recruitment and function during inflammation by engaging chemokine receptors expressed on circulating leukocytes. The D6 chemokine receptor can bind several of these chemokines but appears unable to couple to signal transduction pathways or direct cell migration. Instead, D6 has been proposed to act as a chemokine scavenger, removing pro-inflammatory chemokines to dampen leukocyte responses. In this report, we have examined the role of D6 in th...

  18. Production of Recombinant Chemokines and Validation of Refolding.

    Science.gov (United States)

    Veldkamp, Christopher T; Koplinski, Chad A; Jensen, Davin R; Peterson, Francis C; Smits, Kaitlin M; Smith, Brittney L; Johnson, Scott K; Lettieri, Christina; Buchholz, Wallace G; Solheim, Joyce C; Volkman, Brian F

    2016-01-01

    The diverse roles of chemokines in normal immune function and many human diseases have motivated numerous investigations into the structure and function of this family of proteins. Recombinant chemokines are often used to study how chemokines coordinate the trafficking of immune cells in various biological contexts. A reliable source of biologically active protein is vital for any in vitro or in vivo functional analysis. In this chapter, we describe a general method for the production of recombinant chemokines and robust techniques for efficient refolding that ensure consistently high biological activity. Considerations for initiating development of protocols consistent with Current Good Manufacturing Practices (cGMPs) to produce biologically active chemokines suitable for use in clinical trials are also discussed. PMID:26921961

  19. Differential Chemokine Signature between Human Preadipocytes and Adipocytes

    Science.gov (United States)

    Ignacio, Rosa Mistica C.; Gibbs, Carla R.; Lee, Eun-Sook

    2016-01-01

    Obesity is characterized as an accumulation of adipose tissue mass represented by chronic, low-grade inflammation. Obesity-derived inflammation involves chemokines as important regulators contributing to the pathophysiology of obesity-related diseases such as cardiovascular disease, diabetes and some cancers. The obesity-driven chemokine network is poorly understood. Here, we identified the profiles of chemokine signature between human preadipocytes and adipocytes, using PCR arrays and qRT-PCR. Both preadipocytes and adipocytes showed absent or low levels in chemokine receptors in spite of some changes. On the other hand, the chemokine levels of CCL2, CCL7-8, CCL11, CXCL1-3, CXCL6 and CXCL10-11 were dominantly expressed in preadipocytes compared to adipocytes. Interestingly, CXCL14 was the most dominant chemokine expressed in adipocytes compared to preadipocytes. Moreover, there is significantly higher protein level of CXCL14 in conditioned media from adipocytes. In addition, we analyzed the data of the chemokine signatures in adipocytes obtained from healthy lean and obese postmenopausal women based on Gene Expression Omnibus (GEO) dataset. Adipocytes from obese individuals had significantly higher levels in chemokine signature as follows: CCL2, CCL13, CCL18-19, CCL23, CCL26, CXCL1, CXCL3 and CXCL14, as compared to those from lean ones. Also, among the chemokine networks, CXCL14 appeared to be the highest levels in adipocytes from both lean and obese women. Taken together, these results identify CXCL14 as an important chemokine induced during adipogenesis, requiring further research elucidating its potential therapeutic benefits in obesity. PMID:27340388

  20. Differential Chemokine Signature between Human Preadipocytes and Adipocytes.

    Science.gov (United States)

    Ignacio, Rosa Mistica C; Gibbs, Carla R; Lee, Eun-Sook; Son, Deok-Soo

    2016-06-01

    Obesity is characterized as an accumulation of adipose tissue mass represented by chronic, low-grade inflammation. Obesity-derived inflammation involves chemokines as important regulators contributing to the pathophysiology of obesity-related diseases such as cardiovascular disease, diabetes and some cancers. The obesity-driven chemokine network is poorly understood. Here, we identified the profiles of chemokine signature between human preadipocytes and adipocytes, using PCR arrays and qRT-PCR. Both preadipocytes and adipocytes showed absent or low levels in chemokine receptors in spite of some changes. On the other hand, the chemokine levels of CCL2, CCL7-8, CCL11, CXCL1-3, CXCL6 and CXCL10-11 were dominantly expressed in preadipocytes compared to adipocytes. Interestingly, CXCL14 was the most dominant chemokine expressed in adipocytes compared to preadipocytes. Moreover, there is significantly higher protein level of CXCL14 in conditioned media from adipocytes. In addition, we analyzed the data of the chemokine signatures in adipocytes obtained from healthy lean and obese postmenopausal women based on Gene Expression Omnibus (GEO) dataset. Adipocytes from obese individuals had significantly higher levels in chemokine signature as follows: CCL2, CCL13, CCL18-19, CCL23, CCL26, CXCL1, CXCL3 and CXCL14, as compared to those from lean ones. Also, among the chemokine networks, CXCL14 appeared to be the highest levels in adipocytes from both lean and obese women. Taken together, these results identify CXCL14 as an important chemokine induced during adipogenesis, requiring further research elucidating its potential therapeutic benefits in obesity. PMID:27340388

  1. Understanding stress-induced immunosuppression: exploration of cytokine and chemokine gene profiles in chicken peripheral leukocytes.

    Science.gov (United States)

    Shini, S; Huff, G R; Shini, A; Kaiser, P

    2010-04-01

    At present, the poultry meat and egg industry has gained a lot of ground, being viewed as a provider of a healthy alternative to red meat and other protein sources. If this trend is to be maintained, solutions must be found to improve resistance of chickens to disease, which often is weakened by stressful conditions. In poultry, stress-induced immunosuppression is manifested by failures in vaccination and increased morbidity and mortality of flocks. Currently, several modern cellular and molecular approaches are being used to explore the status of the immune system during stress and disease. It is likely that these new techniques will lead to the development of new strategies for preventing and controlling immunosuppression in poultry. Using quantitative reverse transcription-PCR assays, a broad spectrum of cytokine, chemokine, and their receptor genes can be quantified in birds and then be used as markers to assess the effects of stress on the immune system. Currently, we are investigating immune and endocrine interactions in the chicken, in particular the cells and molecules that are known to be involved in such interactions in mammals. We have evaluated the effects of corticosterone administration in drinking water on peripheral lymphocyte and heterophil cytokine and chemokine gene profiles. In particular, there seems to be effects on cytokine and chemokine mRNA expression levels in both lymphocytes and heterophils, especially expression of the proinflammatory cytokines interleukin (IL)-1beta, IL-6, and IL-18 and chemokines C-C motif, ligand 1 inflammatory (CCLi1); C-C motif, ligand 2 inflammatory (CCLi2); C-C motif, ligand 5 (CCL5); C-C motif, ligand 16 (CCL16); C-X-C motif ligand 1 inflammatory (CXCLi1); and C-X-C motif ligand 2 inflammatory (CXCLi2), which are initially upregulated and are potentially involved in modulating the adaptive immune response. A chronic treatment with corticosterone downregulates proinflammatory cytokines and chemokines, suggesting

  2. Virally encoded chemokines and chemokine receptors in the role of viral infections

    DEFF Research Database (Denmark)

    Holst, Peter J; Lüttichau, Hans R; Schwartz, Thue W;

    2003-01-01

    Large DNA viruses such as pox- and in particular herpesviruses are notorious in their ability to evade the immune system and to be maintained in the general population. Based on the accumulated knowledge reviewed in this study it is evident that important mechanisms of these actions are the acqui......Large DNA viruses such as pox- and in particular herpesviruses are notorious in their ability to evade the immune system and to be maintained in the general population. Based on the accumulated knowledge reviewed in this study it is evident that important mechanisms of these actions...... are the acquisition and modification of host-encoded chemokines and chemokine receptors. The described viral molecules leave nothing to chance and have thoroughly and efficiently corrupted the host immune system. Through this process viruses have identified key molecules in antiviral responses by their inhibition...... for antiviral therapies have been provided by UL33, UL78 and in particular ORF74 and the chances are that many more will follow. In HHV8 vMIP-2 and the chemokine-binding proteins potent anti-inflammatory agents have been provided. These have already had their potential demonstrated in animal models and may...

  3. The Role of Chemokines in Breast Cancer Pathology and Its Possible Use as Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    M. Isabel Palacios-Arreola

    2014-01-01

    Full Text Available Chemokines are small proteins that primarily regulate the traffic of leukocytes under homeostatic conditions and during specific immune responses. The chemokine-chemokine receptor system comprises almost 50 chemokines and approximately 20 chemokine receptors; thus, there is no unique ligand for each receptor and the binding of different chemokines to the same receptor might have disparate effects. Complicating the system further, these effects depend on the cellular milieu. In cancer, although chemokines are associated primarily with the generation of a protumoral microenvironment and organ-directed metastasis, they also mediate other phenomena related to disease progression, such as angiogenesis and even chemoresistance. Therefore, the chemokine system is becoming a target in cancer therapeutics. We review the emerging data and correlations between chemokines/chemokine receptors and breast cancer, their implications in cancer progression, and possible therapeutic strategies that exploit the chemokine system.

  4. Disulfide Trapping for Modeling and Structure Determination of Receptor:Chemokine Complexes

    Science.gov (United States)

    Kufareva, Irina; Gustavsson, Martin; Holden, Lauren G.; Qin, Ling; Zheng, Yi; Handel, Tracy M.

    2016-01-01

    Despite the recent breakthrough advances in GPCR crystallography, structure determination of protein-protein complexes involving chemokine receptors and their endogenous chemokine ligands remains challenging. Here we describe disulfide trapping, a methodology for generating irreversible covalent binary protein complexes from unbound protein partners by introducing two cysteine residues, one per interaction partner, at selected positions within their interaction interface. Disulfide trapping can serve at least two distinct purposes: (i) stabilization of the complex to assist structural studies, and/or (ii) determination of pairwise residue proximities to guide molecular modeling. Methods for characterization of disulfide-trapped complexes are described and evaluated in terms of throughput, sensitivity, and specificity towards the most energetically favorable cross-links. Due to abundance of native disulfide bonds at receptor:chemokine interfaces, disulfide trapping of their complexes can be associated with intramolecular disulfide shuffling and result in misfolding of the component proteins; because of this, evidence from several experiments is typically needed to firmly establish a positive disulfide crosslink. An optimal pipeline that maximizes throughput and minimizes time and costs by early triage of unsuccessful candidate constructs is proposed. PMID:26921956

  5. A Role for the Chemokine Receptor CCR6 in Mammalian Sperm Motility and Chemotaxis

    Science.gov (United States)

    Caballero-Campo, Pedro; Buffone, Mariano G.; Benencia, Fabian; Conejo-García, José R.; Rinaudo, Paolo F.; Gerton, George L.

    2013-01-01

    Although recent evidence indicates that several chemokines and defensins, well-known as inflammatory mediators, are expressed in the male and female reproductive tracts, the location and functional significance of chemokine networks in sperm physiology and sperm reproductive tract interactions are poorly understood. To address this deficiency in our knowledge, we examined the expression and function in sperm of CCR6, a receptor common to several chemoattractant peptides, and screened several reproductive tract fluids for the presence of specific ligands. CCR6 protein is present in mouse and human sperm and mainly localized in the sperm tail with other minor patterns in sperm from mice (neck and acrosomal region) and men (neck and midpiece regions). As expected from the protein immunoblotting and immunofluorescence results, mouse Ccr6 mRNA is expressed in the testis. Furthermore, the Defb29 mRNA encoding the CCR6 ligand, β-defensin DEFB29, is expressed at high levels in the epididymis. As determined by protein chip analysis, several chemokines (including some that act through CCR6, such as CCL20/MIP-3α (formerly Macrophage Inflammatory Protein 3α) and protein hormones were present in human follicular fluid, endometrial secretions, and seminal plasma. In functional chemotaxis assays, capacitated human sperm exhibited a directional movement towards CCL20, and displayed modifications in motility parameters. Our data indicate that chemokine ligand/receptor interactions in the male and female genital tracts promote sperm motility and chemotaxis under non-inflammatory conditions. Therefore, some of the physiological reactions mediated by CCR6 ligands in male reproduction extend beyond a pro-inflammatory response and might find application in clinical reproduction and/or contraception. PMID:23765988

  6. Det chemokine system - en vigtig regulator af angiogenese i sundhed og sygdom

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Schwartz, Thue W

    2004-01-01

    vigtig funktion chemokine systemet. Den chemokine-medieret regulering af angiogenese er meget sofistikeret og finjusteres, og omfatter pro-angiogene chemokines, for eksempel, CXCL8/IL8 interagere med CXCR2 receptoren, og anti-angiogene (dvs. angiostatic) chemokines, for eksempel, CXCL10/IP10...

  7. Chemokines and inflammation in heart disease: adaptive or maladaptive?

    OpenAIRE

    Tarzami, Sima T.

    2011-01-01

    Heart disease is not only the leading cause of death, disability, and healthcare expense in the US, but also the leading cause of death worldwide. Therefore, treatments to lessen ischemia-related cardiac damage could affect a broad swath of the population and have significant health and fiscal impacts. Cardiac dysfunction has been associated with elevated circulating chemokine levels, both in animals and humans. Most studies in this area have focused on chemokine expression as a prominent fea...

  8. Solution structure of CXCL5--a novel chemokine and adipokine implicated in inflammation and obesity.

    Directory of Open Access Journals (Sweden)

    Krishna Mohan Sepuru

    Full Text Available The chemokine CXCL5 is selectively expressed in highly specialized cells such as epithelial type II cells in the lung and white adipose tissue macrophages in muscle, where it mediates diverse functions from combating microbial infections by regulating neutrophil trafficking to promoting obesity by inhibiting insulin signaling. Currently very little is known regarding the structural basis of how CXCL5 mediates its novel functions. Towards this missing knowledge, we have solved the solution structure of the CXCL5 dimer by NMR spectroscopy. CXCL5 is a member of a subset of seven CXCR2-activating chemokines (CAC that are characterized by the highly conserved ELR motif in the N-terminal tail. The structure shows that CXCL5 adopts the typical chemokine fold, but also reveals several distinct differences in the 30 s loop and N-terminal residues; not surprisingly, crosstalk between N-terminal and 30 s loop residues have been implicated as a major determinant of receptor activity. CAC function also involves binding to highly sulfated glycosaminoglycans (GAG, and the CXCL5 structure reveals a distinct distribution of positively charged residues, suggesting that differences in GAG interactions also influence function. The availability of the structure should now facilitate the design of experiments to better understand the molecular basis of various CXCL5 functions, and also serve as a template for the design of inhibitors for use in a clinical setting.

  9. Emerging Concepts and Approaches for Chemokine-Receptor Drug Discovery

    Science.gov (United States)

    O’Hayre, Morgan; Salanga, Catherina L.; Handel, Tracy M.; Hamel, Damon J.

    2010-01-01

    Importance of the field Chemokine receptors are G protein-coupled receptors (GPCRs) most noted for their role in cell migration. However, inappropriate utilization or regulation of these receptors is implicated in many inflammatory diseases, cancer and HIV, making them important drug targets. Areas covered in this review Allostery, oligomerization, and ligand bias are presented as they pertain to chemokine receptors and their associated pathologies. Specific examples of each are described from the recent literature and their implications are discussed in terms of drug discovery efforts targeting chemokine receptors. What the reader will gain Insight into the expanding view of the multitude of pharmacological variables that need to be considered or that may be exploited in chemokine receptor drug discovery. Take home message Since 2007, two drugs targeting chemokine receptors have been approved by the FDA, Maraviroc for preventing HIV infection and Mozobil™ for hematopoietic stem cell mobilization. While these successes permit optimism for chemokine receptors as drug targets, only recently has the complexity of this system begun to be appreciated. The concepts of allosteric inhibitors, biased ligands and functional selectivity raise the possibility that drugs with precisely-defined properties can be developed. Other complexities such as receptor oligomerization and tissue-specific functional states of receptors also offer opportunities for increased target and response specificity, although it will be more challenging to translate these ideas into approved therapeutics compared to traditional approaches. PMID:21132095

  10. Airway epithelial cell PPARγ modulates cigarette smoke-induced chemokine expression and emphysema susceptibility in mice.

    Science.gov (United States)

    Solleti, Siva Kumar; Simon, Dawn M; Srisuma, Sorachai; Arikan, Meltem C; Bhattacharya, Soumyaroop; Rangasamy, Tirumalai; Bijli, Kaiser M; Rahman, Arshad; Crossno, Joseph T; Shapiro, Steven D; Mariani, Thomas J

    2015-08-01

    Chronic obstructive pulmonary disease (COPD) is a highly prevalent, chronic inflammatory lung disease with limited existing therapeutic options. While modulation of peroxisome proliferator-activating receptor (PPAR)-γ activity can modify inflammatory responses in several models of lung injury, the relevance of the PPARG pathway in COPD pathogenesis has not been previously explored. Mice lacking Pparg specifically in airway epithelial cells displayed increased susceptibility to chronic cigarette smoke (CS)-induced emphysema, with excessive macrophage accumulation associated with increased expression of chemokines, Ccl5, Cxcl10, and Cxcl15. Conversely, treatment of mice with a pharmacological PPARγ activator attenuated Cxcl10 and Cxcl15 expression and macrophage accumulation in response to CS. In vitro, CS increased lung epithelial cell chemokine expression in a PPARγ activation-dependent fashion. The ability of PPARγ to regulate CS-induced chemokine expression in vitro was not specifically associated with peroxisome proliferator response element (PPRE)-mediated transactivation activity but was correlated with PPARγ-mediated transrepression of NF-κB activity. Pharmacological or genetic activation of PPARγ activity abrogated CS-dependent induction of NF-κB activity. Regulation of NF-κB activity involved direct PPARγ-NF-κB interaction and PPARγ-mediated effects on IKK activation, IκBα degradation, and nuclear translocation of p65. Our data indicate that PPARG represents a disease-relevant pathophysiological and pharmacological target in COPD. Its activation state likely contributes to NF-κB-dependent, CS-induced chemokine-mediated regulation of inflammatory cell accumulation. PMID:26024894

  11. Human monocyte-derived dendritic cells expressing both chemotactic cytokines IL-8, MCP-1, RANTES and their receptors,and their selective migration to these chemokines

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective To characterize the mRNA expression of CXC chemokine IL-8, CC chemokine monocyte chemothractant protein-1 (MCP-1) and regulated on activation,normal T cell expressed and secreted (RANTES), and a newly defined DC chemokine DC- CK1 as well as the expression of IL-8 receptor, MCP-1 receptor and RANTES receptor in human monocyte derived dendritic cells (MoDCs).The migratory responsiveness of MoDC to IL-8, MCP-1 and RANTES was alsso studied. Methods In vitro generated MoDCs were obtained by differentiating monocytes in the presence of GM-CSF and IL-4 for 5 days. The time course of RNA expression was analyzed by RT-PCR and migratoly ability was assessed by a micromultiwell chemotaxis chamber assay. Results IL-8, MCP-1, RANTES and their corres ponding receptors were consistently expressed in MoDCs. DC-CK-1 expression was detectable efter 48 hours of differentiation. MoDC selectively migrated in response to MCP-1 and RANTES but not to IL-8 though transcripts of IL-8 receptor were present. Conclusion Because the capacity of dendritic cells to initiate immune responses depends on their specialized migratory and tissue homing properties, the expression of chemokines and their receptors along with the migratory responsiveness to chemokines of MoDC in our study suggests a potential role of chemokines in the interaction between dendritic cells and T cells and the induction of immune responses.

  12. CXCL12 chemokine and GABA neurotransmitter systems crosstalk and their putative roles

    Directory of Open Access Journals (Sweden)

    Guyon eAlice

    2014-04-01

    Full Text Available Since CXCL12 and its receptors, CXCR4 and CXCR7, have been found in the brain, the role of this chemokine has been expanded from chemoattractant in the immune system to neuromodulatory in the brain. Several pieces of evidence suggest that this chemokine system could crosstalk with the GABAergic system, known to be the main inhibitory neurotransmitter system in the brain. Indeed, GABA and CXCL12 as well as their receptors are colocalized in many cell types including neurons and there are several examples in which these two systems interact. Several mechanisms can be proposed to explain how these systems interact, including receptor-receptor interactions, crosstalk at the level of second messenger cascades, or direct pharmacological interactions, as GABA and GABAB receptor agonists/antagonists have been shown to be allosteric modulators of CXCR4.The interplay between CXCL12/CXCR4-CXCR7 and GABA/GABAA-GABAB receptors systems could have many physiological implications in neurotransmission, cancer and inflammation. In addition, the GABAB agonist baclofen is currently used in medicine to treat spasticity in patients with spinal cord injury, cerebral palsy, traumatic brain injury, multiple sclerosis and other disorders. More recently it has also been used in the treatment of alcohol dependence and withdrawal. The allosteric effects of this agent on CXCR4 could contribute to these beneficial effects or at the opposite, to its side effects.

  13. Stoichiometry and geometry of the CXC chemokine receptor 4 complex with CXC ligand 12: Molecular modeling and experimental validation

    Science.gov (United States)

    Kufareva, Irina; Stephens, Bryan S.; Holden, Lauren G.; Qin, Ling; Zhao, Chunxia; Kawamura, Tetsuya; Abagyan, Ruben; Handel, Tracy M.

    2014-01-01

    Chemokines and their receptors regulate cell migration during development, immune system function, and in inflammatory diseases, making them important therapeutic targets. Nevertheless, the structural basis of receptor:chemokine interaction is poorly understood. Adding to the complexity of the problem is the persistently dimeric behavior of receptors observed in cell-based studies, which in combination with structural and mutagenesis data, suggest several possibilities for receptor:chemokine complex stoichiometry. In this study, a combination of computational, functional, and biophysical approaches was used to elucidate the stoichiometry and geometry of the interaction between the CXC-type chemokine receptor 4 (CXCR4) and its ligand CXCL12. First, relevance and feasibility of a 2:1 stoichiometry hypothesis was probed using functional complementation experiments with multiple pairs of complementary nonfunctional CXCR4 mutants. Next, the importance of dimers of WT CXCR4 was explored using the strategy of dimer dilution, where WT receptor dimerization is disrupted by increasing expression of nonfunctional CXCR4 mutants. The results of these experiments were supportive of a 1:1 stoichiometry, although the latter could not simultaneously reconcile existing structural and mutagenesis data. To resolve the contradiction, cysteine trapping experiments were used to derive residue proximity constraints that enabled construction of a validated 1:1 receptor:chemokine model, consistent with the paradigmatic two-site hypothesis of receptor activation. The observation of a 1:1 stoichiometry is in line with accumulating evidence supporting monomers as minimal functional units of G protein-coupled receptors, and suggests transmission of conformational changes across the dimer interface as the most probable mechanism of altered signaling by receptor heterodimers. PMID:25468967

  14. Diverging mechanisms of activation of chemokine receptors revealed by novel chemokine agonists.

    Directory of Open Access Journals (Sweden)

    Jose Sarmiento

    Full Text Available CXCL8/interleukin-8 is a pro-inflammatory chemokine that triggers pleiotropic responses, including inflammation, angiogenesis, wound healing and tumorigenesis. We engineered the first selective CXCR1 agonists on the basis of residue substitutions in the conserved ELR triad and CXC motif of CXCL8. Our data reveal that the molecular mechanisms of activation of CXCR1 and CXCR2 are distinct: the N-loop of CXCL8 is the major determinant for CXCR1 activation, whereas the N-terminus of CXCL8 (ELR and CXC is essential for CXCR2 activation. We also found that activation of CXCR1 cross-desensitized CXCR2 responses in human neutrophils co-expressing both receptors, indicating that these novel CXCR1 agonists represent a new class of anti-inflammatory agents. Further, these selective CXCR1 agonists will aid at elucidating the functional significance of CXCR1 in vivo under pathophysiological conditions.

  15. Cytokines, Chemokines, and Chemokine Receptors Quantitative Expressions in Patients with Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Somayeh Rezaeifard

    2015-05-01

    Full Text Available Background: Cytokines, chemokines, and chemokine receptors regulate the proliferation and survival of tumor cells, angiogenesis, and metastasis to other organs. This network of ligands and receptors has been used in molecular targeting of cancer. Methods: We compared the mRNA expression of CXCR3, CXCL-10, CXCR4, CXCL-12, IL-4, and IL-10 in tissues of benign and malignant ovarian tumors by qRT-PCR method and evaluated serum IL-10 and CA-125 content of these patients by ELISA during one year. Results: Our result showed a trend toward a higher expression of CXCR4 in malignant ovarian tissues compared with the benign ovarian cysts (P>0.05. However, SDF-1, IP-10, IL-4, CXCR3, and IL-10 had a lower trend in mRNA expression in malignant ovarian tissues compared to the benign cyst tissues. Except for IL-4 (P=0.01 and SDF-1 (P=0.02, the data for other factors were not statistically significant. A trend toward higher concentration of IL-10 was observed in the serum of ovarian cancer patients compared to those with benign cysts; however, the difference was not significant. CA-125 concentration in the serum of ovarian cancer patients was higher than that of benign cyst patients (P=0.05. Conclusion: According to results obtained, we hypothesize that the lower expression of SDF-1 in malignant tissues may have an important role in ovarian tumor growth. However, this hypothesis requires more investigation. Higher levels of CA125 and IL-10 in the serum of patients might indicate that the combination of these biomarkers could be used for distinguishing patients with ovarian cancer from those with benign cysts.

  16. Cytokines and chemokines in neuromyelitis optica: pathogenetic and therapeutic implications.

    Science.gov (United States)

    Uzawa, Akiyuki; Mori, Masahiro; Masahiro, Mori; Kuwabara, Satoshi

    2014-01-01

    Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extensive transverse myelitis. The discovery of an NMO-specific autoantibody to the aquaporin-4 (AQP4) water channel has improved knowledge of NMO pathogenesis. Many studies have focused on inflammatory and pathological biomarkers of NMO, including cytokines and chemokines. Increased concentrations of T helper (Th)17- and Th2-related cytokines and chemokines may be essential factors for developing NMO inflammatory lesions. For example, interleukin-6 could play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti-AQP4 antibody in peripheral circulation and in the enhancement of inflammation in the central nervous system. Therefore, assessment of these useful biomarkers may become a supportive criterion for diagnosing NMO. Significant advances in the understanding of NMO pathogenesis will lead to the development of novel treatment strategies. This review focuses on the current advances in NMO immunological research, particularly that of cytokines and chemokines.

  17. Human astrocytes: secretome profiles of cytokines and chemokines.

    Directory of Open Access Journals (Sweden)

    Sung S Choi

    Full Text Available Astrocytes play a key role in maintenance of neuronal functions in the central nervous system by producing various cytokines, chemokines, and growth factors, which act as a molecular coordinator of neuron-glia communication. At the site of neuroinflammation, astrocyte-derived cytokines and chemokines play both neuroprotective and neurotoxic roles in brain lesions of human neurological diseases. At present, the comprehensive profile of human astrocyte-derived cytokines and chemokines during inflammation remains to be fully characterized. We investigated the cytokine secretome profile of highly purified human astrocytes by using a protein microarray. Non-stimulated human astrocytes in culture expressed eight cytokines, including G-CSF, GM-CSF, GROα (CXCL1, IL-6, IL-8 (CXCL8, MCP-1 (CCL2, MIF and Serpin E1. Following stimulation with IL-1β and TNF-α, activated astrocytes newly produced IL-1β, IL-1ra, TNF-α, IP-10 (CXCL10, MIP-1α (CCL3 and RANTES (CCL5, in addition to the induction of sICAM-1 and complement component 5. Database search indicated that most of cytokines and chemokines produced by non-stimulated and activated astrocytes are direct targets of the transcription factor NF-kB. These results indicated that cultured human astrocytes express a distinct set of NF-kB-target cytokines and chemokines in resting and activated conditions, suggesting that the NF-kB signaling pathway differentially regulates gene expression of cytokines and chemokines in human astrocytes under physiological and inflammatory conditions.

  18. Generating substrate bound functional chemokine gradients in vitro

    DEFF Research Database (Denmark)

    Hjortø, Gertrud Malene; Hansen, Morten; Larsen, Niels Bent;

    2009-01-01

    Microcontact printing (mCP) is employed to generate discontinuous microscale gradients of active fractalkine, a chemokine expressed by endothelial cells near sites of inflammation where it is believed to form concentration gradients descending away from the inflamed area. In vivo, fractalkine...... is a transmembrane molecule extending its chemokine domain into the vascular lumen. Substrate bound in vitro gradients may thus closely resemble in vivo conditions. Direct mCP of sensitive proteins like fractalkine may cause partial protein denaturation and will not ensure correct orientation of the biologically...

  19. Discovery of indole inhibitors of chemokine receptor 9 (CCR9).

    Science.gov (United States)

    Pandya, Bhaumik A; Baber, Christian; Chan, Audrey; Chamberlain, Brian; Chandonnet, Haoqun; Goss, Jennifer; Hopper, Timothy; Lippa, Blaise; Poutsiaka, Katherine; Romero, Jan; Stucka, Sabrina; Varoglu, Mustafa; Zhang, Jing; Zhang, Xin

    2016-07-15

    Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients. Herein we describe the evolution of a high content screening hit (1) into potent inhibitors of CCR9, such as azaindole 12. PMID:27256913

  20. Receptor expression and responsiveness of human peripheral blood mononuclear cells to a human cytomegalovirus encoded CC chemokine

    Directory of Open Access Journals (Sweden)

    Qi Zheng

    2015-08-01

    Full Text Available Human cytomegalovirus is a ubiquitous pathogen that infects the majority of the world's population. After long period of time co-evolving with human being, this pathogen has developed several strategies to evade host immune surveillance. One of the major trick is encoding homologous to those of the host organism or stealing host cellular genes that have significant functions in immune system. To date, we have found several viral immune analogous which include G protein coupled receptor, class I major histocompatibility complex and chemokine. Chemokine is a small group of molecules which is defined by the presence of four cysteines in highly conserved region. The four kinds of chemokines (C, CC, CXC, and CX3C are classified based on the arrangement of 1 or 2 N-terminal cysteine residues. UL128 protein is one of the analogous that encoded by human cytomegalovirus that has similar amino acid sequences to the human CC chemokine. It has been proved to be one of the essential particles that involved in human cytomegalovirus entry into epithelial/endothelial cells as well as macrophages. It is also the target of potent neutralizing antibodies in human cytomegalovirus-seropositive individuals. We had demonstrated the chemotactic trait of UL128 protein in our previous study. Recombinant UL128 in vitrohas the ability to attract monocytes to the infection region and enhances peripheral blood mononuclear cell proliferation by activating the MAPK/ERK signaling pathway. However, the way that this viral encoded chemokine interacting with peripheral blood mononuclear cells and the detailed mechanism that involving the virus entry into host cells keeps unknown. Here we performed in vitroinvestigation into the effects of UL128 protein on peripheral blood mononuclear cell's activation and receptor binding, which may help us further understand the immunomodulatory function of UL128 protein as well as human cytomegalovirus diffusion mechanism.

  1. Tumor infiltration by chemokine receptor 7 (CCR7)+ T-lymphocytes is a favorable prognostic factor in metastatic colorectal cancer

    OpenAIRE

    Correale, Pierpaolo; Rotundo, Maria Saveria; Botta, Cirino; del Vecchio, Maria Teresa; Tassone, Pierfrancesco; Tagliaferri, Pierosandro

    2012-01-01

    The immune interactions occurring within the tumor microenvironment have a critical role in determining the outcome of colorectal cancer patients. We carried-out an immunohistochemical analysis of tumor infiltrating T-lymphocytes expressing chemokine receptor 7 (CCR7) in a series of colorectal cancer patients enrolled in a prospective clinical trial. We demonstrated that a high tumor infiltration score of this lymphocyte subset is predictive of longer progression free survival and overall sur...

  2. Identification of the bacterial protein FtsX as a unique target of chemokine-mediated antimicrobial activity against Bacillus anthracis.

    Science.gov (United States)

    Crawford, Matthew A; Lowe, David E; Fisher, Debra J; Stibitz, Scott; Plaut, Roger D; Beaber, John W; Zemansky, Jason; Mehrad, Borna; Glomski, Ian J; Strieter, Robert M; Hughes, Molly A

    2011-10-11

    Chemokines are a family of chemotactic cytokines that function in host defense by orchestrating cellular movement during infection. In addition to this function, many chemokines have also been found to mediate the direct killing of a range of pathogenic microorganisms through an as-yet-undefined mechanism. As an understanding of the molecular mechanism and microbial targets of chemokine-mediated antimicrobial activity is likely to lead to the identification of unique, broad-spectrum therapeutic targets for effectively treating infection, we sought to investigate the mechanism by which the chemokine CXCL10 mediates bactericidal activity against the Gram-positive bacterium Bacillus anthracis, the causative agent of anthrax. Here, we report that disruption of the gene ftsX, which encodes the transmembrane domain of a putative ATP-binding cassette transporter, affords resistance to CXCL10-mediated antimicrobial effects against vegetative B. anthracis bacilli. Furthermore, we demonstrate that in the absence of FtsX, CXCL10 is unable to localize to its presumed site of action at the bacterial cell membrane, suggesting that chemokines interact with specific, identifiable bacterial components to mediate direct microbial killing. These findings provide unique insight into the mechanism of CXCL10-mediated bactericidal activity and establish, to our knowledge, the first description of a bacterial component critically involved in the ability of host chemokines to target and kill a bacterial pathogen. These observations also support the notion of chemokine-mediated antimicrobial activity as an important foundation for the development of innovative therapeutic strategies for treating infections caused by pathogenic, potentially multidrug-resistant microorganisms.

  3. IFN-gamma shapes immune invasion of the central nervous system via regulation of chemokines

    DEFF Research Database (Denmark)

    Tran, E H; Prince, E N; Owens, T

    2000-01-01

    Dynamic interplay between cytokines and chemokines directs trafficking of leukocyte subpopulations to tissues in autoimmune inflammation. We have examined the role of IFN-gamma in directing chemokine production and leukocyte infiltration to the CNS in experimental autoimmune encephalomyelitis (EA...

  4. Immunological assays for chemokine detection in in-vitro culture of CNS cells

    OpenAIRE

    Mahajan Supriya D.; Schwartz Stanley A; Nair Madhavan P.N.

    2003-01-01

    Herein we review the various methods currently in use for determining the expression of chemokines by CNS cells in vitro. Chemokine detection assays are used in conjuction with one another to provide a comprehensive, biologically relevant assessment of the chemokines which is necessary for correct data interpretation of a specific observed biological effect. The methods described include bioassays for soluble chemokine receptors, RNA extraction, RT-PCR, Real - time quantitative PCR, gene arra...

  5. Adaptive Gene Loss? Tracing Back the Pseudogenization of the Rabbit CCL8 Chemokine.

    Science.gov (United States)

    van der Loo, Wessel; Magalhaes, Maria João; de Matos, Ana Lemos; Abrantes, Joana; Yamada, Fumio; Esteves, Pedro J

    2016-08-01

    Studies of the process of pseudogenization have widened our understanding of adaptive evolutionary change. In Rabbit, an alteration at the second extra-cellular loop of the CCR5 chemokine receptor was found to be associated with the pseudogenization of one of its prime ligands, the chemokine CCL8. This relationship has raised questions about the existence of a causal link between both events, which would imply adaptive gene loss. This hypothesis is evaluated here by tracing back the history of the genetic modifications underlying the chemokine pseudogenization. The obtained data indicate that mutations at receptor and ligand genes occurred after the lineage split of New World Leporids versus Old World Leporids and prior to the generic split of the of Old World species studied, which occurred an estimated 8-9 million years ago. More important, they revealed the emergence, before this zoographical split, of a "slippery" nucleotide motif (CCCCGGG) at the 3' region of CCL8-exon2. Such motives are liable of generating +1G or -1G frameshifts, which could, however, be overcome by "translesion" synthesis or somatic reversion. The CCL8 pseudogenization in the Old World lineage was apparently initiated by three synapomorphic point mutations at the exon2-intron2 boundary which provide at short range premature terminating codons, independently of the reading frame imposed by the slippery motif. The presence of this motif in New World Leporids might allow verifying this scenario. The importance of CCL8-CCR5 signaling in parasite-host interaction would suggest that the CCL8 knock-out in Old World populations might be related to changes in pathogenic environment. PMID:27306379

  6. Metal complexes of pyridine-fused macrocyclic polyamines targeting the chemokine receptor CXCR4.

    Science.gov (United States)

    Hamal, Sunil; D'huys, Thomas; Rowley, William F; Vermeire, Kurt; Aquaro, Stefano; Frost, Brian J; Schols, Dominique; Bell, Thomas W

    2015-11-14

    The chemokine receptor CXCR4 acts as a key cell surface receptor in HIV infections, multiple forms of cancer, and various other pathologies, such as rheumatoid arthritis and asthma. Macrocyclic polyamines and their metal complexes are known to exert anti-HIV activity, many acting as HIV entry inhibitors by specifically binding to CXCR4. Three series of pyridopentaazacylopentadecanes, in which the pyridine ring is fused to zero, one, or two saturated six-membered rings, were synthesized by manganese(ii)-templated Schiff-base cyclization of triethylenetetramine with various dicarbonyl compounds. By evaluating these macrocyclic polyamines and their complexes with Mn(2+), Cu(2+), Fe(3+), and Zn(2+), we have discovered novel CXCR4-binding compounds. The MnCl2 complex of a new pentaazacyclopentadecane with one fused carbocyclic ring (11) was found to have the greatest potency as an antagonist of the chemokine receptor CXCR4 (IC50: 0.014 μM), as evidenced by inhibiting binding of CXCL12 to PBMCs (peripheral blood mononuclear cells). Consequently, this compound inhibits replication of the CXCR4-using (X4) HIV-1 strain NL4-3 in the TZM-bl cell line with an IC50 value of 0.52 μM and low cytotoxicity (CC50: >100 μM). In addition, 18 other compounds were evaluated for their interaction with CXCR4 via their ability to interfere with ligand chemokine binding and HIV entry and infection. Of these, the metal complexes of the two more hydrophobic series with one or two fused carbocyclic rings exhibited the greatest potency. The Zn(2+) complex 21 was among the most potent, showing that redox activity of the metal center is not associated with CXCR4 antagonist activity. PMID:26338723

  7. Regulation of inflammatory chemokine receptors on blood T cells associated to the circulating versus liver chemokines in dengue fever.

    Science.gov (United States)

    de-Oliveira-Pinto, Luzia Maria; Marinho, Cíntia Ferreira; Povoa, Tiago Fajardo; de Azeredo, Elzinandes Leal; de Souza, Luiza Assed; Barbosa, Luiza Damian Ribeiro; Motta-Castro, Ana Rita C; Alves, Ada M B; Ávila, Carlos André Lins; de Souza, Luiz José; da Cunha, Rivaldo Venâncio; Damasco, Paulo Vieira; Paes, Marciano Viana; Kubelka, Claire Fernandes

    2012-01-01

    Little is known about the role of chemokines/chemokines receptors on T cells in natural DENV infection. Patients from DENV-2 and -3- outbreaks were studied prospectively during the acute or convalescent phases. Expression of chemokine receptor and activation markers on lymphocyte subpopulations were determined by flow cytometry analysis, plasma chemokine ligands concentrations were measured by ELISA and quantification of CCL5/RANTES(+) cells in liver tissues from fatal dengue cases was performed by immunochemistry. In the acute DENV-infection, T-helper/T-cytotoxic type-1 cell (Th1/Tc1)-related CCR5 is significantly higher expressed on both CD4 and CD8 T cells. The Th1-related CXCR3 is up-regulated among CD4 T cells and Tc2-related CCR4 is up-regulated among CD8 T cells. In the convalescent phase, all chemokine receptor or chemokine ligand expression tends to reestablish control healthy levels. Increased CCL2/MCP-1 and CCL4/MIP-1β but decreased CCL5/RANTES levels were observed in DENV-patients during acute infection. Moreover, we showed an increased CD107a expression on CCR5 or CXCR3-expressing T cells and higher expression of CD29, CD44(HIGH) and CD127(LOW) markers on CCR4-expressing CD8 T cells in DENV-patients when compared to controls. Finally, liver from dengue fatal patients showed increased number of cells expressing CCL5/RANTES in three out of four cases compared to three death from a non-dengue patient. In conclusion, both Th1-related CCR5 and CXCR3 among CD4 T cells have a potential ability to exert cytotoxicity function. Moreover, Tc1-related CCR5 and Tc2-related CCR4 among CD8 T cells have a potential ability to exert effector function and migration based on cell markers evaluated. The CCR5 expression would be promoting an enhanced T cell recruitment into liver, a hypothesis that is corroborated by the CCL5/RANTES increase detected in hepatic tissue from dengue fatal cases. The balance between protective and pathogenic immune response mediated by

  8. Regulation of inflammatory chemokine receptors on blood T cells associated to the circulating versus liver chemokines in dengue fever.

    Directory of Open Access Journals (Sweden)

    Luzia Maria de-Oliveira-Pinto

    Full Text Available Little is known about the role of chemokines/chemokines receptors on T cells in natural DENV infection. Patients from DENV-2 and -3- outbreaks were studied prospectively during the acute or convalescent phases. Expression of chemokine receptor and activation markers on lymphocyte subpopulations were determined by flow cytometry analysis, plasma chemokine ligands concentrations were measured by ELISA and quantification of CCL5/RANTES(+ cells in liver tissues from fatal dengue cases was performed by immunochemistry. In the acute DENV-infection, T-helper/T-cytotoxic type-1 cell (Th1/Tc1-related CCR5 is significantly higher expressed on both CD4 and CD8 T cells. The Th1-related CXCR3 is up-regulated among CD4 T cells and Tc2-related CCR4 is up-regulated among CD8 T cells. In the convalescent phase, all chemokine receptor or chemokine ligand expression tends to reestablish control healthy levels. Increased CCL2/MCP-1 and CCL4/MIP-1β but decreased CCL5/RANTES levels were observed in DENV-patients during acute infection. Moreover, we showed an increased CD107a expression on CCR5 or CXCR3-expressing T cells and higher expression of CD29, CD44(HIGH and CD127(LOW markers on CCR4-expressing CD8 T cells in DENV-patients when compared to controls. Finally, liver from dengue fatal patients showed increased number of cells expressing CCL5/RANTES in three out of four cases compared to three death from a non-dengue patient. In conclusion, both Th1-related CCR5 and CXCR3 among CD4 T cells have a potential ability to exert cytotoxicity function. Moreover, Tc1-related CCR5 and Tc2-related CCR4 among CD8 T cells have a potential ability to exert effector function and migration based on cell markers evaluated. The CCR5 expression would be promoting an enhanced T cell recruitment into liver, a hypothesis that is corroborated by the CCL5/RANTES increase detected in hepatic tissue from dengue fatal cases. The balance between protective and pathogenic immune response

  9. Epithelial Anion Transport as Modulator of Chemokine Signaling

    Science.gov (United States)

    Schnúr, Andrea; Hegyi, Péter; Rousseau, Simon; Lukacs, Gergely L.; Veit, Guido

    2016-01-01

    The pivotal role of epithelial cells is to secrete and absorb ions and water in order to allow the formation of a luminal fluid compartment that is fundamental for the epithelial function as a barrier against environmental factors. Importantly, epithelial cells also take part in the innate immune system. As a first line of defense they detect pathogens and react by secreting and responding to chemokines and cytokines, thus aggravating immune responses or resolving inflammatory states. Loss of epithelial anion transport is well documented in a variety of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, pancreatitis, and cholestatic liver disease. Here we review the effect of aberrant anion secretion with focus on the release of inflammatory mediators by epithelial cells and discuss putative mechanisms linking these transport defects to the augmented epithelial release of chemokines and cytokines. These mechanisms may contribute to the excessive and persistent inflammation in many respiratory and gastrointestinal diseases. PMID:27382190

  10. Characterisation of SNP haplotype structure in chemokine and chemokine receptor genes using CEPH pedigrees and statistical estimation

    Directory of Open Access Journals (Sweden)

    Clark Vanessa J

    2004-03-01

    Full Text Available Abstract Chemokine signals and their cell-surface receptors are important modulators of HIV-1 disease and cancer. To aid future case/control association studies, aim to further characterise the haplotype structure of variation in chemokine and chemokine receptor genes. To perform haplotype analysis in a population-based association study, haplotypes must be determined by estimation, in the absence of family information or laboratory methods to establish phase. Here, test the accuracy of estimates of haplotype frequency and linkage disequilibrium by comparing estimated haplotypes generated with the expectation maximisation (EM algorithm to haplotypes determined from Centre d'Etude Polymorphisme Humain (CEPH pedigree data. To do this, they have characterised haplotypes comprising alleles at 11 biallelic loci in four chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2, which span 150 kb on chromosome 3p21, and haplotyes of nine biallelic loci in six chemokine genes [MCP-1(CCL2, Eotaxin(CCL11, RANTES(CCL5, MPIF-1(CCL23, PARC(CCL18 and MIP-1α(CCL3 ] on chromosome 17q11-12. Forty multi-generation CEPH families, totalling 489 individuals, were genotyped by the TaqMan 5'-nuclease assay. Phased haplotypes and haplotypes estimated from unphased genotypes were compared in 103 grandparents who were assumed to have mated at random. For the 3p21 single nucleotide polymorphism (SNP data, haplotypes determined by pedigree analysis and haplotypes generated by the EM algorithm were nearly identical. Linkage disequilibrium, measured by the D' statistic, was nearly maximal across the 150 kb region, with complete disequilibrium maintained at the extremes between CCR3-Y17Y and CCRL2-1243V. D'-values calculated from estimated haplotypes on 3p21 had high concordance with pairwise comparisons between pedigree-phased chromosomes. Conversely, there was less agreement between analyses of haplotype frequencies and linkage disequilibrium using estimated haplotypes when

  11. Elevated CXC chemokines in urine noninvasively discriminate OAB from UTI.

    Science.gov (United States)

    Tyagi, Pradeep; Tyagi, Vikas; Qu, Xianggui; Chuang, Yao Chi; Kuo, Hann-Chorng; Chancellor, Michael

    2016-09-01

    Overlapping symptoms of overactive bladder (OAB) and urinary tract infection (UTI) often complicate the diagnosis and contribute to overprescription of antibiotics. Inflammatory response is a shared characteristic of both UTI and OAB and here we hypothesized that molecular differences in inflammatory response seen in urine can help discriminate OAB from UTI. Subjects in the age range of (20-88 yr) of either sex were recruited for this urine analysis study. Urine specimens were available from 62 UTI patients with positive dipstick test before antibiotic treatment. Six of these patients also provided urine after completion of antibiotic treatment. Subjects in cohorts of OAB (n = 59) and asymptomatic controls (n = 26) were negative for dipstick test. Urinary chemokines were measured by MILLIPLEX MAP Human Cytokine/Chemokine Immunoassay and their association with UTI and OAB was determined by univariate and multivariate statistics. Significant elevation of CXCL-1, CXCL-8 (IL-8), and CXCL-10 together with reduced levels for a receptor antagonist of IL-1A (sIL-1RA) were seen in UTI relative to OAB and asymptomatic controls. Elevated CXCL-1 urine levels predicted UTI with odds ratio of 1.018 and showed a specificity of 80.77% and sensitivity of 59.68%. Postantibiotic treatment, reduction was seen in all CXC chemokines with a significant reduction for CXCL-10. Strong association of CXCL-1 and CXCL-10 for UTI over OAB indicates mechanistic differences in signaling pathways driving inflammation secondary of infection in UTI compared with a lack of infection in OAB. Urinary chemokines highlight molecular differences in the paracrine signaling driving the overlapping symptoms of UTI and OAB.

  12. Elevated CXC chemokines in urine noninvasively discriminate OAB from UTI.

    Science.gov (United States)

    Tyagi, Pradeep; Tyagi, Vikas; Qu, Xianggui; Chuang, Yao Chi; Kuo, Hann-Chorng; Chancellor, Michael

    2016-09-01

    Overlapping symptoms of overactive bladder (OAB) and urinary tract infection (UTI) often complicate the diagnosis and contribute to overprescription of antibiotics. Inflammatory response is a shared characteristic of both UTI and OAB and here we hypothesized that molecular differences in inflammatory response seen in urine can help discriminate OAB from UTI. Subjects in the age range of (20-88 yr) of either sex were recruited for this urine analysis study. Urine specimens were available from 62 UTI patients with positive dipstick test before antibiotic treatment. Six of these patients also provided urine after completion of antibiotic treatment. Subjects in cohorts of OAB (n = 59) and asymptomatic controls (n = 26) were negative for dipstick test. Urinary chemokines were measured by MILLIPLEX MAP Human Cytokine/Chemokine Immunoassay and their association with UTI and OAB was determined by univariate and multivariate statistics. Significant elevation of CXCL-1, CXCL-8 (IL-8), and CXCL-10 together with reduced levels for a receptor antagonist of IL-1A (sIL-1RA) were seen in UTI relative to OAB and asymptomatic controls. Elevated CXCL-1 urine levels predicted UTI with odds ratio of 1.018 and showed a specificity of 80.77% and sensitivity of 59.68%. Postantibiotic treatment, reduction was seen in all CXC chemokines with a significant reduction for CXCL-10. Strong association of CXCL-1 and CXCL-10 for UTI over OAB indicates mechanistic differences in signaling pathways driving inflammation secondary of infection in UTI compared with a lack of infection in OAB. Urinary chemokines highlight molecular differences in the paracrine signaling driving the overlapping symptoms of UTI and OAB. PMID:27335375

  13. Lateral Mobility and Nanoscale Spatial Arrangement of Chemokine-activated α4β1 Integrins on T Cells*

    Science.gov (United States)

    Sosa-Costa, Alberto; Isern de Val, Sol; Sevilla-Movilla, Silvia; Teixidó, Joaquin

    2016-01-01

    Chemokine stimulation of integrin α4β1-dependent T lymphocyte adhesion is a key step during lymphocyte trafficking. A central question regarding α4β1 function is how its lateral mobility and organization influence its affinity and avidity following cell stimulation with chemokines and/or ligands. Using single particle tracking and superresolution imaging approaches, we explored the lateral mobility and spatial arrangement of individual α4β1integrins on T cells exposed to different activating stimuli. We show that CXCL12 stimulation leads to rapid and transient α4β1activation, measured by induction of the activation epitope recognized by the HUTS-21 anti-β1antibody and by increased talin-β1 association. CXCL12-dependent α4β1 activation directly correlated with restricted lateral diffusion and integrin immobilization. Moreover, co-stimulation by CXCL12 together with soluble VCAM-1 potentiated integrin immobilization with a 5-fold increase in immobile integrins compared with unstimulated conditions. Our data indicate that docking by talin of the chemokine-activated α4β1 to the actin cytoskeleton favors integrin immobilization, which likely facilitates ligand interaction and increased adhesiveness. Superresolution imaging showed that the nanoscale organization of high-affinity α4β1 remains unaffected following chemokine and/or ligand addition. Instead, newly activated α4β1 integrins organize on the cell membrane as independent units without joining pre-established integrin sites to contribute to cluster formation. Altogether, our results provide a rationale to understand how the spatiotemporal organization of activated α4β1 integrins regulates T lymphocyte adhesion. PMID:27481944

  14. Modulation of excitatory neurotransmission by neuronal/glial signalling molecules: interplay between purinergic and glutamatergic systems.

    Science.gov (United States)

    Köles, László; Kató, Erzsébet; Hanuska, Adrienn; Zádori, Zoltán S; Al-Khrasani, Mahmoud; Zelles, Tibor; Rubini, Patrizia; Illes, Peter

    2016-03-01

    Glutamate is the main excitatory neurotransmitter of the central nervous system (CNS), released both from neurons and glial cells. Acting via ionotropic (NMDA, AMPA, kainate) and metabotropic glutamate receptors, it is critically involved in essential regulatory functions. Disturbances of glutamatergic neurotransmission can be detected in cognitive and neurodegenerative disorders. This paper summarizes the present knowledge on the modulation of glutamate-mediated responses in the CNS. Emphasis will be put on NMDA receptor channels, which are essential executive and integrative elements of the glutamatergic system. This receptor is crucial for proper functioning of neuronal circuits; its hypofunction or overactivation can result in neuronal disturbances and neurotoxicity. Somewhat surprisingly, NMDA receptors are not widely targeted by pharmacotherapy in clinics; their robust activation or inhibition seems to be desirable only in exceptional cases. However, their fine-tuning might provide a promising manipulation to optimize the activity of the glutamatergic system and to restore proper CNS function. This orchestration utilizes several neuromodulators. Besides the classical ones such as dopamine, novel candidates emerged in the last two decades. The purinergic system is a promising possibility to optimize the activity of the glutamatergic system. It exerts not only direct and indirect influences on NMDA receptors but, by modulating glutamatergic transmission, also plays an important role in glia-neuron communication. These purinergic functions will be illustrated mostly by depicting the modulatory role of the purinergic system on glutamatergic transmission in the prefrontal cortex, a CNS area important for attention, memory and learning. PMID:26542977

  15. Chemokines involved in protection from colitis by CD4+CD25+ regulatory T cells

    DEFF Research Database (Denmark)

    Kristensen, Nanna Ny; Brudzewsky, Dan; Gad, Monika;

    2006-01-01

    , the authors found down regulation of the mRNA expression of the inflammatory chemokine receptors CCR1 and CXCR3 and their ligands CXCL9, CXCL10, CCL5, and CCL7. Also the transcripts for CCR9, CCL25, CCL17, and CXCL1 are found down regulated in protected compared with colitic animals. In addition, the authors......' results suggest that CCL20 is used by CCR6 regulatory T cells in the complex process of controlling colitis because transcripts for this chemokine were expressed to a higher level in protected animals. The chemokine pathways identified in the present study may be of importance for the development of new....../chemokine receptor-specific gene expression profiling system of 67 genes, the authors have determined the expression profile of chemokine and chemokine receptor genes in the rectum of colitic mice and in mice that have been protected fromcolitis by CD4CD25 regulatory T cells. In mice protected from colitis...

  16. CCR5 Expression and β-Chemokine Production During Placental Neonatal Monocyte Differentiation

    OpenAIRE

    Zylla, Dylan; Li, Yuan; BERGENSTAL, EMILY; Merrill, Jeffrey D.; Douglas, Steven D.; MOONEY, KATHY; GUO, CHANG-JIANG; Song, Li; Ho, Wen-Zhe

    2003-01-01

    The stage of maturation of monocytes affects their susceptibility to HIV infection. The β-chemokines and their receptor CCR5 play a crucial role in inflammatory reactions and HIV infection. We therefore examined the correlation between the expression of CCR5 and β-chemokine production and the susceptibility to HIV infection during cord monocyte (CM) differentiation into macrophages. CM and CM-derived macrophages (CMDM) were examined for β-chemokine and CCR5 expression. The susceptibility of t...

  17. Amniotic fluid chemokines and autism spectrum disorders: An exploratory study utilizing a Danish Historic Birth Cohort

    DEFF Research Database (Denmark)

    Abdallah, Morsi; Larsen, Nanna Brink; Grove, Jakob;

    2012-01-01

    Elevated levels of chemokines have been reported in plasma and brain tissue of individuals with Autism Spectrum Disorders (ASD). The aim of this study was to examine chemokine levels in amniotic fluid (AF) samples of individuals diagnosed with ASD and their controls.......Elevated levels of chemokines have been reported in plasma and brain tissue of individuals with Autism Spectrum Disorders (ASD). The aim of this study was to examine chemokine levels in amniotic fluid (AF) samples of individuals diagnosed with ASD and their controls....

  18. Chemokines accentuating protumoral activities in oral cancer microenvironment possess an imperious stratagem for therapeutic resolutions.

    Science.gov (United States)

    Panda, Swagatika; Padhiary, Subrat Kumar; Routray, Samapika

    2016-09-01

    Chemokines, the chemotactic cytokines have established their role in tumorigenesis and tumor progression. Studies, which explored their role in oral cancer for protumoral activity, point towards targeting chemokines for oral squamous cell carcinoma therapy. The need of the hour is to emphasize/divulge in the activities of chemokine ligands and their receptors in the tumor microenvironment for augmentation of such stratagems. This progressing sentience of chemokines and their receptors has inspired this review which is an endeavour to comprehend their role as an aid in accentuating hallmarks of cancer and targeted therapy. PMID:27531867

  19. Transcriptional Regulation of Chemokine Genes: A Link to Pancreatic Islet Inflammation?

    Directory of Open Access Journals (Sweden)

    Susan J. Burke

    2015-05-01

    Full Text Available Enhanced expression of chemotactic cytokines (aka chemokines within pancreatic islets likely contributes to islet inflammation by regulating the recruitment and activation of various leukocyte populations, including macrophages, neutrophils, and T-lymphocytes. Because of the powerful actions of these chemokines, precise transcriptional control is required. In this review, we highlight what is known about the signals and mechanisms that govern the transcription of genes encoding specific chemokine proteins in pancreatic islet β-cells, which include contributions from the NF-κB and STAT1 pathways. We further discuss increased chemokine expression in pancreatic islets during autoimmune-mediated and obesity-related development of diabetes.

  20. Chemokines and their receptors play important roles in thedevelopment of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    The chemokine system consists of four differentsubclasses with over 50 chemokines and 19 receptors.Their functions in the immune system have beenwell elucidated and research during the last decadesunveils their new roles in hepatocellular carcinoma(HCC). The chemokines and their receptors in themicroenvironment influence the development of HCC by several aspects including: inflammation, effects onimmune cells, angiogenesis, and direct effects on HCCcells. Regarding these aspects, pre-clinical research bytargeting the chemokine system has yielded promisingdata, and these findings bring us new clues in thechemokine-based therapies for HCC.

  1. Ubiquitous transgenic overexpression of C-C chemokine ligand 2: a model to assess the combined effect of high energy intake and continuous low-grade inflammation.

    Science.gov (United States)

    Rodríguez-Gallego, Esther; Riera-Borrull, Marta; Hernández-Aguilera, Anna; Mariné-Casadó, Roger; Rull, Anna; Beltrán-Debón, Raúl; Luciano-Mateo, Fedra; Menendez, Javier A; Vazquez-Martin, Alejandro; Sirvent, Juan J; Martín-Paredero, Vicente; Corbí, Angel L; Sierra-Filardi, Elena; Aragonès, Gerard; García-Heredia, Anabel; Camps, Jordi; Alonso-Villaverde, Carlos; Joven, Jorge

    2013-01-01

    Excessive energy management leads to low-grade, chronic inflammation, which is a significant factor predicting noncommunicable diseases. In turn, inflammation, oxidation, and metabolism are associated with the course of these diseases; mitochondrial dysfunction seems to be at the crossroads of mutual relationships. The migration of immune cells during inflammation is governed by the interaction between chemokines and chemokine receptors. Chemokines, especially C-C-chemokine ligand 2 (CCL2), have a variety of additional functions that are involved in the maintenance of normal metabolism. It is our hypothesis that a ubiquitous and continuous secretion of CCL2 may represent an animal model of low-grade chronic inflammation that, in the presence of an energy surplus, could help to ascertain the afore-mentioned relationships and/or to search for specific therapeutic approaches. Here, we present preliminary data on a mouse model created by using targeted gene knock-in technology to integrate an additional copy of the CCl2 gene in the Gt(ROSA)26Sor locus of the mouse genome via homologous recombination in embryonic stem cells. Short-term dietary manipulations were assessed and the findings include metabolic disturbances, premature death, and the manipulation of macrophage plasticity and autophagy. These results raise a number of mechanistic questions for future study.

  2. Ubiquitous Transgenic Overexpression of C-C Chemokine Ligand 2: A Model to Assess the Combined Effect of High Energy Intake and Continuous Low-Grade Inflammation

    Directory of Open Access Journals (Sweden)

    Esther Rodríguez-Gallego

    2013-01-01

    Full Text Available Excessive energy management leads to low-grade, chronic inflammation, which is a significant factor predicting noncommunicable diseases. In turn, inflammation, oxidation, and metabolism are associated with the course of these diseases; mitochondrial dysfunction seems to be at the crossroads of mutual relationships. The migration of immune cells during inflammation is governed by the interaction between chemokines and chemokine receptors. Chemokines, especially C-C-chemokine ligand 2 (CCL2, have a variety of additional functions that are involved in the maintenance of normal metabolism. It is our hypothesis that a ubiquitous and continuous secretion of CCL2 may represent an animal model of low-grade chronic inflammation that, in the presence of an energy surplus, could help to ascertain the afore-mentioned relationships and/or to search for specific therapeutic approaches. Here, we present preliminary data on a mouse model created by using targeted gene knock-in technology to integrate an additional copy of the CCl2 gene in the Gt(ROSA26Sor locus of the mouse genome via homologous recombination in embryonic stem cells. Short-term dietary manipulations were assessed and the findings include metabolic disturbances, premature death, and the manipulation of macrophage plasticity and autophagy. These results raise a number of mechanistic questions for future study.

  3. Backbone dynamics of the human CC-chemokine eotaxin

    Energy Technology Data Exchange (ETDEWEB)

    Ye Jiqing; Mayer, Kristen L.; Stone, Martin J. [Indiana University, Department of Chemistry (United States)

    1999-10-15

    Eotaxin is a CC chemokine with potent chemoattractant activity towards eosinophils. {sup 15}N NMR relaxation data have been used to characterize the backbone dynamics of recombinant human eotaxin. {sup 15}N longitudinal (R{sub 1}) and transverse (R{sub 2}) auto relaxation rates, heteronuclear {sup 1}H-{sup 15}N steady-state NOEs, and transverse cross-relaxation rates ({eta}{sub xy}) were obtained at 30 deg. C for all resolved backbone secondary amide groups using {sup 1} H-detected two-dimensional NMR experiments. Ratios of transverse auto and cross relaxation rates were used to identify NH groups influenced by slow conformational rearrangement. Relaxation data were fit to the extended model free dynamics formalism, yielding parameters describing axially symmetric molecular rotational diffusion and the internal dynamics of each NH group. The molecular rotational correlation time ({tau}{sub m}) is 5.09{+-}0.02 ns, indicating that eotaxin exists predominantly as a monomer under the conditions of the NMR study. The ratio of diffusion rates about unique and perpendicular axes (D{sub parallel}/D{sub perpendicular}) is 0.81{+-}0.02. Residues with large amplitudes of subnanosecond motion are clustered in the N-terminal region (residues 1-19), the C-terminus (residues 68-73) and the loop connecting the first two {beta}-strands (residues 30-37). N-terminal flexibility appears to be conserved throughout the chemokine family and may have implications for the mechanism of chemokine receptor activation. Residues exhibiting significant dynamics on the microsecond-millisecond time scale are located close to the two conserved disulfide bonds, suggesting that these motions may be coupled to disulfide bond isomerization.

  4. Structural And Functional Characterization of CC Chemokine CCL14

    Energy Technology Data Exchange (ETDEWEB)

    Blain, K.Y.; Kwiatkowski, W.; Zhao, Q.; Fleur, D.La; Naik, C.; Chun, T.-W.; Tsareva, T.; Kanakaraj, P.; Laird, M.W.; Shah, R.; George, L.; Sanyal, I.; Moore, P.A.; Demeler, B.; Choe, S.

    2009-06-02

    CC chemokine ligand 14, CCL14, is a human CC chemokine that is of recent interest because of its natural ability, upon proteolytic processing of the first eight NH{sub 2}-terminal residues, to bind to and signal through the human immunodeficiency virus type-1 (HIV-1) co-receptor, CC chemokine receptor 5 (CCR5). We report X-ray crystallographic structures of both full-length CCL14 and signaling-active, truncated CCL14 [9-74] determined at 2.23 and 1.8 {angstrom}, respectively. Although CCL14 and CCL14 [9-74] differ in their ability to bind CCR5 for biological signaling, we find that the NH{sub 2}-terminal eight amino acids (residues 1 through 8) are completely disordered in CCL14 and both show the identical mode of the dimeric assembly characteristic of the CC type chemokine structures. However, analytical ultracentrifugation studies reveal that the CCL14 is stable as a dimer at a concentration as low as 100 nM, whereas CCL14 [9-74] is fully monomeric at the same concentration. By the same method, the equilibrium between monomers of CCL14 [9-74] and higher order oligomers is estimated to be of EC{sub 1,4} = 4.98 {mu}M for monomer-tetramer conversion. The relative instability of CCL14 [9-74] oligomers as compared to CCL14 is also reflected in the K{sub d}'s that are estimated by the surface plasmon resonance method to be {approx}9.84 and 667 nM for CCL14 and CCL14 [9-74], respectively. This {approx}60-fold difference in stability at a physiologically relevant concentration can potentially account for their different signaling ability. Functional data from the activity assays by intracellular calcium flux and inhibition of CCR5-mediated HIV-1 entry show that only CCL14 [9-74] is fully active at these near-physiological concentrations where CCL14 [9-74] is monomeric and CCL14 is dimeric. These results together suggest that the ability of CCL14 [9-74] to monomerize can play a role for cellular activation.

  5. Macrophage derived chemokine (CCL22, thymus and activation-regulated chemokine (CCL17, and CCR4 in idiopathic pulmonary fibrosis

    Directory of Open Access Journals (Sweden)

    Yamaguchi Kazuhiro

    2009-08-01

    Full Text Available Abstract Background Idiopathic pulmonary fibrosis (IPF is a chronically progressive interstitial lung disease of unknown etiology. Previously, we have demonstrated the selective upregulation of the macrophage-derived chemokine CCL22 and the thymus activation-regulated chemokine CCL17 among chemokines, in a rat model of radiation pneumonitis/pulmonary fibrosis and preliminarily observed an increase in bronchoalveolar (BAL fluid CCL22 levels of IPF patients. Methods We examined the expression of CCR4, a specific receptor for CCL22 and CCL17, in bronchoalveolar lavage (BAL fluid cells, as well as the levels of CCL22 and CCL17, to elucidate their pathophysiological roles in pulmonary fibrosis. We also studied their immunohistochemical localization. Results BAL fluid CCL22 and CCL17 levels were significantly higher in patients with IPF than those with collagen vascular diseases and healthy volunteers, and there was a significant correlation between the levels of CCL22 and CCL17 in patients with IPF. CCL22 levels in the BAL fluid did not correlate with the total cell numbers, alveolar lymphocytes, or macrophages in BAL fluid. However, the CCL22 levels significantly correlated with the numbers of CCR4-expressing alveolar macrophages. By immunohistochemical and immunofluorescence analysis, localization of CCL22 and CCR4 to CD68-positive alveolar macrophages as well as that of CCL17 to hyperplastic epithelial cells were shown. Clinically, CCL22 BAL fluid levels inversely correlated with DLco/VA values in IPF patients. Conclusion We speculated that locally overexpressed CCL22 may induce lung dysfunction through recruitment and activation of CCR4-positive alveolar macrophages.

  6. Mesenchymal stem cells exhibit firm adhesion, crawling, spreading and transmigration across aortic endothelial cells: effects of chemokines and shear.

    Directory of Open Access Journals (Sweden)

    Giselle Chamberlain

    Full Text Available Mesenchymal stem cells (MSCs have anti-inflammatory and immunosuppressive properties and may be useful in the therapy of diseases such as arteriosclerosis. MSCs have some ability to traffic into inflamed tissues, however to exploit this therapeutically their migratory mechanisms need to be elucidated. This study examines the interaction of murine MSCs (mMSCs with, and their migration across, murine aortic endothelial cells (MAECs, and the effects of chemokines and shear stress. The interaction of mMSCs with MAECs was examined under physiological flow conditions. mMSCs showed lack of interaction with MAECs under continuous flow. However, when the flow was stopped (for 10 min and then started, mMSCs adhered and crawled on the endothelial surface, extending fine microvillous processes (filopodia. They then spread extending pseudopodia in multiple directions. CXCL9 significantly enhanced the percentage of mMSCs adhering, crawling and spreading and shear forces markedly stimulated crawling and spreading. CXCL9, CXCL16, CCL20 and CCL25 significantly enhanced transendothelial migration across MAECs. The transmigrated mMSCs had down-regulated receptors CXCR3, CXCR6, CCR6 and CCR9. This study furthers the knowledge of MSC transendothelial migration and the effects of chemokines and shear stress which is of relevance to inflammatory diseases such as arteriosclerosis.

  7. Keratinocytes-associated chemokines and enzymatically quiescent heparanase induce the binding of resting CD4+ T cells.

    Science.gov (United States)

    Hershkoviz, R; Marikovsky, M; Gilat, D; Lider, O

    1996-02-01

    Whether the chemokines macrophage inflammatory protein-1 beta (MIP-1 beta) and regulated on activation normal T expressed and secreted (RANTES), which interact specifically with glycosaminoglycans and thus mediate the recruitment, attachment, and migration of leukocytes to vascular endothelia and extracellular matrix, are also involved in interactions between CD4+ murine T lymphocytes and keratinocytes was examined. We have previously observed that depending on the local pH, a mammalian extracellular matrix-degrading enzyme, endo-beta-D glucuronidase (heparanase), which cleaves heparin sulfate proteoglycans, can function wither as an enzyme or as an adhesion molecule for CD4+ T lymphocytes. Herein, the involvement of heparanase in T cell-keratinocyte interactions was also probed. At 37 degree C and pH 7.2, radioactively labeled MIP-1 beta, RANTES, and heparanase bound to confluent layers of resting keratinocytes in a saturable and an heparan sulfate- or heparin-dependent manner, and thereby induced the adhesion of resting CD4+ T cells to keratinocytes. At a relatively acidic pH characteristic of inflammatory milieu, enzymatically active heparanase did not bind to the keratinocytes but, rather, inhibited the binding of MIP-1beta, RANTES, and the enzymatically quiescent heparanase to keratinocytes. These results suggest that certain chemokines and heparanase may function to restrict passing leukocytes, notable T lymphocytes, in the cutaneous micro-environment, a site which is continuously challenged with antigens. These keratinocyte-bound lymphocytes can serve as a reservoir of immediate responders to immunological stimuli. PMID:8601723

  8. Role of chemokines in the pathogenesis of rheumatoid synovitis

    Directory of Open Access Journals (Sweden)

    N. Pipitone

    2011-09-01

    Full Text Available Chemokines play a central role in the pathogenesis of rheumatoid arthritis (RA synovitis which is characterised by new blood vessel formation, thickening of the lining layer and infiltration of immune cells. The inflammatory infiltrate is generated by a series of events which include the recruitment of leukocytes from the blood stream into the tissue, their local retention and activation to effector cells. All these processes are finely regulated by the interplay of different cell adhesion molecules (CAMs and chemoattractant factors called chemokines (CK. CK are a superfamily of small proteins that play a crucial role in immune and inflammatory reactions. These chemoattractant cytokines share structural similarities including four conserved cysteine residues which form disulphide bonds in the tertiary structure of the proteins. CK mediate their effects by binding specific receptors (CK-R characterised by a domain structure which spans the cell membrane seven times and signal through heterotrimeric GPT-binding proteins. Activation of the CK network results in an amplification of the inflammatory cascade and consequently in the progressive destruction of RA joints. The recognition of the central role of CK in inflammation has paved the way to the development of new agents capable of interfering with CK and CK-R. This review will focus in particular on the role of CK in regulating leukocyte trafficking in RA joints.

  9. Chemokine-guided angiogenesis directs coronary vasculature formation in zebrafish.

    Science.gov (United States)

    Harrison, Michael R M; Bussmann, Jeroen; Huang, Ying; Zhao, Long; Osorio, Arthela; Burns, C Geoffrey; Burns, Caroline E; Sucov, Henry M; Siekmann, Arndt F; Lien, Ching-Ling

    2015-05-26

    Interruption of the coronary blood supply severely impairs heart function with often fatal consequences for patients. However, the formation and maturation of these coronary vessels is not fully understood. Here we provide a detailed analysis of coronary vessel development in zebrafish. We observe that coronary vessels form in zebrafish by angiogenic sprouting of arterial cells derived from the endocardium at the atrioventricular canal. Endothelial cells express the CXC-motif chemokine receptor Cxcr4a and migrate to vascularize the ventricle under the guidance of the myocardium-expressed ligand Cxcl12b. cxcr4a mutant zebrafish fail to form a vascular network, whereas ectopic expression of Cxcl12b ligand induces coronary vessel formation. Importantly, cxcr4a mutant zebrafish fail to undergo heart regeneration following injury. Our results suggest that chemokine signaling has an essential role in coronary vessel formation by directing migration of endocardium-derived endothelial cells. Poorly developed vasculature in cxcr4a mutants likely underlies decreased regenerative potential in adults.

  10. Effects of chemokine (C–C motif) ligand 1 on microglial function

    International Nuclear Information System (INIS)

    Highlights: •CCR8, a specific receptor for CCL-1, was expressed on primary cultured microglia. •Expression of CCR-8 in microglia was upregulated in the presence of CCL-1. •CCL-1 increased motility, proliferation and phagocytosis of cultured microglia. •CCL-1promoted BDNF and IL-6 mRNA, and the release of NO from microglia. •CCL-1 activates microglia and may contribute to the development of neuropathic pain. -- Abstract: Microglia, which constitute the resident macrophages of the central nervous system (CNS), are generally considered as the primary immune cells in the brain and spinal cord. Microglial cells respond to various factors which are produced following nerve injury of multiple aetiologies and contribute to the development of neuronal disease. Chemokine (C–C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, has been shown to play an important role in neuropathic pain induced by nerve injury and is also produced in various cell types in the CNS, especially in dorsal root ganglia (DRG). However, the role of CCL-1 in the CNS and the effects on microglia remains unclear. Here we showed the multiple effects of CCL-1 on microglia. We first showed that CCR-8, a specific receptor for CCL-1, was expressed on primary cultured microglia, as well as on astrocytes and neurons, and was upregulated in the presence of CCL-1. CCL-1 at concentration of 1 ng/ml induced chemotaxis, increased motility at a higher concentration (100 ng/ml), and increased proliferation and phagocytosis of cultured microglia. CCL-1 also activated microglia morphologically, promoted mRNA levels for brain-derived neurotrophic factor (BDNF) and IL-6, and increased the release of nitrite from microglia. These indicate that CCL-1 has a role as a mediator in neuron-glia interaction, which may contribute to the development of neurological diseases, especially in neuropathic pain

  11. Effects of chemokine (C–C motif) ligand 1 on microglial function

    Energy Technology Data Exchange (ETDEWEB)

    Akimoto, Nozomi [Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Ifuku, Masataka [Laboratory of Integrative Physiology, Graduate School of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Mori, Yuki [Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Noda, Mami, E-mail: noda@phar.kyushu-u.ac.jp [Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)

    2013-07-05

    Highlights: •CCR8, a specific receptor for CCL-1, was expressed on primary cultured microglia. •Expression of CCR-8 in microglia was upregulated in the presence of CCL-1. •CCL-1 increased motility, proliferation and phagocytosis of cultured microglia. •CCL-1promoted BDNF and IL-6 mRNA, and the release of NO from microglia. •CCL-1 activates microglia and may contribute to the development of neuropathic pain. -- Abstract: Microglia, which constitute the resident macrophages of the central nervous system (CNS), are generally considered as the primary immune cells in the brain and spinal cord. Microglial cells respond to various factors which are produced following nerve injury of multiple aetiologies and contribute to the development of neuronal disease. Chemokine (C–C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, has been shown to play an important role in neuropathic pain induced by nerve injury and is also produced in various cell types in the CNS, especially in dorsal root ganglia (DRG). However, the role of CCL-1 in the CNS and the effects on microglia remains unclear. Here we showed the multiple effects of CCL-1 on microglia. We first showed that CCR-8, a specific receptor for CCL-1, was expressed on primary cultured microglia, as well as on astrocytes and neurons, and was upregulated in the presence of CCL-1. CCL-1 at concentration of 1 ng/ml induced chemotaxis, increased motility at a higher concentration (100 ng/ml), and increased proliferation and phagocytosis of cultured microglia. CCL-1 also activated microglia morphologically, promoted mRNA levels for brain-derived neurotrophic factor (BDNF) and IL-6, and increased the release of nitrite from microglia. These indicate that CCL-1 has a role as a mediator in neuron-glia interaction, which may contribute to the development of neurological diseases, especially in neuropathic pain.

  12. Maternal Plasma and Amniotic Fluid Chemokines Screening in Fetal Down Syndrome

    Directory of Open Access Journals (Sweden)

    Piotr Laudanski

    2014-01-01

    Full Text Available Objective. Chemokines exert different inflammatory responses which can potentially be related to certain fetal chromosomal abnormalities. The aim of the study was to determine the concentration of selected chemokines in plasma and amniotic fluid of women with fetal Down syndrome. Method. Out of 171 amniocentesis, we had 7 patients with confirmed fetal Down syndrome (15th–18th weeks of gestation. For the purpose of our control, we chose 14 women without confirmed chromosomal aberration. To assess the concentration of chemokines in the blood plasma and amniotic fluid, we used a protein macroarray, which allows the simultaneous determination of 40 chemokines per sample. Results. We showed significant decrease in the concentration of 4 chemokines, HCC-4, IL-28A, IL-31, and MCP-2, and increase in the concentration of CXCL7 (NAP-2 in plasma of women with fetal Down syndrome. Furthermore, we showed decrease in concentration of 3 chemokines, ITAC, MCP-3, MIF, and increase in concentration of 4 chemokines, IP-10, MPIF-1, CXCL7, and 6Ckine, in amniotic fluid of women with fetal Down syndrome. Conclusion. On the basis of our findings, our hypothesis is that the chemokines may play role in the pathogenesis of Down syndrome. Defining their potential as biochemical markers of Down syndrome requires further investigation on larger group of patients.

  13. Chemokine stromal cell-derived factor 1alpha activates basophils by means of CXCR4

    DEFF Research Database (Denmark)

    Jinquan, T; Jacobi, H H; Jing, C;

    2000-01-01

    The CXC chemokine receptor 4 (CXCR4) is predominantly expressed on inactivated naive T lymphocytes, B lymphocytes, dendritic cells, and endothelial cells. CXC chemokine stromal cell-derived factor 1alpha (SDF-1alpha) is the only known ligand for CXCR4. To date, the CXCR4 expression and function o...

  14. Inflammation-induced chemokine expression in uveal melanoma cell lines stimulates monocyte chemotaxis

    DEFF Research Database (Denmark)

    Jehs, Tina; Faber, Carsten; Juel, Helene B;

    2014-01-01

    resulted in an upregulation of chemokines such as CXCL8, CXCL9, CXCL10, CXCL11, CCL2, CCL5, VEGF, intracellular adhesion molecule 1 (ICAM1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). The upregulation of these molecules was confirmed at the protein level. This increase of chemokines...

  15. Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity

    DEFF Research Database (Denmark)

    Holst, P J; Rosenkilde, M M; Manfra, D;

    2001-01-01

    ORF74 (or KSHV-vGPCR) is a highly constitutively active G protein-coupled receptor encoded by HHV8 that is regulated both positively and negatively by endogenous chemokines. When expressed in transgenic mice, this chemokine receptor induces an angioproliferative disease closely resembling Kaposi...

  16. Targeting the chemokine receptor CXCR3 and its ligand CXCL10 in the central nervous system

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke

    2004-01-01

    focuses on the present data regarding CXCL10 (previously known as IP-10) and CXRC3 in multiple sclerosis, since consistent data has suggested that this chemokine/chemokine receptor pair has a pivotal role in leukocyte recruitment into the central nervous system (CNS) in multiple sclerosis....

  17. Cytokine and chemokine inter-regulation in the inflamed or injured CNS

    DEFF Research Database (Denmark)

    Owens, Trevor; Babcock, Alicia A; Millward, Jason M;

    2005-01-01

    The distinction between immune-regulatory and effector cytokines and chemokines, and neural growth and survival factors (neurotrophins) becomes increasingly blurred. We discuss here the role of immune cytokines and chemokines as mediators of innate glial responses in the central nervous system. G...

  18. Expression of CC Chemokine Ligand 20 and CC Chemokine Receptor 6 mRNA in Patients with Psoriasis Vulgaris

    Institute of Scientific and Technical Information of China (English)

    吴艳; 李家文

    2004-01-01

    Summary: In order to explore the possible role of CC chemokine ligand 20 (CCL20) and its receptor CC chemokine receptor 6 (CCR6) in the pathogenesis of psoriasis, the expression levels of mRNA of them in psoriatic lesions were investigated. The skin biopsies were collected from skin lesions in 35 cases of psoriasis vulgaris and 18 normal controls. RT-PCR was used to semi-quantitatively analyze the mRNA expression of CCL20 and CCR6 in the psoriatic lesions and the normal skin tissues.The results showed that the mRNA of CCL20 and CCR6 was present in every specimen. The expression levels of CCL20 mRNA in skin lesions were 1. 1397±0. 0521, which were greatly higher than those in normal controls (0.8681±0.0308) (P<0. 001). The expression levels of CCR6 mRNA in skin lesions were 1.1103±0.0538, significantly higher than in the controls (0.9131±0.0433, P<0. 001). These findings indicate that up-regulated expression of CCL20 and CCR6 mRNA might be related to the pathogenesis of psoriasis.

  19. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor

    Energy Technology Data Exchange (ETDEWEB)

    Burg, John S.; Ingram, Jessica R.; Venkatakrishnan, A.J.; Jude, Kevin M.; Dukkipati, Abhiram; Feinberg, Evan N.; Angelini, Alessandro; Waghray, Deepa; Dror, Ron O.; Ploegh, Hidde L.; Garcia, K. Christopher (Stanford); (Stanford-MED); (Whitehead); (MIT)

    2015-03-05

    Chemokines are small proteins that function as immune modulators through activation of chemokine G protein-coupled receptors (GPCRs). Several viruses also encode chemokines and chemokine receptors to subvert the host immune response. How protein ligands activate GPCRs remains unknown. We report the crystal structure at 2.9 angstrom resolution of the human cytomegalovirus GPCR US28 in complex with the chemokine domain of human CX3CL1 (fractalkine). The globular body of CX3CL1 is perched on top of the US28 extracellular vestibule, whereas its amino terminus projects into the central core of US28. The transmembrane helices of US28 adopt an active-state-like conformation. Atomic-level simulations suggest that the agonist-independent activity of US28 may be due to an amino acid network evolved in the viral GPCR to destabilize the receptor’s inactive state.

  20. Immunological assays for chemokine detection in in-vitro culture of CNS cells

    Directory of Open Access Journals (Sweden)

    Mahajan Supriya D.

    2003-01-01

    Full Text Available Herein we review the various methods currently in use for determining the expression of chemokines by CNS cells in vitro. Chemokine detection assays are used in conjuction with one another to provide a comprehensive, biologically relevant assessment of the chemokines which is necessary for correct data interpretation of a specific observed biological effect. The methods described include bioassays for soluble chemokine receptors, RNA extraction, RT-PCR, Real - time quantitative PCR, gene array analysis, northern blot analysis, Ribonuclease Protection assay, Flow cytometry, ELISPOT, western blot analysis, and ELISA. No single method of analysis meets the criteria for a comprehensive, biologically relevant assessment of the chemokines, therefore more than one assay might be necessary for correct data interpretation, a choice that is based on development of a scientific rationale for the method with emphasis on the reliability and relevance of the method.

  1. Genetic characterization of the chemokine receptor CXCR4 gene in lagomorphs: comparison between the families Ochotonidae and Leporidae

    OpenAIRE

    Abrantes, J; esteves, pj; carmo, cr; Muller, A.; Thompson, G.; LOO, W

    2008-01-01

    Chemokines receptors are transmembrane proteins that bind chemokines. Chemokines and their receptors are known to play a crucial role in the immune system and in pathogen entry. There is evidence that myxoma virus, the causative agent of myxomatosis, can use the chemokine receptor CXCR4 to infect cells. This virus causes a benign disease in its natural host, Sylvilagus, but in the European rabbit (Oryctolagus cuniculus) it causes a highly fatal and infectious disease known as myxomatosis. We ...

  2. Chemokine receptor expression by inflammatory T cells in EAE.

    Science.gov (United States)

    Mony, Jyothi Thyagabhavan; Khorooshi, Reza; Owens, Trevor

    2014-01-01

    Chemokines direct cellular infiltration to tissues, and their receptors and signaling pathways represent targets for therapy in diseases such as multiple sclerosis (MS). The chemokine CCL20 is expressed in choroid plexus, a site of entry of T cells to the central nervous system (CNS). The CCL20 receptor CCR6 has been reported to be selectively expressed by CD4(+) T cells that produce the cytokine IL-17 (Th17 cells). Th17 cells and interferon-gamma (IFNγ)-producing Th1 cells are implicated in induction of MS and its animal model experimental autoimmune encephalomyelitis (EAE). We have assessed whether CCR6 identifies specific inflammatory T cell subsets in EAE. Our approach was to induce EAE, and then examine chemokine receptor expression by cytokine-producing T cells sorted from CNS at peak disease. About 7% of CNS-infiltrating CD4(+) T cells produced IFNγ in flow cytometric cytokine assays, whereas less than 1% produced IL-17. About 1% of CD4(+) T cells produced both cytokines. CCR6 was expressed by Th1, Th1+17 and by Th17 cells, but not by CD8(+) T cells. CD8(+) T cells expressed CXCR3, which was also expressed by CD4(+) T cells, with no correlation to cytokine profile. Messenger RNA for IFNγ, IL-17A, and the Th1 and Th17-associated transcription factors T-bet and RORγt was detected in both CCR6(+) and CXCR3(+) CD4(+) T cells. IFNγ, but not IL-17A mRNA expression was detected in CD8(+) T cells in CNS. CCR6 and CD4 were co-localized in spinal cord infiltrates by double immunofluorescence. Consistent with flow cytometry data some but not all CD4(+) T cells expressed CCR6 within infiltrates. CD4-negative CCR6(+) cells included macrophage/microglial cells. Thus we have for the first time directly studied CD4(+) and CD8(+) T cells in the CNS of mice with peak EAE, and determined IFNγ and IL17 expression by cells expressing CCR6 and CXCR3. We show that neither CCR6 or CXCR3 align with CD4 T cell subsets, and Th1 or mixed Th1+17 predominate in EAE.

  3. Chemokine receptor expression by inflammatory T cells in EAE

    Directory of Open Access Journals (Sweden)

    Jyothi Thyagabhavan Mony

    2014-07-01

    Full Text Available Chemokines direct cellular infiltration to tissues, and their receptors and signaling pathways represent targets for therapy in diseases such as multiple sclerosis (MS. The chemokine CCL20 is expressed in choroid plexus, a site of entry of T cells to the central nervous system (CNS. The CCL20 receptor CCR6 has been reported to be selectively expressed by CD4+ T cells that produce the cytokine IL-17 (Th17 cells. Th17 cells and interferon-gamma (IFNγ-producing Th1 cells are implicated in induction of MS and its animal model experimental autoimmune encephalomyelitis (EAE. We have assessed whether CCR6 identifies specific inflammatory T cell subsets in EAE. Our approach was to induce EAE, and then examine chemokine receptor expression by cytokine-producing T cells sorted from CNS at peak disease. About 7% of CNS-infiltrating CD4+ T cells produced IFNγ in flow cytometric cytokine assays, whereas less than 1% produced IL-17. About 7.7% of CD4+ T cells produced both cytokines. CCR6 was expressed by Th1, Th1+17 and by Th17 cells, but not by CD8+ T cells. CD8+ T cells expressed CXCR3, which was also expressed by CD4+ T cells, with no correlation to cytokine profile. Messenger RNA for IFNγ, IL-17A, and the Th1 and Th17-associated transcription factors T-bet and RORγt was detected in both CCR6+ and CXCR3+ CD4+ T cells. IFNγ, but not IL-17A mRNA expression was detected in CD8+ T cells in CNS. CCR6 and CD4 were co-localized in spinal cord infiltrates by double immunofluorescence. Consistent with flow cytometry data some but not all CD4+ T cells expressed CCR6 within infiltrates. CD4-negative CCR6+ cells included macrophage/microglial cells. Thus we have for the first time directly studied CD4+ and CD8+ T cells in the CNS of mice with peak EAE, and determined IFNγ and IL17 expression by cells expressing CCR6 and CXCR3. We show that neither CCR6 or CXCR3 align with CD4 T cell subsets, and Th1 or mixed Th1+17 predominate in EAE.

  4. Modeling neuron-glia interactions: from parametric model to neuromorphic hardware.

    Science.gov (United States)

    Ghaderi, Viviane S; Allam, Sushmita L; Ambert, N; Bouteiller, J-M C; Choma, J; Berger, T W

    2011-01-01

    Recent experimental evidence suggests that glial cells are more than just supporting cells to neurons - they play an active role in signal transmission in the brain. We herein propose to investigate the importance of these mechanisms and model neuron-glia interactions at synapses using three approaches: A parametric model that takes into account the underlying mechanisms of the physiological system, a non-parametric model that extracts its input-output properties, and an ultra-low power, fast processing, neuromorphic hardware model. We use the EONS (Elementary Objects of the Nervous System) platform, a highly elaborate synaptic modeling platform to investigate the influence of astrocytic glutamate transporters on postsynaptic responses in the detailed micro-environment of a tri-partite synapse. The simulation results obtained using EONS are then used to build a non-parametric model that captures the essential features of glutamate dynamics. The structure of the non-parametric model we use is specifically designed for efficient hardware implementation using ultra-low power subthreshold CMOS building blocks. The utilization of the approach described allows us to build large-scale models of neuron/glial interaction and consequently provide useful insights on glial modulation during normal and pathological neural function. PMID:22255113

  5. Knock-down of CD44 regulates endothelial cell differentiation via NFκB-mediated chemokine production.

    Directory of Open Access Journals (Sweden)

    Berit Olofsson

    Full Text Available A striking feature of microvascular endothelial cells is their capacity to fuse and differentiate into tubular structures when grown in three-dimensional (3D extracellular matrices, in collagen or Matrigel, mimicking the in vivo blood vessel formation. In this study we demonstrate that human telomerase-immortalised foreskin microvascular endothelial (TIME cells express high levels of the hyaluronan receptor CD44 and the hyaluronidase HYAL2. Knock-down of CD44 or HYAL2 resulted in an inability of TIME cells to form a tubular network, suggesting a key regulatory role of hyaluronan in controlling TIME cell tubulogenesis in 3D matrices. Knock-down of CD44 resulted in an upregulation of mRNA expression of the chemokines CXCL9 and CXCL12, as well as their receptors CXCR3 and CXCR4. This was accompanied by a defect maturation of the tubular structure network and increased phosphorylation of the inhibitor of NFκB kinase (IKK complex and thus translocation of NFκB into the nucleus and activation of chemokine targed genes. Furthermore, the interaction between CD44 and hyaluronan determines the adhesion of breast cancer cells. In summary, our observations support the notion that the interaction between CD44 and hyaluronan regulates microvascular endothelial cell tubulogenesis by affecting the expression of cytokines and their receptors, as well as breast cancer dissemination.

  6. Production of cytokine and chemokines by human mononuclear cells and whole blood cells after infection with Trypanosoma cruzi

    Directory of Open Access Journals (Sweden)

    Karine Rezende-Oliveira

    2012-02-01

    Full Text Available INTRODUCTION: The innate immune response is the first mechanism of protection against Trypanosoma cruzi, and the interaction of inflammatory cells with parasite molecules may activate this response and modulate the adaptive immune system. This study aimed to analyze the levels of cytokines and chemokines synthesized by the whole blood cells (WBC and peripheral blood mononuclear cells (PBMC of individuals seronegative for Chagas disease after interaction with live T. cruzi trypomastigotes. METHODS: IL-12, IL-10, TNF-α, TGF-β, CCL-5, CCL-2, CCL-3, and CXCL-9 were measured by ELISA. Nitrite was determined by the Griess method. RESULTS: IL-10 was produced at high levels by WBC compared with PBMC, even after incubation with live trypomastigotes. Production of TNF-α by both PBMC and WBC was significantly higher after stimulation with trypomastigotes. Only PBMC produced significantly higher levels of IL-12 after parasite stimulation. Stimulation of cultures with trypomastigotes induced an increase of CXCL-9 levels produced by WBC. Nitrite levels produced by PBMC increased after the addition of parasites to the culture. CONCLUSIONS: Surface molecules of T. cruzi may induce the production of cytokines and chemokines by cells of the innate immune system through the activation of specific receptors not evaluated in this experiment. The ability to induce IL-12 and TNF-α contributes to shift the adaptive response towards a Th1 profile.

  7. Chemokine receptor CCR5 in interferon-treated multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F; Kristiansen, Thomas Birk; Wittenhagen, P;

    2007-01-01

    OBJECTIVE: To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta). METHODS: The CCR5 Delta32 allele and a CCR5 promoter polymorphism associated with cell surface expression of CCR5 were...... analyzed in 109 patients with relapsing-remitting MS treated with IFN-beta who were followed clinically for 1 year. Cellular CCR5 expression was measured by flow cytometry. RESULTS: Patients with MS had a higher percentage of CCR5-positive monocytes than healthy controls. Increased monocyte expression...... of CCR5 correlated weakly with an increased short-term relapse risk but there was no relationship between CCR5 Delta32 allele and CCR5 promoter polymorphism genotypes and relapse risk. CONCLUSIONS: The results do not support a major role of CCR5 in the pathogenesis of relapses in MS patients treated...

  8. Study of structure function correlation of chemokine receptor CXCR4

    Institute of Scientific and Technical Information of China (English)

    ZHENG Hong; Stephen C PEIPER; ZHU Xi-hua

    2002-01-01

    Objective: To explore the correlation between structure domains and functions of chemokine receptor CXCR4. Methods: After the establishment of wild type chemokine receptor CXCR4 and CXCR2 expressing cell lines, 5 CXCR4/CXCR2 chimeras, 2 CXCR4 mutants were stably expressed on CHO cell line.Binding activities of all variants with the ligand, recombinant human SDF-1β, signal transduction ability after stimulation and their function as coreceptor for HIV-1 were studied with ligand-binding assay, Cytosensor/microphysiometry and cell-cell reporter gene fusion assay. Results: Among all 7 changed CXCR4 receptors, 3 chimeras (2444a, 4442, 4122), and 1 mutant (CXCR4-Tr) bond with SDF-1β in varying degrees, of which only 2444a totally and CXCR4-Tr partially maintain signaling. All changed receptors except for 4222 could act as coreceptors for HIV-1(LAI) in varying degrees. Conclusion: Several structure domains of CXCR4 are involved in the binding with SDF-1β, among which, N-terminal extracellular domain has high affinity of binding with SDF-1β, and the 3rd extracellular loop contributes to the binding, too. Although the C-terminal intracellular domain has no association with the maintenance of the overall structure of the receptor and ligand binding capability, the signaling is decreased when this domain is truncated. For CXCR4 signaling, not only is the conserved motif DRY box needed, but also the characterized conformation of the whole molecule must be formed when activation is required. There are some overlaps between SDF-1β binding domains and coreceptor function domains in molecular structure of CXCR4.

  9. Immune response CC Chemokines, CCL2 and CCL5 are associated with Pulmonary Sarcoidosis

    LENUS (Irish Health Repository)

    Palchevskiy, Vyacheslav

    2011-04-04

    Abstract Background Pulmonary sarcoidosis involves an intense leukocyte infiltration of the lung with the formation of non-necrotizing granulomas. CC chemokines (chemokine (C-C motif) ligand 2 (CCL2)-CCL5) are chemoattractants of mononuclear cells and act through seven transmembrane G-coupled receptors. Previous studies have demonstrated conflicting results with regard to the associations of these chemokines with sarcoidosis. In an effort to clarify previous discrepancies, we performed the largest observational study to date of CC chemokines in bronchoalveolar lavage fluid (BALF) from patients with pulmonary sarcoidosis. Results BALF chemokine levels from 72 patients affected by pulmonary sarcoidosis were analyzed by enzyme-linked immunosorbent assay (ELISA) and compared to 8 healthy volunteers. BALF CCL3 and CCL4 levels from pulmonary sarcoidosis patients were not increased compared to controls. However, CCL2 and CCL5 levels were elevated, and subgroup analysis showed higher levels of both chemokines in all stages of pulmonary sarcoidosis. CCL2, CCL5, CC chemokine receptor type 1 (CCR1), CCR2 and CCR3 were expressed from mononuclear cells forming the lung granulomas, while CCR5 was only found on mast cells. Conclusions These data suggest that CCL2 and CCL5 are important mediators in recruiting CCR1, CCR2, and CCR3 expressing mononuclear cells as well as CCR5-expressing mast cells during all stages of pulmonary sarcoidosis.

  10. C-terminal engineering of CXCL12 and CCL5 chemokines: functional characterization by electrophysiological recordings.

    Directory of Open Access Journals (Sweden)

    Antoine Picciocchi

    Full Text Available Chemokines are chemotactic cytokines comprised of 70-100 amino acids. The chemokines CXCL12 and CCL5 are the endogenous ligands of the CXCR4 and CCR5 G protein-coupled receptors that are also HIV co-receptors. Biochemical, structural and functional studies of receptors are ligand-consuming and the cost of commercial chemokines hinders their use in such studies. Here, we describe methods for the expression, refolding, purification, and functional characterization of CXCL12 and CCL5 constructs incorporating C-terminal epitope tags. The model tags used were hexahistidines and Strep-Tag for affinity purification, and the double lanthanoid binding tag for fluorescence imaging and crystal structure resolution. The ability of modified and purified chemokines to bind and activate CXCR4 and CCR5 receptors was tested in Xenopus oocytes expressing the receptors, together with a Kir3 G-protein activated K(+ channel that served as a reporter of receptor activation. Results demonstrate that tags greatly influence the biochemical properties of the recombinant chemokines. Besides, despite the absence of any evidence for CXCL12 or CCL5 C-terminus involvement in receptor binding and activation, we demonstrated unpredictable effects of tag insertion on the ligand apparent affinity and efficacy or on the ligand dissociation. These tagged chemokines should constitute useful tools for the selective purification of properly-folded chemokines receptors and the study of their native quaternary structures.

  11. Immune response CC chemokines CCL2 and CCL5 are associated with pulmonary sarcoidosis

    Directory of Open Access Journals (Sweden)

    Palchevskiy Vyacheslav

    2011-04-01

    Full Text Available Abstract Background Pulmonary sarcoidosis involves an intense leukocyte infiltration of the lung with the formation of non-necrotizing granulomas. CC chemokines (chemokine (C-C motif ligand 2 (CCL2-CCL5 are chemoattractants of mononuclear cells and act through seven transmembrane G-coupled receptors. Previous studies have demonstrated conflicting results with regard to the associations of these chemokines with sarcoidosis. In an effort to clarify previous discrepancies, we performed the largest observational study to date of CC chemokines in bronchoalveolar lavage fluid (BALF from patients with pulmonary sarcoidosis. Results BALF chemokine levels from 72 patients affected by pulmonary sarcoidosis were analyzed by enzyme-linked immunosorbent assay (ELISA and compared to 8 healthy volunteers. BALF CCL3 and CCL4 levels from pulmonary sarcoidosis patients were not increased compared to controls. However, CCL2 and CCL5 levels were elevated, and subgroup analysis showed higher levels of both chemokines in all stages of pulmonary sarcoidosis. CCL2, CCL5, CC chemokine receptor type 1 (CCR1, CCR2 and CCR3 were expressed from mononuclear cells forming the lung granulomas, while CCR5 was only found on mast cells. Conclusions These data suggest that CCL2 and CCL5 are important mediators in recruiting CCR1, CCR2, and CCR3 expressing mononuclear cells as well as CCR5-expressing mast cells during all stages of pulmonary sarcoidosis.

  12. Fulminant lymphocytic choriomeningitis virus-induced inflammation of the CNS involves a cytokine-chemokine-cytokine-chemokine cascade

    DEFF Research Database (Denmark)

    Christensen, Jeanette Erbo; Simonsen, Stine; Fenger, Christina;

    2009-01-01

    Intracerebral inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) normally results in fatal CD8+ T cell mediated meningoencephalitis. However, in CXCL10-deficient mice, the virus-induced CD8+ T cell accumulation in the neural parenchyma is impaired, and only 30......-50% of the mice succumb to the infection. Similar results are obtained in mice deficient in the matching chemokine receptor, CXCR3. Together, these findings point to a key role for CXCL10 in regulating the severity of the LCMV-induced inflammatory process. For this reason, we now address the mechanisms regulating...... the expression of CXCL10 in the CNS of LCMV-infected mice. Using mice deficient in type I IFN receptor, type II IFN receptor, or type II IFN, as well as bone marrow chimeras expressing CXCL10 only in resident cells or only in bone marrow-derived cells, we analyzed the up-stream regulation as well as the cellular...

  13. IFN-gamma-induced chemokines synergize with pertussis toxin to promote T cell entry to the central nervous system

    DEFF Research Database (Denmark)

    Millward, Jason M; Caruso, Maria; Campbell, Iain L;

    2007-01-01

    for the chemokines CXCL10 and CCL5, to levels comparable to those seen during experimental autoimmune encephalomyelitis. Other chemokines (CXCL2, CCL2, CCL3) were not induced. Mice lacking the IFN-gammaR showed no response, and a control viral vector did not induce chemokine expression. Chemokine expression...... was predominantly localized to meningeal and ependymal cells, and was also seen in astrocytes and microglia. IFN-gamma-induced chemokine expression did not lead to inflammation. However, when pertussis toxin was given i.p. to mice infected with the IFN-gamma vector, there was a dramatic increase in the number of T...

  14. Dogs infected with the blood trypomastigote form of Trypanosoma cruzi display an increase expression of cytokines and chemokines plus an intense cardiac parasitism during acute infection.

    Science.gov (United States)

    de Souza, Sheler Martins; Vieira, Paula Melo de Abreu; Roatt, Bruno Mendes; Reis, Levi Eduardo Soares; da Silva Fonseca, Kátia; Nogueira, Nívia Carolina; Reis, Alexandre Barbosa; Tafuri, Washington Luiz; Carneiro, Cláudia Martins

    2014-03-01

    The recent increase in immigration of people from areas endemic for Chagas disease (Trypanosoma cruzi) to the United States and Europe has raised concerns about the transmission via blood transfusion and organ transplants in these countries. Infection by these pathways occurs through blood trypomastigotes (BT), and these forms of T. cruzi are completely distinct of metacyclic trypomastigotes (MT), released by triatomine vector, in relation to parasite-host interaction. Thus, research comparing infection with these different infective forms is important for explaining the potential impacts on the disease course. Here, we investigated tissue parasitism and relative mRNA expression of cytokines, chemokines, and chemokine receptors in the heart during acute infection by MT or BT forms in dogs. BT-infected dogs presented a higher cardiac parasitism, increased relative mRNA expression of pro-inflammatory and immunomodulatory cytokines and of the chemokines CCL3/MIP-1α, CCL5/RANTES, and the chemokine receptor CCR5 during the acute phase of infection, as compared to MT-infected dogs. These results suggest that infection with BT forms may lead to an increased immune response, as revealed by the cytokines ratio, but this kind of immune response was not able to control the cardiac parasitism. Infection with the MT form presented an increase in the relative mRNA expression of IL-12p40 as compared to that of IL-10 or TGF-β1. Correlation analysis showed increased relative mRNA expression of IFN-γ as well as IL-10, which may be an immunomodulatory response, as well as an increase in the correlation of CCL5/RANTES and its CCR5 receptor. Our findings revealed a difference between inoculum sources of T. cruzi, as vectorial or transfusional routes of T. cruzi infection may trigger distinct parasite-host interactions during the acute phase, which may influence immunopathological aspects of Chagas disease.

  15. The murine gammaherpesvirus-68 chemokine-binding protein M3 inhibits experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Millward, Jason M; Holst, Peter J; Høgh-Petersen, Mette;

    2010-01-01

    Chemokines are critical mediators of immune cell entry into the central nervous system (CNS), as occurs in neuroinflammatory disease such as multiple sclerosis. Chemokines are also implicated in the immune response to viral infections. Many viruses encode proteins that mimic or block chemokine...... M3 (AdM3) directly to the CNS to evaluate the capacity of this protein to inhibit neuroinflammation using the experimental autoimmune encephalomyelitis (EAE) model. Treatment with the AdM3 vector significantly reduced the clinical severity of EAE, attenuated CNS histopathology, and reduced numbers...

  16. Extracellular Disulfide Bridges Serve Different Purposes in Two Homologous Chemokine Receptors, CCR1 and CCR5

    DEFF Research Database (Denmark)

    Rummel, Pia Cwarzko; Thiele, Stefanie; Hansen, Laerke Smidt;

    2013-01-01

    chemokine receptors, high affinity CCL3 chemokine binding was maintained in the absence of either bridge. In CCR5, the closest homolog to CCR1, a completely different dependency was observed as neither chemokine activation nor binding was retained in the absence of either bridge. In contrast, both bridges...... where dispensable for small-molecule activation. This indicates that CCR5 activity is independent of extracellular regions, whereas in CCR1, preserved folding of ECL2 is necessary for activation. These results indicate that conserved structural features in a receptor subgroup, does not necessarily...

  17. CX3CL1, a chemokine finely tuned to adhesion: critical roles of the stalk glycosylation and the membrane domain

    Directory of Open Access Journals (Sweden)

    Mariano A. Ostuni

    2014-11-01

    Full Text Available The multi-domain CX3CL1 transmembrane chemokine triggers leukocyte adherence without rolling and migration by presenting its chemokine domain (CD to its receptor CX3CR1. Through the combination of functional adhesion assays with structural analysis using FRAP, we investigated the functional role of the other domains of CX3CL1, i.e., its mucin stalk, transmembrane domain, and cytosolic domain. Our results indicate that the CX3CL1 molecular structure is finely adapted to capture CX3CR1 in circulating cells and that each domain has a specific purpose: the mucin stalk is stiffened by its high glycosylation to present the CD away from the membrane, the transmembrane domain generates the permanent aggregation of an adequate amount of monomers to guarantee adhesion and prevent rolling, and the cytosolic domain ensures adhesive robustness by interacting with the cytoskeleton. We propose a model in which quasi-immobile CX3CL1 bundles are organized to quickly generate adhesive patches with sufficiently high strength to capture CX3CR1+ leukocytes but with sufficiently low strength to allow their patrolling behavior.

  18. Chemokine (C-X-C) ligand 1 (CXCL1) protein expression is increased in aggressive bladder cancers

    International Nuclear Information System (INIS)

    Chemokines, including chemokine (C-X-C motif) ligand 1 (CXCL1), may regulate tumor epithelial-stromal interactions that facilitate tumor growth and invasion. Studies have linked CXCL1 expression to gastric, colon and skin cancers, but limited studies to date have described CXCL1 protein expression in human bladder cancer (BCa). CXCL1 protein expression was examined in 152 bladder tissue specimens (142 BCa) by immunohistochemical staining. The expression of CXCL1 was scored by assigning a combined score based on the proportion of cells staining and intensity of staining. CXCL1 expression patterns were correlated with clinicopathological features and follow-up data. CXCL1 protein expression was present in cancerous tissues, but was entirely absent in benign tissue. CXCL1 combined immunostaining score was significantly higher in high-grade tumors relative to low-grade tumors (p = 0.012). Similarly, CXCL1 combined immunostaining score was higher in high stage tumors (T2-T4) than in low stage tumors (Ta-T1) (p < 0.0001). An increase in the combined immunostaining score of CXCL1 was also associated with reduced disease-specific survival. To date, this is the largest study describing increased CXCL1 protein expression in more aggressive phenotypes in human BCa. Further studies are warranted to define the role CXCL1 plays in bladder carcinogenesis and progression

  19. INTERACT

    DEFF Research Database (Denmark)

    Jochum, Elizabeth; Borggreen, Gunhild; Murphey, TD

    This paper considers the impact of visual art and performance on robotics and human-computer interaction and outlines a research project that combines puppetry and live performance with robotics. Kinesics—communication through movement—is the foundation of many theatre and performance traditions...... interaction between a human operator and an artificial actor or agent. We can apply insights from puppetry to develop culturally-aware robots. Here we describe the development of a robotic marionette theatre wherein robotic controllers assume the role of human puppeteers. The system has been built, tested......, and demonstrated in public settings. We then describe INTERACT, a proposed research project that stages the robotic marionettes in a live performance. The interdisciplinary project brings humanities research to bear on scientific and technological inquiry, and culminates in the development a live performance which...

  20. Interactions

    DEFF Research Database (Denmark)

    The main theme of this anthology is the unique interaction between mathematics, physics and philosophy during the beginning of the 20th century. Seminal theories of modern physics and new fundamental mathematical structures were discovered or formed in this period. Significant physicists such as ......The main theme of this anthology is the unique interaction between mathematics, physics and philosophy during the beginning of the 20th century. Seminal theories of modern physics and new fundamental mathematical structures were discovered or formed in this period. Significant physicists...... also key figures in the philosophical discussions of nature and science - from philosophical tendencies like logical empiricism via critical rationalism to various neo-Kantian trends....

  1. Adipose derived stem cells isolated from omentum: A novel source of chemokines for ovarian cancer growth

    Directory of Open Access Journals (Sweden)

    Somayeh Rezaeifard

    2014-01-01

    Conclusion: Omental adipose tissue may play crucial roles for tumor promotion through the expression of tumor promoting chemokines. Accordingly, tumor surrounding adipose tissue may be a novel target for immunotherapy of cancer.

  2. CC-chemokine receptors: a potential therapeutic target for Trypanosoma cruzi-elicited myocarditis.

    Science.gov (United States)

    Marino, A P M P; Silva, A A; Santos, P V A; Pinto, L M O; Gazinelli, R T; Teixeira, M M; Lannes-Vieira, J

    2005-03-01

    The comprehension of the pathogenesis of Trypanosoma cruzi-elicited myocarditis is crucial to delineate new therapeutic strategies aiming to ameliorate the inflammation that leads to heart dysfunction, without hampering parasite control. The augmented expression of CCL5/RANTES and CCL3/MIP-1alpha, and their receptor CCR5, in the heart of T. cruzi-infected mice suggests a role for CC-chemokines and their receptors in the pathogenesis of T. cruzi-elicited myocarditis. Herein, we discuss our recent results using a CC-chemokine receptor inhibitor (Met-RANTES), showing the participation of CC-chemokines in T. cruzi infection and unraveling CC-chemokine receptors as an attractive therapeutic target for further evaluation in Chagas disease.

  3. CC-chemokine receptors: a potential therapeutic target for Trypanosoma cruzi-elicited myocarditis

    Directory of Open Access Journals (Sweden)

    APMP Marino

    2005-03-01

    Full Text Available The comprehension of the pathogenesis of Trypanosoma cruzi-elicited myocarditis is crucial to delineate new therapeutic strategies aiming to ameliorate the inflammation that leads to heart dysfunction, without hampering parasite control. The augmented expression of CCL5/RANTES and CCL3/MIP-1alpha, and their receptor CCR5, in the heart of T. cruzi-infected mice suggests a role for CC-chemokines and their receptors in the pathogenesis of T. cruzi-elicited myocarditis. Herein, we discuss our recent results using a CC-chemokine receptor inhibitor (Met-RANTES, showing the participation of CC-chemokines in T. cruzi infection and unraveling CC-chemokine receptors as an attractive therapeutic target for further evaluation in Chagas disease.

  4. Structure-function analysis of the extracellular domains of the Duffy antigen/receptor for chemokines: characterization of antibody and chemokine binding sites.

    Science.gov (United States)

    Tournamille, Christophe; Filipe, Anne; Wasniowska, Kazimiera; Gane, Pierre; Lisowska, Elwira; Cartron, Jean-Pierre; Colin, Yves; Le Van Kim, Caroline

    2003-09-01

    The Duffy antigen/receptor for chemokines (DARC), a seven-transmembrane glycoprotein carrying the Duffy (Fy) blood group, acts as a widely expressed promiscuous chemokine receptor. In a structure-function study, we analysed the binding of chemokines and anti-Fy monoclonal antibodies (mAbs) to K562 cells expressing 39 mutant forms of DARC with alanine substitutions spread out on the four extracellular domains (ECDs). Using synthetic peptides, we defined previously the Fy6 epitope (22-FEDVW-26), and we characterized the Fya epitope as the linear sequence 41-YGANLE-46. In agreement with these results, mutations of F22-E23, V25 and Y41, G42, N44, L45 on ECD1 abolished the binding of anti-Fy6 and anti-Fya mAbs to K562 cells respectively, Anti-Fy3 binding was abolished by D58-D59 (ECD1), R124 (ECD2), D263 and D283 (ECD4) substitutions. Mutations of C51 (ECD1), C129 (ECD2), C195 (ECD3) and C276 (ECD4 severely reduced anti-Fy3 and CXC-chemokine ligand 8 (CXCL-8) binding. CXCL-8 binding was also abrogated by mutations of F22-E23, P50 (ECD1) and D263, R267, D283 (ECD4). These results defined the Fya epitope and suggested that (1) two disulphide bridges are involved in the creation of an active chemokine binding pocket; (2) a limited number of amino acids in ECDs 1-4 participate in CXCL-8 binding; and (3) Fy3 is a conformation-dependent epitope involving all ECDs. We also showed that N-glycosylation of DARC occurred on N16SS and did not influence antibody and chemokine binding. PMID:12956774

  5. The Coordinated Action of CC Chemokines in the Lung Orchestrates Allergic Inflammation and Airway Hyperresponsiveness

    OpenAIRE

    Gonzalo, Jose-Angel; Lloyd, Clare M.; Wen, Danyi; Albar, Juan P.; Wells, Timothy N.C.; Proudfoot, Amanda; Martinez-A, C.; Dorf, Martin; Bjerke, Torbjörn; Coyle, Anthony J.; Gutierrez-Ramos, Jose-Carlos

    1998-01-01

    The complex pathophysiology of lung allergic inflammation and bronchial hyperresponsiveness (BHR) that characterize asthma is achieved by the regulated accumulation and activation of different leukocyte subsets in the lung. The development and maintenance of these processes correlate with the coordinated production of chemokines. Here, we have assessed the role that different chemokines play in lung allergic inflammation and BHR by blocking their activities in vivo. Our results show that bloc...

  6. Role of Chemokines in Non-Small Cell Lung Cancer: Angiogenesis and Inflammation

    OpenAIRE

    Rivas-Fuentes, Selma; Salgado-Aguayo, Alfonso; Pertuz Belloso, Silvana; Gorocica Rosete, Patricia; Alvarado-Vásquez, Noé; Aquino-Jarquin, Guillermo

    2015-01-01

    Non-small cell lung cancer (NSCLC) is one of the most common types of aggressive cancer. The tumor tissue, which shows an active angiogenesis, is composed of neoplastic and stromal cells, and an abundant inflammatory infiltrate. Angiogenesis is important to support tumor growth, while infiltrating cells contribute to the tumor microenvironment through the secretion of growth factors, cytokines and chemokines, important molecules in the progression of the disease. Chemokines are important in d...

  7. Expression of IP-10 Chemokine is Regulated by Pro-inflammatory Cytokines in Cultured Hepatocytes

    Directory of Open Access Journals (Sweden)

    Gholamhossein Hassanshahi

    2007-09-01

    Full Text Available Chemokines are classified in four distinct groups as CXC, CC, CX3C and C, depending on the presence or absence of a motif called ELR (Arg-Leu-Glu before the first cysteine residue in their structure. CXC chemokines are also subdivided into ELR+ and ELR-. Increasing evidence has indicated the existence of a chemokine network in the liver which is involved in both physiological responses and, under certain circumstances, pathological and repair processes following hepatic injury.  The CXC chemokines play a major role in both these processes, and much attention has been focused on their therapeutic applications to liver disease. The aim of this study was to examine the response of cultured hepatocytes to exogenous inflammatory cytokines (TNF-a and IFN-g regarding expression of IP-10 and growth regulatory oncogen (Gro chemokines. In this study we employed western and northern analysis to measure chemokines at the level of protein and mRNA by hepatocytes in response to pro-inflammatory cytokines. We found that, the pro-inflammatory cytokines, TNF-a and IFN-g, selectively stimulated expression of IP-10 but were without effect on Gro. This confirms a potential direct involvement of these cytokines in chemokine production by hepatocytes. Thus, IFN-g and TNF-a may play a role in hepatic injury and inflammation and produce some of their biological effects by localized induction of chemokines by hepatocytes. Given the similarity to an acute phase response, we were able to show that IFN-g and TNF-a mimicked the effects of cell isolation and culture on induction of IP-10 expression. Further, evidence for linkages between IFN-g and TNF-a and liver injuries is seen in hepatitis C and hepatitis B in which increased levels of TNF-a and its soluble receptor were reported. 

  8. Molecular cloning and functional analysis of zebrafish (Danio rerio) chemokine genes.

    Science.gov (United States)

    Chen, Li-Chen; Chen, Jyh-Yih; Hour, Ai-Ling; Shiau, Chyuan-Yuan; Hui, Cho-Fat; Wu, Jen-Leih

    2008-12-01

    Chemokines control leukocyte trafficking which plays important roles in resistance to pathogenic infection. Five CXC chemokines have been reported in the zebrafish (Danio rerio) in GenBank, and herein we named them CXC-46, -56, -64, -66, and scyba. Through RT-PCR for cloning and sequencing these chemokines, the cDNA sequences of CXC-46, -56, -64, and -66 of zebrafish were determined, and it was found that the cDNA sequences were the same as those published in GenBank. Phylogenetic analysis revealed that zebrafish scyba is closest to the CXCL14 subgroup, CXC-46 is closest to the human CCL25 and catfish CXCL-2-like gene, and CXC-56, -64, and -66 are closest to the catfish CXCL10 subgroup. Further study of the tissue-specific, lipopolysaccharide (LPS) stimulation-specific, and polyinosinic-polycytidylic acid (poly I:C) stimulation-specific expressions of these five zebrafish CXC chemokine messenger (m)RNAs were determined by a comparative reverse-transcription polymerase chain reaction (RT-PCR). The RT-PCR revealed a high level of constitutive expression of CXC-56 in many tissues including the eyes, fins, heart, liver, muscles, and skin. Starvation had significant effects on the gene expressions of several zebrafish CXC chemokines including CXC-56, -64, -66, and scyba compared to the control group. Zebrafish CXC chemokines showed a concave pattern of expression after stimulation with LPS. Following poly I:C treatment of between 0.1 and 10 g/fish, dose-dependent effects were revealed. Temperature and acid-base conditions affected these zebrafish chemokines by increasing their induction compared to the control group, except for CXC-64 which exhibited no significant differences in either condition. Furthermore, these novel research results indicate that chemokines can be markers of different experimental conditions. PMID:18778789

  9. Chemokines as Therapeutic Targets to Improve Healing Efficiency of Chronic Wounds

    OpenAIRE

    Satish, Latha

    2015-01-01

    Significance: Impaired wound healing leading to chronic wounds is an important clinical problem that needs immediate attention to develop new effective therapies. Members of the chemokine family seem to be attractive and amenable to stimulate the healing process in chronic wounds. Targeting specific chemokines and/or their receptors has the potential to modify chronic inflammation to acute inflammation, which will hasten the healing process.

  10. Modulation in selectivity and allosteric properties of small-molecule ligands for CC-chemokine receptors

    DEFF Research Database (Denmark)

    Thiele, Stefanie; Malmgaard-Clausen, Mikkel; Engel-Andreasen, Jens;

    2012-01-01

    Among 18 human chemokine receptors, CCR1, CCR4, CCR5, and CCR8 were activated by metal ion Zn(II) or Cu(II) in complex with 2,2'-bipyridine or 1,10-phenanthroline with similar potencies (EC(50) from 3.9 to 172 μM). Besides being agonists, they acted as selective allosteric enhancers of CCL3...... exploration of chemokine receptors as possible targets for therapeutic intervention....

  11. Heparins modulate the IFN-γ-induced production of chemokines in human breast cancer cells.

    Science.gov (United States)

    Fluhr, Herbert; Seitz, Tina; Zygmunt, Marek

    2013-01-01

    Heparins seem to improve survival in patients with advanced malignancies independently of their anticoagulatory function. As the treatment options in advanced and metastatic breast cancer are still very limited, heparins might be an interesting addition to the existing systemic therapies. The interferon (IFN)-γ-inducible chemokines CXCL9 and CXCL10 play an essential role in the regulation of the immune milieu in malignant tumours, thereby being interesting targets for an immunological intervention. We therefore wanted to test whether heparins have an impact on the chemokines CXCL9 and CXCL10 as well as the IFN-γ signalling in human breast cancer cells in vitro. The well-established cell lines BT-474, MCF-7, SK-BR-3 and MDA-MB-231 were incubated with IFN-γ, unfractionated heparin (UFH), different low molecular weight heparins (LMWHs) and the heparin-related polyanions danaparoid and dextran sulphate. The production of CXCL9 and CXCL10 was measured by ELISA and real-time RT-PCR, the phosphorylation of signal transducer and activator of transcription (STAT) 1 was detected by an in-cell western assay and the amount of cellular bound IFN-γ was analysed by a high sensitivity ELISA. We observed that IFN-γ induced CXCL9 and CXCL10 production in MCF-7, SK-BR-3 and MDA-MB-231 cells but not in BT-474. UFH dose dependently inhibited the effect of IFN-γ on the secretion and expression of CXCL9 and CXCL10. LMWHs and heparin-related compounds differentially modulated IFN-γ-effects-the results depended on their molecular size and charge, but were independent of their anticoagulatory properties. As a reason for these heparin effects, we could show that the IFN-γ-induced phosphorylation of STAT1 was modulated by heparins, caused by an interaction with the cellular binding of IFN-γ. In conclusion, these results support the significance of the immunomodulatory properties of heparins independently of their classical anticoagulatory function. Heparin-derived sulphated

  12. Differential effects of Radix Paeoniae Rubra (Chishao on cytokine and chemokine expression inducible by mycobacteria

    Directory of Open Access Journals (Sweden)

    Li James

    2011-03-01

    Full Text Available Abstract Background Upon initial infection with mycobacteria, macrophages secrete multiple cytokines and chemokines, including interleukin-6 (IL-6, IL-8 and tumor necrosis factor-α (TNF-α, to mediate host immune responses against the pathogen. Mycobacteria also induce the production of IL-10 via PKR activation in primary human monocytes and macrophages. As an anti-inflammatory cytokine, over-expression of IL-10 may contribute to mycobacterial evasion of the host immunity. Radix Paeoniae Rubra (RPR, Chishao, a Chinese medicinal herb with potentials of anti-inflammatory, hepatoprotective and neuroprotective effects, is used to treat tuberculosis. This study investigates the immunoregulatory effects of RPR on primary human blood macrophages (PBMac during mycobacterial infection. Methods The interaction of Bacillus Calmette-Guerin (BCG with PBMac was used as an experimental model. A series of procedures involving solvent extraction and fractionation were used to isolate bioactive constituents in RPR. RPR-EA-S1, a fraction with potent immunoregulatory effects was obtained with a bioactivity guided fractionation scheme. PBMac were treated with crude RPR extracts or RPR-EA-S1 before BCG stimulation. The expression levels of IL-6, IL-8, IL-10 and TNF-α were measured by qPCR and ELISA. Western blotting was used to determine the effects of RPR-EA-S1 on signaling kinases and transcriptional factors in the BCG-activated PBMac. Results In BCG-stimulated macrophages, crude RPR extracts and fraction RPR-EA-S1 specifically inhibited IL-10 production while enhanced IL-8 expression at both mRNA and protein levels without affecting the expressions of IL-6 and TNF-α. Inhibition of BCG-induced IL-10 expression by RPR-EA-S1 occurred in a dose- and time-dependent manner. RPR-EA-S1 did not affect the phosphorylation of cellular protein kinases including MAPK, Akt and GSK3β. Instead, it suppressed the degradation of IκBα in the cytoplasm and inhibited the

  13. Chemokines: a new dendritic cell signal for T cell activation

    Directory of Open Access Journals (Sweden)

    Christoph A Thaiss

    2011-08-01

    Full Text Available Dendritic cells (DCs are the main inducers and regulators of cytotoxic T lymphocyte (CTL responses against viruses and tumors. One checkpoint to avoid misguided CTL activation, which might damage healthy cells of the body, is the necessity for multiple activation signals, involving both antigenic as well as additional signals that reflect the presence of pathogens. DCs provide both signals when activated by ligands of pattern recognition receptors and licensed by helper lymphocytes. Recently, it has been established that such T cell licensing can be facilitated by CD4+ T helper cells (classical licensing or by NKT cells (alternative licensing. Licensing regulates the DC/CTL cross-talk at multiple layers. Direct recruitment of CTLs through chemokines released by licensed DCs has recently emerged as a common theme and has a crucial impact on the efficiency of CTL responses. Here, we discuss recent advances in our understanding of DC licensing for cross-priming and implications for the temporal and spatial regulation underlying this process. Future vaccination strategies will benefit from a deeper insight into the mechanisms that govern CTL activation.

  14. [Chemokine Receptor-5 and Graft-versus-Host Disease].

    Science.gov (United States)

    Yuan, Jing; Liu, Wei; Ren, Han-Yun

    2015-06-01

    Chemokine receptor-5 (CCR5) belongs to a G-protein coupled receptors superfamily. It is mainly expressed on a wide variety of immune cells. CCR5 can bind with its specific ligands, which plays very important roles in inflammatory cell growth, differentiation, activation, adhesion and migration. CCR5 was identified as a co-receptor for human immunodeficiency virus type-1 (HIV-1) to infect CD4+ T cells. In addition, CCR5 not only participates in the pathogenic mechanisms of many inflammation disease such as AIDS, auto-immune disease, and atherosclerosis, but also plays important roles in the development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Recent studies using murine models have demonstrated the critical role of CCR5 and its ligands which direct T-cell infiltration and recruitment into target tissues during acute GVHD. CCR5 has become the focus of intense interest and discussion, and this review will attempt to describe what is understood about the structure and function, internalization, signal transduction of CCR5, in order to investigate the relationship between CCR5 and acute GVHD. PMID:26117055

  15. Follicular Proinflammatory Cytokines and Chemokines as Markers of IVF Success

    Directory of Open Access Journals (Sweden)

    Aili Sarapik

    2012-01-01

    Full Text Available Cytokines are key modulators of the immune system and also contribute to regulation of the ovarian cycle. In this study, Bender MedSystems FlowCytomix technology was used to analyze follicular cytokines (proinflammatory: IL-1β, IL-6, IL-18, IFN-γ, IFN-α, TNF-α, IL-12, and IL-23;, and anti-inflammatory: G-CSF, chemokines (MIP-1α, MIP-1β, MCP-1, RANTES, and IL-8, and other biomarkers (sAPO-1/Fas, CD44(v6 in 153 women undergoing in vitro fertilization (IVF. Cytokine origin was studied by mRNA analysis of granulosa cells. Higher follicular MIP-1α and CD44(v6 were found to correlate with polycystic ovary syndrome, IL-23, INF-γ, and TNF-α with endometriosis, higher CD44(v6 but lower IL-β and INF-α correlated with tubal factor infertility, and lower levels of IL-18 and CD44(v6 characterized unexplained infertility. IL-12 positively correlated with oocyte fertilization and embryo development, while increased IL-18, IL-8, and MIP-1β were associated with successful IVF-induced pregnancy.

  16. CD8 chemokine receptors in chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Smyth, L J C; Starkey, C; Gordon, F S;

    2008-01-01

    Increased lung CD8 cells and their expression of chemokine receptors CXCR3 and CCR5 have been previously reported in chronic obstructive pulmonary disease (COPD). Alterations of CD8-CCR3 and -CCR4 expression and their ligands in COPD patients have not been fully investigated. The objective......, smokers and healthy non-smokers (HNS). CCL5 and CCL11 levels were measured in BAL, and from the supernatants of lung resection explant cultures. CD8-CCR3 and -CCR5 expression (means) were increased in COPD patients (22% and 46% respectively) and smokers (20% and 45%) compared with HNS (3% and 22%); P ....05 for all comparisons. CD3CXCR3 expression was raised in smokers and COPD while CD8CXCR3 and CD3 and CD8 CCR4 expression was similar between groups. CD8CCR5 expression correlated to smoking pack years (r = 0.42, P = 0.01). COPD explants released more CCL5 compared with smokers (P = 0.02), while...

  17. Chemokine expression in hepatocellular carcinoma versus colorectal liver metastases

    Institute of Scientific and Technical Information of China (English)

    Claudia Rubie; Vilma Oliveira Frick; Mathias Wagner; Christina Weber; Bianca Kruse; Katja Kempf; Jochen K(o)nig; Bettina Rau; Martin Schilling

    2006-01-01

    AIM: To evaluate and compare the expression profiles of CXCL12 (SDF-1), CCL19 (MIP-3β), CCL20 (MIP-3α) and CCL21 (6Ckine, Exodus2) and their receptors on RNA and protein levels in hepatocellular carcinoma (HCC) versus colorectal liver metastases (CRLM) and to elucidate their impact on the carcinogenesis and progression of malignant liver diseases.METHODS: Chemokine expression was analyzed by RT-PCR and ELISA in 11 cases of HCC specimens and in 23 cases of CRLM and corresponding adjacent nontumorous liver tissues, respectively. Expressions of their receptors CXCR4, CCR6 and CCR7 were analyzed by RTPCR and Western blot analysis in the same cases of HCC and CRLM.RESULTS: Significant up-regulation for CCL20/CCR6 was detected in both cancer types. Moreover, CCL20demonstrated significant overexpression in CRLM in relation to the HCC tissues. Being significantly upregulated only in CRLM, CXCR4 displayed an aberrant expression pattern with respect to the HCC tissues.CONCLUSION: Correlation of CXCR4 expression with CRLM suggests CXCR4 as a potential predictive factor for CRLM. High level expression of CCL20 and its receptor CCR6 in HCC and CRLM with marked upregulation of CCL20 in CRLM in relation to HCC tissues indicates involvement of the CCL20/CCR6 ligand-receptor pair in the carcinogenesis and progression of hepatic malignancies.

  18. Principal component analysis of the cytokine and chemokine response to human traumatic brain injury.

    Directory of Open Access Journals (Sweden)

    Adel Helmy

    Full Text Available There is a growing realisation that neuro-inflammation plays a fundamental role in the pathology of Traumatic Brain Injury (TBI. This has led to the search for biomarkers that reflect these underlying inflammatory processes using techniques such as cerebral microdialysis. The interpretation of such biomarker data has been limited by the statistical methods used. When analysing data of this sort the multiple putative interactions between mediators need to be considered as well as the timing of production and high degree of statistical co-variance in levels of these mediators. Here we present a cytokine and chemokine dataset from human brain following human traumatic brain injury and use principal component analysis and partial least squares discriminant analysis to demonstrate the pattern of production following TBI, distinct phases of the humoral inflammatory response and the differing patterns of response in brain and in peripheral blood. This technique has the added advantage of making no assumptions about the Relative Recovery (RR of microdialysis derived parameters. Taken together these techniques can be used in complex microdialysis datasets to summarise the data succinctly and generate hypotheses for future study.

  19. Chagas' disease and Duffy antigen/receptor for chemokine (DARC: a mini-review

    Directory of Open Access Journals (Sweden)

    AP Oliveira

    2011-01-01

    Full Text Available Duffy gene (FY codifies the transmembrane glycoprotein Duffy (gp-Fy of 35 to 43 kDa which is moderately immunogenic. This glycoprotein is polymorphic, and constitutes the antigens of the Duffy histo-blood system which were designated receptors for chemokines and denominated DARC (Duffy antigen/receptor for chemokine. This receptor has an important role in the regulation of chemokine levels in the circulation, as it binds and adsorbs them on the surface of red cells as a reservoir. It plays a "sink" role, which can contribute to homeostasis by removing inflammatory chemokines from circulation as well as maintaining them in plasmatic levels. Chronic Chagas' cardiopathy (CCC is the most frequent form of the disease. It is an inflammatory disease, in which infiltrated inflammatory cells play an important role in the development and progress of the infection. High chemokine levels in the plasma have been associated with the disease severity in patients with heart failure. In this context, the profile of DARC expression could play an important function as a receptor for chemokines in Chagas' disease, in patients with CCC, as it can modulate damage from this inflammatory disease.

  20. The role of CXC chemokine ligand (CXCL)12-CXC chemokine receptor (CXCR)4 signalling in the migration of neural stem cells towards a brain tumour

    NARCIS (Netherlands)

    van der Meulen, A. A. E.; Biber, K.; Lukovac, S.; Balasubramaniyan, V.; den Dunnen, W. F. A.; Boddeke, H. W. G. M.; Mooij, J. J. A.

    2009-01-01

    Aims: It has been shown that neural stem cells (NSCs) migrate towards areas of brain injury or brain tumours and that NSCs have the capacity to track infiltrating tumour cells. The possible mechanism behind the migratory behaviour of NSCs is not yet completely understood. As chemokines are involved

  1. Down-regulation of the chemokine receptor CCR5 by activation of chemotactic formyl peptide receptor in human monocytes.

    Science.gov (United States)

    Shen, W; Li, B; Wetzel, M A; Rogers, T J; Henderson, E E; Su, S B; Gong, W; Le, Y; Sargeant, R; Dimitrov, D S; Oppenheim, J J; Wang, J M

    2000-10-15

    Interactions between cell surface receptors are important regulatory elements in the complex host responses to infections. In this study, it is shown that a classic chemotactic factor, the bacterial chemotactic peptide N-formyl-methionyl-leucylphenyl-alanine (fMLF), rapidly induced a protein-kinase-C-mediated serine phosphorylation and down-regulation of the chemokine receptor CCR5, which serves as a major human immunodeficiency virus (HIV)-1 coreceptor. The fMLF binding to its receptor, formyl peptide receptor (FPR), resulted in significant attenuation of cell responses to CCR5 ligands and in inhibition of HIV-1-envelope-glycoprotein-mediated fusion and infection of cells expressing CD4, CCR5, and FPR. The finding that the expression and function of CCR5 can be regulated by peptides that use an unrelated receptor may provide a novel approach to the design of anti-inflamatory and antiretroviral agents. (Blood. 2000;96:2887-2894)

  2. The atypical chemokine receptor D6 contributes to the development of experimental colitis1

    Science.gov (United States)

    Bordon, Yvonne; Hansell, Chris A. H.; Sester, David P; Clarke, Mairi; Mowat, Allan McI.; Nibbs, Robert J. B.

    2009-01-01

    Pro-inflammatory CC chemokines control leukocyte recruitment and function during inflammation by engaging chemokine receptors expressed on circulating leukocytes. The D6 chemokine receptor can bind several of these chemokines but appears unable to couple to signal transduction pathways or direct cell migration. Instead, D6 has been proposed to act as a chemokine scavenger, removing pro-inflammatory chemokines to dampen leukocyte responses. In this report, we have examined the role of D6 in the colon using the dextran sodium sulphate-induced model of colitis. We show that D6 is expressed in the resting colon, predominantly by stromal cells and B cells, and is up-regulated during colitis. Unexpectedly, D6-deficient mice showed reduced susceptibility to colitis and had less pronounced clinical symptoms associated with this model. D6 deletion had no impact on the level of pro-inflammatory CC chemokines released from cultured colon explants, or on the balance of leukocyte subsets recruited to the inflamed colon. However, late in colitis, inflamed D6-deficient colons showed enhanced production of several pro-inflammatory cytokines, including IFNγ and IL-17A, and there was a marked increase in IL-17A-secreting γδ T cells in the lamina propria. Moreover, antibody-mediated neutralisation of IL-17A worsened the clinical symptoms of colitis at these later stages of the response in D6-deficient, but not wild-type, mice. Thus, D6 can contribute to the development of colitis by regulating IL-17A secretion by γδ T cells in the inflamed colon. PMID:19342683

  3. Induction of the Chemokines CCL3α, CCL3α and CCL5 in Atherosclerotic Patients

    Directory of Open Access Journals (Sweden)

    Alyaa Mousa

    2007-01-01

    Full Text Available Chemokines recruit immune cells to inflammatory sites and promote the process of inflammation. The role of these mediators in the disease process in atherosclerosis is not fully studied. The spontaneous mRNA expression and intracellular protein production of the potential inflammatory chemokines CCL3 and CCL3 (macrophage- inflammatory protein-1and ; CCR3 ligand and CCL5 (regulated upon activation, normal T cell expressed and secreted (RANTES; CCR5 ligand in atherosclerotic patients was examined together with the effects of the chlamydial antigen HSP60 and LPS on the gene expression and protein induction of these mediators. Detection of chemokine mRNA and protein levels was assessed by in situ hybridization and immunohistochemistry respectively. The examined chemokines were detected at significantly high levels on atherosclerotic patients compared to healthy controls at both mRNA and protein levels. Stimulation with HSP60 and LPS from Chlamydia pneumoniae (C. pneumoniae and E. coli showed increased numbers of CCL3, CCL3 and CCL5 mRNA expressing cells in patients compared to health controls. Protein translation of these chemokines was depicted in correspondence to the mRNA gene expression for all examined chemokines spontaneously and after stimulation with chlamydial HSP60 and LPS and E. coli LPS. Thus, the herein data demonstrate the induction of potential inflammatory chemokines in atherosclerotic patients and that bacterial antigens play a role in the immunopathologic events in this disease by generating more inflammatory mediators.

  4. Chemokine Ligand 5 (CCL5 and chemokine receptor (CCR5 genetic variants and prostate cancer risk among men of African Descent: a case-control study

    Directory of Open Access Journals (Sweden)

    Kidd LaCreis R

    2012-11-01

    Full Text Available Abstract Background Chemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs are associated with various cancers, their impact on prostate cancer (PCA among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses. Methods Sequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls using Illumina’s Goldengate genotyping system. Results Inheritance of CCL5 rs2107538 (AA, GA+AA and rs3817655 (AA, AG, AG+AA genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively. Conclusions In summary, CCL5 (rs2107538, rs3817655 and CCR5 (rs1799988 sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent.

  5. The chemokine receptor CXCR6 contributes to recruitment of bone marrow-derived fibroblast precursors in renal fibrosis

    OpenAIRE

    Xia, Yunfeng; Yan, Jingyin; Jin, Xiaogao; Entman, Mark L.; Wang, Yanlin

    2014-01-01

    Bone marrow-derived fibroblasts in circulation are of hematopoietic origin, proliferate, differentiate into myofibroblasts, and express the chemokine receptor CXCR6. Since chemokines mediate the trafficking of circulating cells to sites of injury, we studied the role of CXCR6 in mouse models of renal injury. Significantly fewer bone marrow-derived fibroblasts accumulated in the kidney of CXCR6 knockout mice in response to injury, expressed less profibrotic chemokines and cytokines, displayed ...

  6. Comparative study of CXC chemokines modulation in brown trout (Salmo trutta) following infection with a bacterial or viral pathogen.

    Science.gov (United States)

    Gorgoglione, Bartolomeo; Zahran, Eman; Taylor, Nick G H; Feist, Stephen W; Zou, Jun; Secombes, Christopher J

    2016-03-01

    Chemokine modulation in response to pathogens still needs to be fully characterised in fish, in view of the recently described novel chemokines present. This paper reports the first comparative study of CXC chemokine genes transcription in salmonids (brown trout), with a particular focus on the fish specific CXC chemokines (CXCL_F). Adopting new primer sets, optimised to specifically target mRNA, a RT-qPCR gene screening was carried out. Constitutive gene expression was assessed first in six tissues from SPF brown trout. Transcription modulation was next investigated in kidney and spleen during septicaemic infection induced by a RNA virus (Viral Haemorrhagic Septicaemia virus, genotype Ia) or by a Gram negative bacterium (Yersinia ruckeri, ser. O1/biot. 2). From each target organ specific pathogen burden, measured detecting VHSV-glycoprotein or Y. ruckeri 16S rRNA, and IFN-γ gene expression were analysed for their correlation to chemokine transcription. Both pathogens modulated CXC chemokine gene transcript levels, with marked up-regulation seen in some cases, and with both temporal and tissue specific effects apparent. For example, Y. ruckeri strongly induced chemokine transcription in spleen within 24h, whilst VHS generally induced the largest increases at 3d.p.i. in both tissues. This study gives clues to the role of the novel CXC chemokines, in comparison to the other known CXC chemokines in salmonids. PMID:26866873

  7. The Relation Chemokines ENA-78 of and Acute Pancreatitis%趋化因子ENA-78与急性胰腺炎关系的研究进展

    Institute of Scientific and Technical Information of China (English)

    魏小峰

    2011-01-01

    Some researches confirmed that chemokines ENA-78 is important in the pathogenesis of acute pancreatitis. It is a source of a wide range of chemokines of diverse biological functions, through interaction with its receptor,causing neutrophils and other leukocyte chemotaxis and activation may be one of factors in acute pancreatitis. The high-expression of the chemokines ENA-78 is postulated to play an essential role in the local inflammatory reactions seen in acute pancreatitis and its associated organ injury. The deep research of the chemokines ENA-78 and its receptors,will provide new strategy for the therapy of acute pancreatitis.%趋化因子ENA-78在急性胰腺炎(AP)的发病和发展中所起的作用越来越受到重视,它是一种来源广泛、生物功能多样的趋化因子,通过与其受体相互作用,引起中性粒细胞等白细胞的趋化及活化可能是AP的原因之一.趋化因子ENA-78的高表达对AP和其相关脏器损伤的发生、发展有重要意义.对趋化因子ENA-78及其受体的深入研究能给AP的治疗提供新的策略.

  8. Inhibition of dengue virus production and cytokine/chemokine expression by ribavirin and compound A.

    Science.gov (United States)

    Rattanaburee, Thidarath; Junking, Mutita; Panya, Aussara; Sawasdee, Nunghathai; Songprakhon, Pucharee; Suttitheptumrong, Aroonroong; Limjindaporn, Thawornchai; Haegeman, Guy; Yenchitsomanus, Pa-thai

    2015-12-01

    Dengue virus (DENV) infection is a worldwide public health problem with an increasing magnitude. The severity of disease in the patients with DENV infection correlates with high viral load and massive cytokine production - the condition referred to as "cytokine storm". Thus, concurrent inhibition of DENV and cytokine production should be more effective for treatment of DENV infection. In this study, we investigated the effects of the antiviral agent - ribavirin (RV), and the anti-inflammatory compound - compound A (CpdA), individually or in combination, on DENV production and cytokine/chemokine transcription in human lung epithelial carcinoma (A549) cells infected with DENV. Initially, the cells infected with DENV serotype 2 (DENV2) was studied. The results showed that treatment of DENV-infected cells with RV could significantly reduce both DENV production and cytokine (IL-6 and TNF-α) and chemokine (IP-10 and RANTES) transcription while treatment of DENV-infected cells with CpdA could significantly reduce cytokine (IL-6 and TNF-α) and chemokine (RANTES) transcription. Combined RV and CpdA treatment of the infected cells showed greater reduction of DENV production and cytokine/chemokine transcription. Similar results of this combined treatment were observed for infection with any one of the four DENV (DENV1, 2, 3, and 4) serotypes. These results indicate that combination of the antiviral agent and the anti-inflammatory compound offers a greater efficiency in reduction of DENV and cytokine/chemokine production, providing a new therapeutic approach for DENV infection.

  9. Emerging importance of chemokine receptor CXCR3 and its ligands in cardiovascular diseases.

    Science.gov (United States)

    Altara, Raffaele; Manca, Marco; Brandão, Rita D; Zeidan, Asad; Booz, George W; Zouein, Fouad A

    2016-04-01

    The CXC chemokines, CXCL4, -9, -10, -11, CXCL4L1, and the CC chemokine CCL21, activate CXC chemokine receptor 3 (CXCR3), a cell-surface G protein-coupled receptor expressed mainly by Th1 cells, cytotoxic T (Tc) cells and NK cells that have a key role in immunity and inflammation. However, CXCR3 is also expressed by vascular smooth muscle and endothelial cells, and appears to be important in controlling physiological vascular function. In the last decade, evidence from pre-clinical and clinical studies has revealed the participation of CXCR3 and its ligands in multiple cardiovascular diseases (CVDs) of different aetiologies including atherosclerosis, hypertension, cardiac hypertrophy and heart failure, as well as in heart transplant rejection and transplant coronary artery disease (CAD). CXCR3 ligands have also proven to be valid biomarkers for the development of heart failure and left ventricular dysfunction, suggesting an underlining pathophysiological relation between levels of these chemokines and the development of adverse cardiac remodelling. The observation that several of the above-mentioned chemokines exert biological actions independent of CXCR3 provides both opportunities and challenges for developing effective drug strategies. In this review, we provide evidence to support our contention that CXCR3 and its ligands actively participate in the development and progression of CVDs, and may additionally have utility as diagnostic and prognostic biomarkers. PMID:26888559

  10. The integrative roles of chemokines at the maternal-fetal interface in early pregnancy.

    Science.gov (United States)

    Du, Mei-Rong; Wang, Song-Cun; Li, Da-Jin

    2014-09-01

    Embryos express paternal antigens that are foreign to the mother, but the mother provides a special immune milieu at the fetal-maternal interface to permit rather than reject the embryo growth in the uterus until parturition by establishing precise crosstalk between the mother and the fetus. There are unanswered questions in the maintenance of pregnancy, including the poorly understood phenomenon of maternal tolerance to the allogeneic conceptus, and the remarkable biological roles of placental trophoblasts that invade the uterine wall. Chemokines are multifunctional molecules initially described as having a role in leukocyte trafficking and later found to participate in developmental processes such as differentiation and directed migration. It is increasingly evident that the gestational uterine microenvironment is characterized, at least in part, by the differential expression and secretion of chemokines that induce selective trafficking of leukocyte subsets to the maternal-fetal interface and regulate multiple events that are closely associated with normal pregnancy. Here, we review the expression and function of chemokines and their receptors at the maternal-fetal interface, with a special focus on chemokine as a key component in trophoblast invasiveness and placental angiogenesis, recruitment and instruction of immune cells so as to form a fetus-supporting milieu during pregnancy. The chemokine network is also involved in pregnancy complications. PMID:25109684

  11. CXC chemokine ligand 12/Stromal cell-derived factor-1 regulates cell adhesion in human colon cancer cells by induction of intercellular adhesion molecule-1

    OpenAIRE

    Tung Shui-Yi; Chang Shun-Fu; Chou Ming-Hui; Huang Wen-Shih; Hsieh Yung-Yu; Shen Chien-Heng; Kuo Hsing-Chun; Chen Cheng-Nan

    2012-01-01

    Abstract Background The CXC chemokine ligand 12 (CXCL12)/stromal cell-derived factor-1 (SDF-1) and CXC receptor 4 (CXCR4) axis is involved in human colorectal cancer (CRC) carcinogenesis and can promote the progression of CRC. Interaction between CRC cells and endothelium is a key event in tumor progression. The aim of this study was to investigate the effect of SDF-1 on the adhesion of CRC cells. Methods Human CRC DLD-1 cells were used to study the effect of SDF-1 on intercellular adhesion m...

  12. CCR5 signalling, but not DARC or D6 regulatory, chemokine receptors are targeted by herpesvirus U83A chemokine which delays receptor internalisation via diversion to a caveolin-linked pathway

    Directory of Open Access Journals (Sweden)

    Gompels Ursula A

    2009-07-01

    Full Text Available Abstract Background Herpesviruses have evolved chemokines and chemokine receptors, which modulate the recruitment of human leukocytes during the inflammatory response to infection. Early post-infection, human herpesvirus 6A (HHV-6A infected cells express the chemokine receptor U51A and chemokine U83A which have complementary effects in subverting the CC-chemokine family thereby controlling anti-viral leukocyte recruitment. Here we show that, to potentiate this activity, the viral chemokine can also avoid clearance by scavenger chemokine receptors, DARC and D6, which normally regulate an inflammatory response. Conversely, U83A delays internalisation of its signalling target receptor CCR5 with diversion to caveolin rich membrane domains. This mechanism can redirect displaced human chemokines to DARC and D6 for clearance of the anti-viral inflammatory response, leaving the viral chemokine unchecked. Methods Cell models for competitive binding assays were established using radiolabeled human chemokines and cold U83A on CCR5, DARC or D6 expressing cells. Flow cytometry was used to assess specific chemotaxis of CCR5 bearing cells to U83A, and internalisation of CCR5 specific chemokine CCL4 after stimulation with U83A. Internalisation analyses were supported by confocal microscopy of internalisation and co-localisation of CCR5 with caveosome marker caveolin-1, after virus or human chemokine stimulation. Results U83A displaced efficiently human chemokines from CCR5, with a high affinity of 0.01nM, but not from DARC or D6. Signalling via CCR5 resulted in specific chemoattraction of primary human leukocytes bearing CCR5. However, U83A effective binding and signalling to CCR5 resulted in delayed internalisation and recycling up to 2 hours in the absence of continual re-stimulation. This resulted in diversion to a delayed caveolin-linked pathway rather than the rapid clathrin mediated endocytosis previously shown with human chemokines CCL3 or CCL4

  13. Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain

    Directory of Open Access Journals (Sweden)

    Zhang Zhi-Jun

    2012-07-01

    Full Text Available Abstract Background Neuropathic pain in the trigeminal system is frequently observed in clinic, but the mechanisms involved are largely unknown. In addition, the function of immune cells and related chemicals in the mechanism of pain has been recognized, whereas few studies have addressed the potential role of chemokines in the trigeminal system in chronic pain. The present study was undertaken to test the hypothesis that chemokine C-C motif ligand 2 (CCL2-chemokine C-C motif receptor 2 (CCR2 signaling in the trigeminal nucleus is involved in the maintenance of trigeminal neuropathic pain. Methods The inferior alveolar nerve and mental nerve transection (IAMNT was used to induce trigeminal neuropathic pain. The expression of ATF3, CCL2, glial fibrillary acidic protein (GFAP, and CCR2 were detected by immunofluorescence histochemical staining and western blot. The cellular localization of CCL2 and CCR2 were examined by immunofluorescence double staining. The effect of a selective CCR2 antagonist, RS504393 on pain hypersensitivity was checked by behavioral testing. Results IAMNT induced persistent (>21 days heat hyperalgesia of the orofacial region and ATF3 expression in the mandibular division of the trigeminal ganglion. Meanwhile, CCL2 expression was increased in the medullary dorsal horn (MDH from 3 days to 21 days after IAMNT. The induced CCL2 was colocalized with astroglial marker GFAP, but not with neuronal marker NeuN or microglial marker OX-42. Astrocytes activation was also found in the MDH and it started at 3 days, peaked at 10 days and maintained at 21 days after IAMNT. In addition, CCR2 was upregulated by IAMNT in the ipsilateral medulla and lasted for more than 21 days. CCR2 was mainly colocalized with NeuN and few cells were colocalized with GFAP. Finally, intracisternal injection of CCR2 antagonist, RS504393 (1, 10 μg significantly attenuated IAMNT-induced heat hyperalgesia. Conclusion The data suggest that CCL2-CCR

  14. Dynamic T-lymphocyte chemokine receptor expression induced by interferon-beta therapy in multiple sclerosis

    DEFF Research Database (Denmark)

    Krakauer, M; Sorensen, P S; Khademi, M;

    2006-01-01

    as these influence central nervous system (CNS) transmigration and inflammation. At 'steady state' (>/=1 day after the most recent IFN-beta injection), IFN-beta treatment increased CD4(+) T-cell surface expression of CC chemokine receptor (CCR)4, CCR5 and CCR7 after 3 months of treatment, whereas that of CXC...... and immunoregulatory genes. In conclusion, IFN-beta treatment caused 'steady-state' increases of several chemokine receptors relevant for CD4(+) T-lymphocyte trafficking and function, possibly facilitating lymphocyte migration into the CNS. An important therapeutic effect of IFN-beta treatment may be the normalization...... of a decreased Th2-related CD4(+) T-cell CCR4 expression in MS patients. Surface chemokine receptor expression and CXCL10 varied according to the timing of blood sampling in relation to the most recent IFN-beta injection. Thus, it is imperative to distinguish acute effects of IFN-beta from steady-state effects....

  15. Structure of the CCR5 Chemokine Receptor-HIV Entry Inhibitor Maraviroc Complex

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Qiuxiang; Zhu, Ya; Li, Jian; Chen, Zhuxi; Han, Gye Won; Kufareva, Irina; Li, Tingting; Ma, Limin; Fenalti, Gustavo; Li, Jing; Zhang, Wenru; Xie, Xin; Yang, Huaiyu; Jiang, Hualiang; Cherezov, Vadim; Liu, Hong; Stevens, Raymond C.; Zhao, Qiang; Wu, Beili [Scripps; (Chinese Aca. Sci.); (UCSD)

    2013-10-21

    The CCR5 chemokine receptor acts as a co-receptor for HIV-1 viral entry. Here we report the 2.7 angstrom–resolution crystal structure of human CCR5 bound to the marketed HIV drug maraviroc. The structure reveals a ligand-binding site that is distinct from the proposed major recognition sites for chemokines and the viral glycoprotein gp120, providing insights into the mechanism of allosteric inhibition of chemokine signaling and viral entry. A comparison between CCR5 and CXCR4 crystal structures, along with models of co-receptor–gp120-V3 complexes, suggests that different charge distributions and steric hindrances caused by residue substitutions may be major determinants of HIV-1 co-receptor selectivity. These high-resolution insights into CCR5 can enable structure-based drug discovery for the treatment of HIV-1 infection.

  16. Chemokines in Chronic Liver Allograft Dysfunction Pathogenesis and Potential Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Bin Liu

    2013-01-01

    Full Text Available Despite advances in immunosuppressive drugs, long-term success of liver transplantation is still limited by the development of chronic liver allograft dysfunction. Although the exact pathogenesis of chronic liver allograft dysfunction remains to be established, there is strong evidence that chemokines are involved in organ damage induced by inflammatory and immune responses after liver surgery. Chemokines are a group of low-molecular-weight molecules whose function includes angiogenesis, haematopoiesis, mitogenesis, organ fibrogenesis, tumour growth and metastasis, and participating in the development of the immune system and in inflammatory and immune responses. The purpose of this review is to collect all the research that has been done so far concerning chemokines and the pathogenesis of chronic liver allograft dysfunction and helpfully, to pave the way for designing therapeutic strategies and pharmaceutical agents to ameliorate chronic allograft dysfunction after liver transplantation.

  17. Chemokine-Releasing Microparticles Improve Bacterial Clearance and Survival of Anthrax Spore-Challenged Mice

    Science.gov (United States)

    Espina, Virginia; Liotta, Lance A.; Popov, Serguei G.

    2016-01-01

    In this study the hydrogel microparticles (MPs) were used to enhance migration of neutrophils in order to improve outcome of anthrax infection in a mouse model. Two MP formulations were tested. In the first one the polyacrylamide gel MPs were chemically coupled with Cibacron Blue (CB) affinity bait. In the second one the bait molecules within the MPs were additionally loaded with neutrophil-attracting chemokines (CKs), human CXCL8 and mouse CCL3. A non-covalent interaction of the bait with the CKs provided their gradual release after administration of the MPs to the host. Mice were challenged into footpads with Bacillus anthracis Sterne spores and given a dose of MPs a few hours before and/or after the spores. Pre-treatment with a single dose of CK-releasing MPs without any additional intervention was able to induce influx of neutrophils to the site of spore inoculation and regional lymph nodes correlating with reduced bacterial burden and decreased inflammatory response in footpads. On average, in two independent experiments, up to 53% of mice survived over 13 days. All control spore-challenged but MP-untreated mice died. The CB-coupled particles were also found to improve survival likely due to the capacity to stimulate release of endogenous CKs, but were less potent at decreasing the inflammatory host response than the CK-releasing MPs. The CK post-treatment did not improve survival compared to the untreated mice which died within 4 to 6 days with a strong inflammation of footpads, indicating quick dissemination of spores though the lymphatics after challenge. This is the first report on the enhanced innate host resistance to anthrax in response to CKs delivered and/or endogenously induced by the MPs. PMID:27632537

  18. T cells respond to heat shock protein 60 via TLR2: activation of adhesion and inhibition of chemokine receptors.

    Science.gov (United States)

    Zanin-Zhorov, Alexandra; Nussbaum, Gabriel; Franitza, Susanne; Cohen, Irun R; Lider, Ofer

    2003-08-01

    Soluble 60 kDa heat shock protein (HSP60) activates macrophages via TLR4. We now report that soluble HSP60 activates T cells via the innate receptor TLR2. HSP60 activated T cell adhesion to fibronectin to a degree similar to other activators: IL-2, SDF-1alpha, and RANTES. T cell type and state of activation was important; nonactivated CD45RA+ and IL-2-activated CD45RO+ T cells responded optimally (1 h) at low concentrations (0.1-1 ng/ml), but nonactivated CD45RO+ T cells required higher concentrations (approximately 1 microg/ml) of HSP60. T cell HSP60 signaling was inhibited specifically by monoclonal antibodies (mAb) to TLR2 but not by a mAb to TLR4. Indeed, T cells from mice with mutated TLR4 could still respond to HSP60, whereas Chinese hamster T cells with mutated TLR2 did not respond. The human T cell response to soluble HSP60 depended on phosphatidylinositol 3-kinase and protein kinase C signaling and involved the phosphorylation of Pyk-2. Soluble HSP60 also inhibited actin polymerization and T cell chemotaxis through extracellular matrix-like gels toward the chemokines SDF-1alpha (CXCL12) or ELC (CCL19). Exposure to HSP60 for longer times (18 h) down-regulated chemokine receptor expression: CXCR4 and CCR7. These results suggest that soluble HSP60, through TLR2-dependent interactions, can regulate T cell behavior in inflammation. PMID:12824285

  19. Chemokines: structure, receptors and functions. A new target for inflammation and asthma therapy?

    Directory of Open Access Journals (Sweden)

    F. A. A. van Acker

    1996-01-01

    Full Text Available Five to 10% of the human population have a disorder of the respiratory tract called ‘asthma’. It has been known as a potentially dangerous disease for over 2000 years, as it was already described by Hippocrates and recognized as a disease entity by Egyptian and Hebrew physicians. At the beginning of this decade, there has been a fundamental change in asthma management. The emphasis has shifted from symptom relief with bronchodilator therapies (e.g. β2-agonists to a much earlier introduction of anti-inflammatory treatment (e.g. corticosteroids. Asthma is now recognized to be a chronic inflammatory disease of the airways, involving various inflammatory cells and their mediators. Although asthma has been the subject of many investigations, the exact role of the different inflammatory cells has not been elucidated completely. Many suggestions have been made and several cells have been implicated in the pathogenesis of asthma, such as the eosinophils, the mast cells, the basophils and the lymphocytes. To date, however, the relative importance of these cells is not completely understood. The cell type predominantly found in the asthmatic lung is the eosinophil and the recruitment of these eosinophils can be seen as a characteristic of asthma. In recent years much attention is given to the role of the newly identified chemokines in asthma pathology. Chemokines are structurally and functionally related 8–10 kDa peptides that are the products of distinct genes clustered on human chromosomes 4 and 17 and can be found at sites of inflammation. They form a superfamily of proinflammatory mediators that promote the recruitment of various kinds of leukocytes and lymphocytes. The chemokine superfamily can be divided into three subgroups based on overall sequence homology. Although the chemokines have highly conserved amino acid sequences, each of the chemokines binds to and induces the chemotaxis of particular classes of white blood cells. Certain

  20. Chemokine receptor expression on B cells and effect of interferon-beta in multiple sclerosis

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Roed, Hanne; Sellebjerg, Finn

    2002-01-01

    We investigated the B-cell expression of chemokine receptors CXCR3, CXCR5 and CCR5 in the blood and cerebrospinal fluid (CSF) from patients in relapse of multiple sclerosis (MS) and in neurological controls. Chemokine receptor expression was also studied in interferon-beta-treated patients...... with relapsing-remitting or secondary progressive MS. We observed significantly higher expression of CXCR3 on B cells in the CSF in active MS than in controls. Patients with active MS also had higher B-cell expression of CCR5 in blood. No major differences between RRMS and SPMS patients were detected...

  1. Structure, function and physiological consequences of virally encoded chemokine seven transmembrane receptors

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Smit, M J; Waldhoer, M

    2008-01-01

    A number of human and animal herpes viruses encode G-protein coupled receptors with seven transmembrane (7TM) segments-most of which are clearly related to human chemokine receptors. It appears, that these receptors are used by the virus for immune evasion, cellular transformation, tissue targeting...... pathogenesis is still poorly understood. Here we focus on the current knowledge of structure, function and trafficking patterns of virally encoded chemokine receptors and further address the putative roles of these receptors in virus survival and host -cell and/or -immune system modulation. Finally, we...

  2. Inhibition of Epithelial CC-Family Chemokine Synthesis by the Synthetic Chalcone DMPF-1 via Disruption of NF-κB Nuclear Translocation and Suppression of Experimental Asthma in Mice

    OpenAIRE

    Revathee Rajajendram; Chau Ling Tham; Mohamad Nadeem Akhtar; Mohd Roslan Sulaiman; Daud Ahmad Israf

    2015-01-01

    Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The interaction between airway epithelium and inflammatory mediators plays a key role in the pathogenesis of asthma. In vitro studies evaluated the inhibitory effects of 3-(2,5-dimethoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one (DMPF-1), a synthetic chalcone analogue, upon inflammation in the A549 lung epithelial cell line. DMPF-1 selectively inhibited TNF-α-stimulated CC chemokine secretion (RANTES...

  3. Dual blockade of the pro-inflammatory chemokine CCL2 and the homeostatic chemokine CXCL12 is as effective as high dose cyclophosphamide in murine proliferative lupus nephritis.

    Science.gov (United States)

    Devarapu, Satish Kumar; Kumar Vr, Santhosh; Rupanagudi, Khader Valli; Kulkarni, Onkar P; Eulberg, Dirk; Klussmann, Sven; Anders, Hans-Joachim

    2016-08-01

    Induction therapy of proliferative lupus nephritis still requires the use of unselective immunosuppressive drugs with significant toxicities. In search of more specific drugs with equal efficacy but fewer side effects we considered blocking pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) and homeostatic chemokine stromal cell-derived factor-1 (SDF-1/CXCL12), which both contribute to the onset and progression of proliferative lupus nephritis yet through different mechanisms. We hypothesized that dual antagonism could be as potent on lupus nephritis as the unselective immunosuppressant cyclophosphamide (CYC). We estimated serum levels of CCL2 and CXCL12 in patients with SLE (n=99) and compared the results with healthy individuals (n=21). In order to prove our hypothesis we used l-enantiomeric RNA Spiegelmer® chemokine antagonists, i.e. the CCL2-specific mNOX-E36 and the CXCL12-specific NOX-A12 to treat female MRL/lpr mice from week 12 to 20 of age with either anti-CXCL12 or anti-CCL2 alone or both. SLE patients showed elevated serum levels of CCL2 but not of CXCL12. Female MRL/lpr mice treated with dual blockade showed significantly more effective than either monotherapy in preventing proteinuria, immune complex glomerulonephritis, and renal excretory failure and the results are at par with CYC treatment. Dual blockade reduced leukocyte counts and renal IL-6, IL-12p40, CCL-5, CCL-2 and CCR-2 mRNA expression. Dual blockade of CCL2 and CXCL12 can be as potent as CYC to suppress the progression of proliferative lupus nephritis probably because the respective chemokine targets mediate different disease pathomechanisms, i.e. systemic autoimmunity and peripheral tissue inflammation. PMID:27392463

  4. The herpesvirus 8-encoded chemokine vMIP-II, but not the poxvirus-encoded chemokine MC148, inhibits the CCR10 receptor

    DEFF Research Database (Denmark)

    Lüttichau, H R; Lewis, I C; Gerstoft, J;

    2001-01-01

    chemokines are expressed in the skin we suspected MC148 to block CCR10. However, in calcium mobilization assays we found MC148 unable to block CCR10 in micromolar concentrations in contrast to vMIP-II. (125)I-MC148 was only able to bind to CCR8, but not to CCR10, CCR11, CXCR6 / BONZO, APJ, DARC or the orphan...

  5. Systemic administration of the chemokine macrophage inflammatory protein 1α exacerbates inflammatory bowel disease in a mouse model

    OpenAIRE

    Pender, S L-F; Chance, V; Whiting, C V; Buckley, M; Edwards, M.; Pettipher, R; MacDonald, T T

    2005-01-01

    Introduction: Exacerbations of inflammatory bowel disease are thought to be related to concurrent infections. As infections are associated with elevated local and serum concentrations of chemokines, we have determined whether systemic administration of the CC chemokine macrophage inflammatory protein 1α (MIP-1α) exacerbates colitis in a mouse model.

  6. Molecular cloning of porcine chemokine CXC motif ligand 2 (CXCL2) and mapping to the SSC8

    Science.gov (United States)

    Maternal recognition of pregnancy is accompanied by inflammatory responses with leukocytosis and increased levels of cytokines and chemokines. Human trophoblast cells secrete chemokine CXC motif ligand 1 (CXCL1)/Gro-a and other chemotactic proteins, while monocytes co-cultured with trophoblast cells...

  7. Low prevalence of antibodies and other plasma factors binding to CC chemokines and IL-2 in HIV-positive patients

    DEFF Research Database (Denmark)

    Meyer, C N; Svenson, M; Larsen, Carsten Schade;

    2000-01-01

    Neutralizing cytokine antibodies are found in healthy and diseased individuals, including patients treated with recombinant cytokines. Identification of CCR-5 as co-receptor for HIV has focused interest on CC chemokines and their potential therapeutic use. Chemokine-binding components in plasma...

  8. Evidence favoring the involvement of CC chemokine receptor (CCR) 5 in T-lymphocyte accumulation in optic neuritis

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Ransohoff, R M; Jensen, J;

    2003-01-01

    To define the relationships between levels of chemokine receptor (CCR)5+ T-cells in blood and cerebrospinal fluid (CSF) of optic neuritis (ON) and control patients (CON).......To define the relationships between levels of chemokine receptor (CCR)5+ T-cells in blood and cerebrospinal fluid (CSF) of optic neuritis (ON) and control patients (CON)....

  9. Differential gene expression during capillary morphogenesis in a microcarrier-based three-dimensional in vitro model of angiogenesis with focus on chemokines and chemokine receptors

    Institute of Scientific and Technical Information of China (English)

    Xi-Tai Sun; Min-Yue Zhang; Chang Shu; Qiang Li; Xiao-Gui Yan; Ni Cheng; Yu-Dong Qiu; Yi-Tao Ding

    2005-01-01

    AIM: To globally compare the gene expression profiles during the capillary morphogenesis of human microvascular endothelial cells (HMVECs) in an in vitro angiogenesis system with affymetrix oligonucleotide array.METHODS: A microcarrier-based in vitro angiogenesis system was developed, in which ECs migrated into the matrix,proliferated, and formed capillary sprouts. The sprouts elongated, branched and formed networks. The total RNA samples from the HMVECs at the selected time points (0.5,24, and 72 h) during the capillary morphogenesis were used for microarray analyses, and the data were processed with the softwares provided by the manufacturers. The expression patterns of some genes were validated and confirmed by semi-quantitative RT-PCR. The regulated genes were grouped based on their molecular functions and expression patterns, and among them the expression of chemokines and chemokine receptors was specially examined and their functional implications were analyzed.RESULTS: A total of 1 961 genes were up- or downregulated two-folds or above, and among them, 468 genes were up- or down-regulated three-folds or above. The regulated genes could be grouped into categories based on their molecular functions, and were also clustered into six groups based on their patterns of expression. As for chemokines and chemokine receptors, CXCL1/GRO-α,CXCL2/GRO-β, CXCLS/ENA-78, CXCL6/GCP2, IL-8/CXCL8,CXCL12/SDF-1, CXCL9/Mig, CXC11/ITAC, CX3CL1/fractalkine,CCL2/MCP-1, CCL3, CCLS/RANTES, CCL7, CCL15, CCL21,CCL23, CCL28, and CCR1, CCR9, CXCR4 were identified.Moreover, these genes demonstrated different changing patterns during the capillary morphogenesis, which implied that they might have different roles in the sequential process. Among the chemokines identified, CCL2/MCP-1,CCL5/RANTES and CX3CL1 were specially up-regulated at the 24-h time point when the sprouting characterized the morphological change. It was thus suggested that they might exert crucial roles at the early stage

  10. Targeting cytokine/chemokine receptors : a challenge for molecular nuclear medicine

    NARCIS (Netherlands)

    Signore, A; Chianelli, M; Bei, R; Oyen, W; Modesti, A

    2003-01-01

    Radiolabelled cytokines and chemokines are a group of radiopharmaceuticals that, by highlighting in vivo the binding to specific high-affinity receptors expressed on selected cell populations, allow the molecular and functional characterisation of immune-mediated processes Recently, several authors

  11. Smoothing T cell roads to the tumor: Chemokine post-translational regulation.

    Science.gov (United States)

    Molon, Barbara; Viola, Antonella; Bronte, Vincenzo

    2012-05-01

    We described a novel tumor-associated immunosuppressive mechanism based on post-translational modifications of chemokines by reactive nitrogen species (RNS). To overcome tumor immunosuppressive hindrances, we designed and developed a new drug, AT38, that inhibits RNS generation at the tumor site. Combinatorial approaches with AT38 boost the effectiveness of cancer immunotherapy protocols.

  12. Doxycycline Is Anti-Inflammatory and Inhibits Staphylococcal Exotoxin-Induced Cytokines and Chemokines

    OpenAIRE

    Krakauer, Teresa; Buckley, Marilyn

    2003-01-01

    Proinflammatory cytokines mediate the toxic effect of superantigenic staphylococcal exotoxins (SE). Doxycycline inhibited SE-stimulated T-cell proliferation and production of cytokines and chemokines by human peripheral blood mononuclear cells. These results suggest that the antibiotic doxycycline has anti-inflammatory effects and is therapeutically useful for mitigating the pathogenic effects of SE.

  13. Channel catfish, Ictalurus punctatus, chemokine receptor CXCR4 cDNA

    Science.gov (United States)

    Chemokine receptor CXCR4, a member of the G protein-coupled receptor superfamily, binds selectively CXCL12. This protein plays many important roles in immunological as well as pathophysiological functions. In this communication, we identified and characterized the channel catfish CXCR4 transcript....

  14. Chemokines responses to Plasmodium falciparum malaria and co-infections among rural Cameroonians.

    Science.gov (United States)

    Che, Jane Nchangnwi; Nmorsi, Onyebiguwa Patrick Goddey; Nkot, Baleguel Pierre; Isaac, Clement; Okonkwo, Browne Chukwudi

    2015-04-01

    Malaria remains the major cause of disease morbidity and mortality in sub-Saharan Africa with complex immune responses associated with disease outcomes. Symptoms associated with severe malaria have generally shown chemokine upregulation but little is known of responses to uncomplicated malaria. Eight villages in central Cameroon of 1045 volunteers were screened. Among these, malaria-positive individuals with some healthy controls were selected for chemokine analysis using Enzyme-Linked Immunosorbent Assay (ELISA) kits. Depressed serum levels of CXCL5 and raised CCL28 were observed in malarial positives when compared with healthy controls. The mean concentration of CXCL11 was higher in symptomatic than asymptomatic group, while CCL28 was lower in symptomatic individuals. Lower chemokine levels were associated with symptoms of uncomplicated malaria except for CXCL11 which was upregulated among fever-positive group. The mean CXCL5 level was higher in malaria sole infection than co-infections with HIV and Loa loa. Also, there was a raised mean level of malaria+HIV co-infection for CXCL9. This study hypothesises a situation where depressed chemokines in the face of clinical presentations could indicate an attempt by the immune system in preventing a progression process from uncomplicated to complicated outcomes with CXCL11 being identified as possible biomarker for malarial fever.

  15. Bicyclams, selective antagonists of the human chemokine receptor CXCR4, potently inhibit feline immunodeficiency virus replication

    NARCIS (Netherlands)

    Horzinek, M.C.; Egberink, H.F.; Clercq, E. de; Vliet, A.L.W. van; Balzarini, J.; Bridger, G.J.; Henson, G.; Schols, D.

    1999-01-01

    Bicyclams are low-molecular-weight anti-human immunodeficiency virus (HIV) agents that have been shown to act as potent and selective CXC chemokine receptor 4 (CXCR4) antagonists. Here, we demonstrate that bicyclams are potent inhibitors of feline immunodeficiency virus (FIV) replication when evalua

  16. Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

    OpenAIRE

    Rees, Peter Adam; Greaves, Nicholas Stuart; Baguneid, Mohamed; Bayat, Ardeshir

    2015-01-01

    Significance: Cutaneous scarring is an almost inevitable end point of adult human wound healing. It is associated with significant morbidity, both physical and psychological. Pathological scarring, including hypertrophic and keloid scars, can be particularly debilitating. Manipulation of the chemokine system may lead to effective therapies for problematic lesions.

  17. Design, synthesis, and functionalization of dimeric peptides targeting chemokine receptor CXCR4.

    NARCIS (Netherlands)

    Demmer, O.; Dijkgraaf, I.; Schumacher, U.; Marinelli, L.; Cosconati, S.; Gourni, E.; Wester, H.J.; Kessler, H.

    2011-01-01

    The chemokine receptor CXCR4 is a critical regulator of inflammation and immune surveillance, and it is specifically implicated in cancer metastasis and HIV-1 infection. On the basis of the observation that several of the known antagonists remarkably share a C(2) symmetry element, we constructed sym

  18. Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices.

    Science.gov (United States)

    Wescott, Melanie P; Kufareva, Irina; Paes, Cheryl; Goodman, Jason R; Thaker, Yana; Puffer, Bridget A; Berdougo, Eli; Rucker, Joseph B; Handel, Tracy M; Doranz, Benjamin J

    2016-08-30

    The atomic-level mechanisms by which G protein-coupled receptors (GPCRs) transmit extracellular ligand binding events through their transmembrane helices to activate intracellular G proteins remain unclear. Using a comprehensive library of mutations covering all 352 residues of the GPCR CXC chemokine receptor 4 (CXCR4), we identified 41 amino acids that are required for signaling induced by the chemokine ligand CXCL12 (stromal cell-derived factor 1). CXCR4 variants with each of these mutations do not signal properly but remain folded, based on receptor surface trafficking, reactivity to conformationally sensitive monoclonal antibodies, and ligand binding. When visualized on the structure of CXCR4, the majority of these residues form a continuous intramolecular signaling chain through the transmembrane helices; this chain connects chemokine binding residues on the extracellular side of CXCR4 to G protein-coupling residues on its intracellular side. Integrated into a cohesive model of signal transmission, these CXCR4 residues cluster into five functional groups that mediate (i) chemokine engagement, (ii) signal initiation, (iii) signal propagation, (iv) microswitch activation, and (v) G protein coupling. Propagation of the signal passes through a "hydrophobic bridge" on helix VI that coordinates with nearly every known GPCR signaling motif. Our results agree with known conserved mechanisms of GPCR activation and significantly expand on understanding the structural principles of CXCR4 signaling. PMID:27543332

  19. Staphylococcus aureus Targets the Duffy Antigen Receptor for Chemokines (DARC) to Lyse Erythrocytes

    NARCIS (Netherlands)

    Spaan, András N.; Reyes-Robles, Tamara; Badiou, Cédric; Cochet, Sylvie; Boguslawski, Kristina M.; Yoong, Pauline; Day, Christopher J.; Gosselaar-de Haas, Carla J C; van Kessel, Kok P M; Vandenesch, François; Jennings, Michael P.; Le Van Kim, Caroline; Colin, Yves; Van Strijp, Jos A G; Henry, Thomas; Torres, Victor J.

    2015-01-01

    In order for Staphylococcus aureus to thrive inside the mammalian host, the bacterium has to overcome iron scarcity. S. aureus is thought to produce toxins that lyse erythrocytes, releasing hemoglobin, the most abundant iron source in mammals. Here we identify the Duffy antigen receptor for chemokin

  20. Analysis of Arrestin Recruitment to Chemokine Receptors by Bioluminescence Resonance Energy Transfer.

    Science.gov (United States)

    Bonneterre, J; Montpas, N; Boularan, C; Galés, C; Heveker, N

    2016-01-01

    Chemokine receptors recruit the multifunctional scaffolding protein beta arrestin in response to binding of their chemokine ligands. Given that arrestin recruitment represents a signaling axis that is in part independent from G-protein signaling, it has become a hallmark of G protein-coupled receptor functional selectivity. Therefore, quantification of arrestin recruitment has become a requirement for the delineation of chemokine and drug candidate activity along different signaling axes. Bioluminescence resonance energy transfer (BRET) techniques provide methodology for such quantification that can reveal differences between nonredundant chemokines binding the same receptor, and that can be upscaled for high-throughput testing. We here provide protocols for the careful setup of BRET-based arrestin recruitment assays, and examples for the application of such systems in dose-response or time-course experiments. Suggestions are given for troubleshooting, optimizing test systems, and the interpretation of results obtained with BRET-based assays, which indeed yield an intricate blend of quantitative and qualitative information.

  1. Dengue virus requires the CC-chemokine receptor CCR5 for replication and infection development.

    Science.gov (United States)

    Marques, Rafael E; Guabiraba, Rodrigo; Del Sarto, Juliana L; Rocha, Rebeca F; Queiroz, Ana Luiza; Cisalpino, Daniel; Marques, Pedro E; Pacca, Carolina C; Fagundes, Caio T; Menezes, Gustavo B; Nogueira, Maurício L; Souza, Danielle G; Teixeira, Mauro M

    2015-08-01

    Dengue is a mosquito-borne disease that affects millions of people worldwide yearly. Currently, there is no vaccine or specific treatment available. Further investigation on dengue pathogenesis is required to better understand the disease and to identify potential therapeutic targets. The chemokine system has been implicated in dengue pathogenesis, although the specific role of chemokines and their receptors remains elusive. Here we describe the role of the CC-chemokine receptor CCR5 in Dengue virus (DENV-2) infection. In vitro experiments showed that CCR5 is a host factor required for DENV-2 replication in human and mouse macrophages. DENV-2 infection induces the expression of CCR5 ligands. Incubation with an antagonist prevents CCR5 activation and reduces DENV-2 positive-stranded (+) RNA inside macrophages. Using an immunocompetent mouse model of DENV-2 infection we found that CCR5(-/-) mice were resistant to lethal infection, presenting at least 100-fold reduction of viral load in target organs and significant reduction in disease severity. This phenotype was reproduced in wild-type mice treated with CCR5-blocking compounds. Therefore, CCR5 is a host factor required for DENV-2 replication and disease development. Targeting CCR5 might represent a therapeutic strategy for dengue fever. These data bring new insights on the association between viral infections and the chemokine receptor CCR5.

  2. Platelet-Derived CCL5 Regulates CXC Chemokine Formation and Neutrophil Recruitment in Acute Experimental Colitis.

    Science.gov (United States)

    Yu, Changhui; Zhang, Songen; Wang, Yongzhi; Zhang, Su; Luo, Lingtao; Thorlacius, Henrik

    2016-02-01

    Accumulating data suggest that platelets not only regulate thrombosis and haemostasis but also inflammatory processes. Platelets contain numerous potent pro-inflammatory compounds, including the chemokines CCL5 and CXCL4, although their role in acute colitis remains elusive. The aim of this study is to examine the role of platelets and platelet-derived chemokines in acute colitis. Acute colitis is induced in female Balb/c mice by administration of 5% dextran sodium sulfate (DSS) for 5 days. Animals receive a platelet-depleting, anti-CCL5, anti-CXCL4, or a control antibody prior to DSS challenge. Colonic tissue is collected for quantification of myeloperoxidase (MPO) activity, CXCL5, CXCL2, interleukin-6 (IL-6), and CCL5 levels as well as morphological analyses. Platelet depletion reduce tissue damage and clinical disease activity index in DSS-exposed animals. Platelet depletion not only reduces levels of CXCL2 and CXCL5 but also levels of CCL5 in the inflamed colon. Immunoneutralization of CCL5 but not CXCL4 reduces tissue damage, CXC chemokine expression, and neutrophil recruitment in DSS-treated animals. These findings show that platelets play a key role in acute colitis by regulating CXC chemokine generation, neutrophil infiltration, and tissue damage in the colon. Moreover, our results suggest that platelet-derived CCL5 is an important link between platelet activation and neutrophil recruitment in acute colitis.

  3. Tumor Necrosis Factor (TNF) and Chemokines in Colitis-Associated Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mukaida, Naofumi, E-mail: naofumim@kenroku.kanazawa-u.ac.jp; Sasakki, So-ichiro [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Popivanova, Boryana K. [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Present Address, Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan)

    2011-06-27

    The connection between inflammation and tumorigenesis has been well established, based on a great deal of supporting evidence obtained from epidemiological, pharmacological, and genetic studies. One representative example is inflammatory bowel disease, because it is an important risk factor for the development of colon cancer. Moreover, intratumoral infiltration of inflammatory cells suggests the involvement of inflammatory responses also in other forms of sporadic as well as heritable colon cancer. Inflammatory responses and tumorigenesis activate similar sets of transcription factors such as NF-κB, Stat3, and hypoxia inducible factor and eventually enhances the expression of inflammatory cytokines including tumor necrosis factor (TNF) and chemokines. The expression of TNF and chemokines is aberrantly expressed in a mouse model of colitis-associated carcinogenesis as well as in inflammatory bowel disease and colon cancer in humans. Here, after summarizing the presumed actions of TNF and chemokines in tumor biology, we will discuss the potential roles of TNF and chemokines in chronic inflammation-associated colon cancer in mice.

  4. 77 FR 10598 - BIOTECH Holdings Ltd., California Oil & Gas Corp., Central Minera Corp., Chemokine Therapeutics...

    Science.gov (United States)

    2012-02-22

    ... From the Federal Register Online via the Government Publishing Office SECURITIES AND EXCHANGE COMMISSION BIOTECH Holdings Ltd., California Oil & Gas Corp., Central Minera Corp., Chemokine Therapeutics... concerning the securities of BIOTECH Holdings Ltd. because it has not filed any annual reports since...

  5. Molecular interaction of a potent nonpeptide agonist with the chemokine receptor CCR8

    DEFF Research Database (Denmark)

    Jensen, Pia C; Nygaard, Rie; Thiele, Stefanie;

    2007-01-01

    ), and N-(1-(3-(2-methoxyphenoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydro-2-oxoquinoline-4-carboxamide (LMD-174)] included several key-residues for nonpeptide antagonists targeting CCR1, -2, and -5. It is noteworthy that a decrease in potency of nearly 1000-fold was observed for all five compounds for...

  6. Environmental mold and mycotoxin exposures elicit specific cytokine and chemokine responses.

    Directory of Open Access Journals (Sweden)

    Jamie H Rosenblum Lichtenstein

    Full Text Available Molds can cause respiratory symptoms and asthma. We sought to use isolated peripheral blood mononuclear cells (PBMCs to understand changes in cytokine and chemokine levels in response to mold and mycotoxin exposures and to link these levels with respiratory symptoms in humans. We did this by utilizing an ex vivo assay approach to differentiate mold-exposed patients and unexposed controls. While circulating plasma chemokine and cytokine levels from these two groups might be similar, we hypothesized that by challenging their isolated white blood cells with mold or mold extracts, we would see a differential chemokine and cytokine release.Peripheral blood mononuclear cells (PBMCs were isolated from blood from 33 patients with a history of mold exposures and from 17 controls. Cultured PBMCs were incubated with the most prominent Stachybotrys chartarum mycotoxin, satratoxin G, or with aqueous mold extract, ionomycin, or media, each with or without PMA. Additional PBMCs were exposed to spores of Aspergillus niger, Cladosporium herbarum and Penicillium chrysogenum. After 18 hours, cytokines and chemokines released into the culture medium were measured by multiplex assay. Clinical histories, physical examinations and pulmonary function tests were also conducted. After ex vivo PBMC exposures to molds or mycotoxins, the chemokine and cytokine profiles from patients with a history of mold exposure were significantly different from those of unexposed controls. In contrast, biomarker profiles from cells exposed to media alone showed no difference between the patients and controls.These findings demonstrate that chronic mold exposures induced changes in inflammatory and immune system responses to specific mold and mycotoxin challenges. These responses can differentiate mold-exposed patients from unexposed controls. This strategy may be a powerful approach to document immune system responsiveness to molds and other inflammation-inducing environmental agents.

  7. High doses of dietary zinc induce cytokines, chemokines, and apoptosis in reproductive tissues during regression.

    Science.gov (United States)

    Sundaresan, N R; Anish, D; Sastry, K V H; Saxena, V K; Nagarajan, K; Subramani, J; Leo, M D M; Shit, N; Mohan, J; Saxena, M; Ahmed, K A

    2008-06-01

    In chickens, high levels of dietary zinc cause molting, and the reproductive system undergoes complete remodeling concomitant to feather replacement. In the present study, the expression profiles of cytokines and chemokines were investigated in the ovary and oviduct of control hens and of hens induced to molt by zinc feeding. The zinc-induced feed-intake suppression, the changes in corticosterone levels, the immune cell populations in the reproductive tract, and the apoptosis of reproductive tissues were analyzed. The expression of mRNAs for interleukin-6 (IL-6), interferon-gamma (IFN-gamma), the avian ortholog of mammalian IL-8 (chCXCLi2), and a chicken MIP-1beta-like chemokine (chCCLi2) in the ovary and of mRNAs for IL-1beta, IL-6, IFN-gamma, transforming growth factor-beta2, chCXCLi2, and chCCLi2 in the oviduct were upregulated significantly during zinc-induced molting. A simultaneous feed-intake reduction was observed with higher expression of cytokines and chemokines. The results of the present investigation also suggested that the upregulation of corticosterone was closely associated with the increased expression of cytokines and chemokines. An increase in apoptosis within reproductive tissue during tissue regression was also noted. We had previously observed the upregulation of these cytokines expression in an earlier study (molting by feed withdrawal). However, the pattern and the level of expression were different among these two methods. These findings indicate that cytokines might be a common mediator of tissue regression during molting induced by diverse methods, although the pattern of induction is different. Thus, a high dose of dietary zinc seems to induce reproductive regression via the upregulation of cytokines and chemokines, the suppression of feed intake, and the increase in serum corticosterone, resulting finally in the apoptosis of reproductive tissues. PMID:18351392

  8. Chemokines responses to ascaris lumbricoides sole infection and co-infection with hookworm among Nigerians

    Directory of Open Access Journals (Sweden)

    Omorodion Oriri Asemota

    2014-01-01

    Full Text Available Background: Geohelminth infections are predominant in Nigeria and communities at greatest risks are those with poor environmental/sanitary conditions and unhygienic habits. Chemokine ligands (CXCL a class under chemokine group play important roles in the immune system by either mediating susceptible or protective immune responses to parasitic infections. Aim: This study was to assess the impact of Ascaris lumbricoides sole infection and co-infection on some serum chemokines (CXCL5, CXCL9, and CXCL11 in infected Nigerians. Materials and Methods: A total of 194 individuals attending Agbor general hospital were examined for A. lumbricoides and hookworm infections. Thereafter, sera were obtained from positive volunteers and control group using enzyme-linked immunosorbent assay to examine the impact of these helminth infections on the serum concentration of some chemokines (CXCL5, CXCL9, and CXCL11. Results: The mean sera levels of CXCL5 and CXCL9 in infected volunteers were higher than the control subjects. Also, positive correlation was recorded for CXCL9 (P > 0.05, while negative responses were seen for CXCL5 and CXCL11 (P > 0.05 in relation to increase in the intensities of infections. CXCL9 was more expressed in A. lumbricoides + hookworm co-infections than single. Furthermore, the mean concentration of CXCL5 was higher in infected females than males (P < 0.05. Conclusion: The proinflammatory responses of CXCL5 and CXCL9 to A. lumbricoides and hookworm infections could be an indication of the meditating roles of these chemokines in the immune system to either confer some form of host/parasite immunity or susceptibility.

  9. LEVELS OF ANGIOGENESIS-REGULATORY CHEMOKINES IN THE SYNOVIAL FLUID OF PATIENTS WITH RHEUMATOID ARTHRITIS

    Directory of Open Access Journals (Sweden)

    D. A. Zhebrun

    2015-01-01

    Full Text Available The role of chemokines in the immunopathogenesis of rheumatoid arthritis (RA has been actively investigated in recent years. Angiogenic and angiostatic chemokines are important mediators of angiogenesis in the development and extent of pannus. Peripheral blood and synovial fluid (SF is a major biomaterial in clinical and immunological studies. At the same time, it is the SF test that may yield the most informative results since that gives an idea of the processes that occur locally within a joint. Objective: to perform a comparative analysis of the levels of a number of CXC, CC, and CX3C chemokines in the SF of patients with RA, osteoarthritis (OA, and joint injuries. Subjects and methods. The multiplex analysis using xMAP technology (Luminex, USA was used to analyze levels of CXC, CC, and CX3C chemokines in SF and serum of patients with RA (n = 20, OA (n = 9 and controls (n = 9. Results and discussion. The SF levels of CCL24/eotaxin-2, as well as those of the angiostatic chemokines CXCL9/MIG, CXCL10/IP10, CXCL11/ITAC, and CXCL13/BCA-1 were higher in the RA group than in the control and OA groups. There was a direct correlation between SF levels of CCL5/RANTES and DAS28, as well as patient global disease activity assessment on visual analogue scale, and that between the level of CCL2/MCP-1 in the SF and that of anticyclic citrullinated peptide (anti-CCP antibodies in the serum. The SF concentrations of CXCL5/ENA78 and CXCL7/NAP-2 were shown to depend on the presence of serum anti-CCP. Serum CXCL13/BCA-1 levels were higher in RA than those in OA, as that of CXCL7/NAP-2 than in the control group.

  10. Chemokines, innate and adaptive immunity, and respiratory disease

    OpenAIRE

    Sabroe, I.; Lloyd, C.M.; Whyte, M K B; Dower, S.K.; Williams, T J; Pease, J.E.

    2002-01-01

    Selective leukocyte trafficking and recruitment is primarily regulated by a specific family of small proteins called “chemokines”. This extended family shepherds and guides leukocytes through their lives, facilitating their development, regulating their interactions with other leukocyte types, and guiding their recruitment to sites of inflammation.

  11. Activation of the CXCR3 chemokine receptor through anchoring of a small molecule chelator ligand between TM-III, -IV, and -VI

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Andersen, Michael B; Nygaard, Rie;

    2006-01-01

    between the extracellular ends of transmembrane (TM) III and TM-IV to anchor aromatic chelators at a location corresponding to the presumed binding pocket for adrenergic receptor agonists. In this construct, free metal ions had no agonistic effect in accordance with the optimal geometry of the metal ion...... site in molecular models built over the inactive form of rhodopsin. In contrast, the aromatic chelators bipyridine or phenanthrolene in complex with Zn(II) or Cu(II) acted as potent agonists displaying signaling efficacies similar to or even better than the endogenous chemokine agonists. Molecular...... modeling and molecular simulations combined with mutational analysis indicated that the metal ion site-anchored chelators act as agonists by establishing an aromatic-aromatic, second-site interaction with TyrVI:16 on the inner face of TM-VI. It is noteworthy that this interaction required...

  12. Circulating thymus and activation-regulated chemokine/CC chemokine ligand 17 is a strong candidate diagnostic marker for interstitial lung disease in patients with malignant tumors: a result from a pilot study

    OpenAIRE

    Yamane H; Ochi N; Yamagishi T; Honda Y; Takeyama M; Takigawa N

    2015-01-01

    Hiromichi Yamane, Nobuaki Ochi, Tomoko Yamagishi, Yoshihiro Honda, Masami Takeyama, Nagio TakigawaDepartment of General Internal Medicine 4, Kawasaki Medical School, Kita-ku, Okayama, JapanIntroduction: Serum Krebs von den Lungen-6 (KL-6) level is an established diagnostic marker of interstitial lung disease (ILD). However, it is also elevated in patients with non-small cell lung cancer (NSCLC). The significance of circulating thymus and activation-regulated chemokine (TARC)/CC chemokine liga...

  13. Classification of distinct subtypes of peripheral T-cell lymphoma unspecified, identified by chemokine and chemokine receptor expression: Analysis of prognosis.

    Science.gov (United States)

    Ohshima, Koichi; Karube, Kennosuke; Kawano, Riko; Tsuchiya, Takeshi; Suefuji, Hiroaki; Yamaguchi, Takahiro; Suzumiya, Junji; Kikuchii, Masahiro

    2004-09-01

    WHO classification for malignant lymphoma was recently proposed. However, PTCL is heterogeneous. Chemokines and its receptors are closely associated with the T-cell subtypes. To clarify the T-cell subtype in PTCL, we conducted DNA chips of chemokine, its receptor (R) and cytokines. Angioimmunoblastic T-cell lymphoma (AILD, n=4), anaplastic large cell lymphoma (ALCL, n=4), adult T-cell leukemia lymphoma (ATLL, n=7), NK-cell lymphoma (NKL, n=2) and PTCL, unspecified (PTCL-U, n=6) were analyzed using DNA chips. In addition, immunological stainings were performed in 280 cases. In DNA chip, AILD, ALCL, NKL and ATLL showed a tendency for respective clusters, otherwise, PTCL-U clustered with AILD, ALCL and ATLL. From the gene expression profiling, CCR4, CCR3, MIG, CXCR3 and BLC were selected for immunohistochemistry. ATLL (n=48) expressed CCR4. ALCL (n=26) expressed CCR3, NKL (n=20) expressed MIG, and AILD (n=29) expressed CXCR3 and/or BLC. From the expression patterns, PTCL-U (n=134) were classified into three groups; CCR4 type (CCR4(+), n=42), CCR3 type (CCR3(+), n=31) and CXCR3 type (CXCR3(+) BLC(+/-), n=54). The prognosis was poor for ATLL, intermediate for AILD and favorable for ALCL (P=0.0014). Among PTCL-U, CCR4 type, CXCR3 type and CCR3 type had prognoses equivalent to ATLL, AILD and ALCL, respectively (P<0.0001).

  14. Osteolytic lesions, cytogenetic features and bone marrow levels of cytokines and chemokines in multiple myeloma patients: Role of chemokine (C-C motif) ligand 20.

    Science.gov (United States)

    Palma, B Dalla; Guasco, D; Pedrazzoni, M; Bolzoni, M; Accardi, F; Costa, F; Sammarelli, G; Craviotto, L; De Filippo, M; Ruffini, L; Omedè, P; Ria, R; Aversa, F; Giuliani, N

    2016-02-01

    The relationship between bone marrow (BM) cytokine and chemokine levels, cytogenetic profiles and skeletal involvement in multiple myeloma (MM) patients is not yet defined. This study investigated a cohort of 455 patients including monoclonal gammopathy of uncertain significance (MGUS), smoldering MM and symptomatic MM patients. Skeletal surveys, positron emission tomography (PET)/computerized tomography (CT) and magnetic resonance imaging (MRI) were used to identify myeloma bone disease. Significantly higher median BM levels of both C-C motif Ligand (CCL)3 and CCL20 were found in MM patients with radiographic evidence of osteolytic lesions as compared with those without, and in all MM patients with positive PET/CT scans. BM levels of CCL3, CCL20, Activin-A and Dickkopf-1 (DKK-1) were significantly higher in patients with high bone disease as compared with patients with low bone disease. Moreover, CCL20 BM levels were significant predictors of osteolysis on X-rays by multivariate logistic analysis. On the other hand, DKK-1 levels were related to the presence of MRI lesions independently of the osteolysis at the X-rays. Our data define the relationship between bone disease and the BM cytokine and chemokine patterns highlighting the tight relationship between CCL20 BM levels and osteolysis in MM. PMID:26419509

  15. Strong Expression of Chemokine Receptor CXCR4 by Renal Cell Carcinoma Correlates with Advanced Disease

    Directory of Open Access Journals (Sweden)

    Thomas C. Wehler

    2008-01-01

    Full Text Available Diverse chemokines and their receptors have been associated with tumor growth, tumor dissemination, and local immune escape. In different tumor entities, the level of chemokine receptor CXCR4 expression has been linked with tumor progression and decreased survival. The aim of this study was to evaluate the influence of CXCR4 expression on the progression of human renal cell carcinoma. CXCR4 expression of renal cell carcinoma was assessed by immunohistochemistry in 113 patients. Intensity of CXCR4 expression was correlated with both tumor and patient characteristics. Human renal cell carcinoma revealed variable intensities of CXCR4 expression. Strong CXCR4 expression of renal cell carcinoma was significantly associated with advanced T-status (P=.039, tumor dedifferentiation (P = .0005, and low hemoglobin (P = .039. In summary, strong CXCR4 expression was significantly associated with advanced dedifferentiated renal cell carcinoma.

  16. The chemokine receptor CCR5 Δ32 allele in natalizumab-treated multiple sclerosis

    DEFF Research Database (Denmark)

    Møller, M; Søndergaard, Helle B; Koch-Henriksen, N;

    2014-01-01

    OBJECTIVE: The chemokine receptor CCR5 may be important for the recruitment of pathogenic T cells to the CNS in multiple sclerosis (MS). We hypothesized that this chemokine receptor might still be important for T-cell migration during treatment with anti-very late antigen (VLA)-4 antibody. We...... therefore analysed whether natalizumab-treated MS patients carrying the CCR5 Δ32 deletion allele, which results in reduced expression of CCR5 on the cell surface, had lower disease activity. METHODS: CCR5 Δ32 was analysed in 212 natalizumab-treated MS patients. RESULTS: CCR5 Δ32 status had no significant...... impact on the frequency of relapses 1 year prior to natalizumab treatment or during the first 48 weeks of treatment. The multiple sclerosis severity score (MSSS) was significantly lower at baseline in patients carrying CCR5 Δ32 (P = 0.031). CONCLUSIONS: CCR5 Δ32 is not associated with lower disease...

  17. Chemokine receptor expression on the surface of peripheral blood mononuclear cells in Chagas disease.

    Science.gov (United States)

    Talvani, Andre; Rocha, Manoel O C; Ribeiro, Antonio L; Correa-Oliveira, Rodrigo; Teixeira, Mauro M

    2004-01-15

    We evaluated the expression of chemokine receptors (CCR1, CCR2, CCR5, and CXCR4) on the surface of peripheral blood mononuclear cells obtained from patients with chronic chagasic cardiomyopathy (CCC) and noninfected individuals. Only CCR5 and CXCR4 expression was different on the surface of the subsets (CD4, CD8, and CD14) evaluated. Patients with mild CCC had elevated leukocyte expression of CCR5, compared with noninfected individuals or those with severe disease. CXCR4 expression was lower on leukocytes from patients with severe CCC. The differential expression of both receptors on leukocytes of patients with CCC was consistent and clearly correlated with the degree of heart function such that the lower the heart function, the lower the expression of either CCR5 or CXCR4. These results highlight the possible participation of the chemokine system in early forms of chagasic cardiomyopathy and the relevance of heart failure-induced remodeling in modifying immune parameters in infected individuals.

  18. Decoding the chemokine network that links leukocytes with decidual cells and the trophoblast during early implantation.

    Science.gov (United States)

    Ramhorst, Rosanna; Grasso, Esteban; Paparini, Daniel; Hauk, Vanesa; Gallino, Lucila; Calo, Guillermina; Vota, Daiana; Pérez Leirós, Claudia

    2016-03-01

    Chemokine network is central to the innate and adaptive immunity and entails a variety of proteins and membrane receptors that control physiological processes such as wound healing, angiogenesis, embryo growth and development. During early pregnancy, the chemokine network coordinates not only the recruitment of different leukocyte populations to generate the maternal-placental interface, but also constitutes an additional checkpoint for tissue homeostasis maintenance. The normal switch from a pro-inflammatory to an anti-inflammatory predominant microenvironment characteristic of the post-implantation stage requires redundant immune tolerance circuits triggered by key master regulators. In this review we will focus on the recruitment and conditioning of maternal immune cells to the uterus at the early implantation period with special interest on high plasticity macrophages and dendritic cells and their ability to induce regulatory T cells. We will also point to putative immunomodulatory polypeptides involved in immune homeostasis maintenance at the maternal-placental interface. PMID:26891097

  19. Low prevalence of antibodies and other plasma factors binding to CC chemokines and IL-2 in HIV-positive patients

    DEFF Research Database (Denmark)

    Meyer, C N; Svenson, M; Schade Larsen, C;

    2000-01-01

    Neutralizing cytokine antibodies are found in healthy and diseased individuals, including patients treated with recombinant cytokines. Identification of CCR-5 as co-receptor for HIV has focused interest on CC chemokines and their potential therapeutic use. Chemokine-binding components in plasma...... of HIV-infected patients were therefore assessed by radioimmunoassay and radioreceptor assay. IgG from 4/505 HIV patients and 9/2000 healthy controls (p>0.05) bound rMIP-1alpha and rMIP-1beta, but not rRANTES. No other plasma factors bound the chemokines. The antibodies inhibited receptor binding of both...... chemokines. There was no association between presence of antibodies and disease stage or HIV progression rate. Three of 11 patients treated with rIL-2 developed IgG antibodies suppressing cellular binding and growth promotion of rIL-2. Hence, circulating factors, including antibodies MIP-1alpha/MIP-1beta...

  20. Relationship between plasma resistin concentrations, inflammatory chemokines, and components of the metabolic syndrome in adults.

    Science.gov (United States)

    Aquilante, Christina L; Kosmiski, Lisa A; Knutsen, Shannon D; Zineh, Issam

    2008-04-01

    Recent data suggest that resistin, an adipocyte-derived cytokine, has a putative role in inflammatory processes and metabolic derangements. In vitro data suggest that resistin stimulates the production of inflammatory chemokines, yet the relationship in vivo is largely unknown. The purpose of this study was to determine if a relationship exists between plasma resistin concentrations, plasma inflammatory chemokine aged concentrations (ie, monocyte chemoattractant protein 1 [MCP-1] and epithelial neutrophil activator 78 [ENA-78]), and components of the metabolic syndrome in nondiabetic subjects without known cardiovascular disease (CVD). Plasma samples were obtained from nondiabetic subjects (N = 123) aged 18 to 55 years without known CVD or CVD risk equivalents. The presence of the metabolic syndrome was assessed using consensus guidelines. Fasting plasma resistin, MCP-1, ENA-78, and high-sensitivity C-reactive protein (hs-CRP) concentrations were analyzed. The study population consisted of 67.5% women and 68.3% Caucasians (mean age = 44 +/- 7 years and mean body mass index = 33.3 +/- 6 kg/m(2)). The metabolic syndrome was present in 46.3% of study participants. Resistin concentrations were significantly correlated with white blood cell count (r = 0.326, P metabolic syndrome compared with those without the metabolic syndrome (P = .003). In stepwise regression analysis, white blood cell count (P metabolic syndrome, and high-density lipoprotein cholesterol. Data from our cross-sectional study demonstrate that plasma resistin concentrations are associated with circulating chemokine markers of inflammation, namely, MCP-1, and white blood cell count in nondiabetic adults without CVD. Future studies examining the causal relationship between plasma resistin concentrations, chemokine markers of inflammation, CVD, and diabetes are warranted.

  1. Mechanisms of dexamethasone-mediated chemokine down-regulation in mild and severe acute pancreatitis

    OpenAIRE

    Yubero, S.; Ramudo, L.; Manso, M.A.; De Dios, I.

    2009-01-01

    Abstract This study aimed to investigate the role of therapeutic dexamethaxone (Dex) treatment on the mechanisms underlying chemokine expression during mild and severe acute pancreatitis (AP) experimentally induced in rats. Regardless of the AP severity, Dex (1 mg/kg), administered 1 hour after AP, reduced the acinar cell activation of extracellular signal-regulated kinase (ERK) and c-Jun-NH2-terminal kinase (JNK) but failed to reduce p38-mitogen activated protein kinas (MAPK) in s...

  2. Up-regulation of the chemokine CCL21 in the skin of subjects exposed to irritants

    OpenAIRE

    Kuznitzky Raquel; Ruiz Lascano Alejandro; Ortiz Susana; Eberhard Yanina; Serra Horacio

    2004-01-01

    Abstract Background Expression of murine CCL21 by dermal lymphatic endothelial cells (LEC) has been demonstrated to be one of the most important steps in Langerhans cell emigration from skin. Previously, our group and others have found that this chemokine is up-regulated in different human inflammatory skin diseases mediated by diverse specific immune responses. This study was carried out to investigate the involvement of CCL21 in human skin after challenge with irritant agents responsible fo...

  3. Lipopolysaccharide Biosynthesis Genes of Yersinia pseudotuberculosis Promote Resistance to Antimicrobial Chemokines

    OpenAIRE

    Erickson, David L.; Lew, Cynthia S.; Brittany Kartchner; Porter, Nathan T.; S Wade McDaniel; Jones, Nathan M.; Sara Mason; Erin Wu; Eric Wilson

    2016-01-01

    Antimicrobial chemokines (AMCs) are a recently described family of host defense peptides that play an important role in protecting a wide variety of organisms from bacterial infection. Very little is known about the bacterial targets of AMCs or factors that influence bacterial susceptibility to AMCs. In an effort to understand how bacterial pathogens resist killing by AMCs, we screened Yersinia pseudotuberculosis transposon mutants for those with increased binding to the AMCs CCL28 and CCL25....

  4. Contrasting Effects of Natural Selection on Human and Chimpanzee CC Chemokine Receptor 5

    OpenAIRE

    Wooding, Stephen ; Stone, Anne C. ; Dunn, Diane M. ; Mummidi, Srinivas ; Jorde, Lynn B. ; Weiss, Robert K. ; Ahuja, Sunil ; Bamshad, Michael J. 

    2004-01-01

    Human immunodeficiency virus type 1 (HIV-1) evolved via cross-species transmission of simian immunodeficiency virus (SIVcpz) from chimpanzees (Pan troglodytes). Chimpanzees, like humans, are susceptible to infection by HIV-1. However, unlike humans, infected chimpanzees seldom develop immunodeficiency when infected with SIVcpz or HIV-1. SIVcpz and most strains of HIV-1 require the cell-surface receptor CC chemokine receptor 5 (CCR5) to infect specific leukocyte subsets, and, subsequent to inf...

  5. Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs

    OpenAIRE

    Pradelli, Emmanuelle; Karimdjee-Soilihi, Babou; Michiels, Jean-François; Ricci, Jean-Ehrland; Millet, Marie-Ange; Vandenbos, Fanny; Sullivan, Timothy J.; Collins, Tassie L.; Johnson, Michael G.; Medina, Julio C.; Kleinerman, Eugenie S; Schmid-Alliana, Annie; Schmid-Antomarchi, Heidy

    2009-01-01

    Metastasis continues to be the leading cause of mortality for patients with cancer. Several years ago, it became clear that chemokines and their receptors could control the tumor progress. CXCR3 has now been identified in many cancers including osteosarcoma and CXCR3 ligands were expressed by lungs that are the primary sites to which this tumor metastasize. This study tested the hypothesis that disruption of the CXCR3/CXCR3 ligands complexes could lead to a decrease in lungs metastasis. The e...

  6. CXC Chemokine Receptor 3 Alternative Splice Variants Selectively Activate Different Signaling Pathways.

    Science.gov (United States)

    Berchiche, Yamina A; Sakmar, Thomas P

    2016-10-01

    The G protein-coupled receptor (GPCR) C-X-C chemokine receptor 3 (CXCR3) is a potential drug target that mediates signaling involved in cancer metastasis and inflammatory diseases. The CXCR3 primary transcript has three potential alternative splice variants and cell-type specific expression results in receptor variants that are believed to have different functional characteristics. However, the molecular pharmacology of ligand binding to CXCR3 alternative splice variants and their downstream signaling pathways remain poorly explored. To better understand the role of the functional consequences of alternative splicing of CXCR3, we measured signaling in response to four different chemokine ligands (CXCL4, CXCL9, CXCL10, and CXCL11) with agonist activity at CXCR3. Both CXCL10 and CXCL11 activated splice variant CXCR3A. Whereas CXCL10 displayed full agonistic activity for Gαi activation and extracellular signal regulated kinase (ERK) 1/2 phosphorylation and partial agonist activity for β-arrestin recruitment, CXCL9 triggered only modest ERK1/2 phosphorylation. CXCL11 induced CXCR3B-mediated β-arrestin recruitment and little ERK phosphorylation. CXCR3Alt signaling was limited to modest ligand-induced receptor internalization and ERK1/2 phosphorylation in response to chemokines CXCL11, CXCL10, and CXCL9. These results show that CXCR3 splice variants activate different signaling pathways and that CXCR3 variant function is not redundant, suggesting a mechanism for tissue specific biased agonism. Our data show an additional layer of complexity for chemokine receptor signaling that might be exploited to target specific CXCR3 splice variants. PMID:27512119

  7. Reduced locomotor activity and exploratory behavior in CC chemokine receptor 4 deficient mice.

    Science.gov (United States)

    Ambrée, Oliver; Klassen, Irene; Förster, Irmgard; Arolt, Volker; Scheu, Stefanie; Alferink, Judith

    2016-11-01

    Chemokines and their receptors are key regulators of immune cell trafficking and activation. Recent findings suggest that they may also play pathophysiological roles in psychiatric diseases like depression and anxiety disorders. The CC chemokine receptor 4 (CCR4) and its two ligands, CCL17 and CCL22, are functionally involved in neuroinflammation as well as anti-infectious and autoimmune responses. However, their influence on behavior remains unknown. Here we characterized the functional role of the CCR4-CCL17 chemokine-receptor axis in the modulation of anxiety-related behavior, locomotor activity, and object exploration and recognition. Additionally, we investigated social exploration of CCR4 and CCL17 knockout mice and wild type (WT) controls. CCR4 knockout (CCR4(-/-)) mice exhibited fewer anxiety-related behaviors in the elevated plus-maze, diminished locomotor activity, exploratory behavior, and social exploration, while their recognition memory was not affected. In contrast, CCL17 deficient mice did not show an altered behavior compared to WT mice regarding locomotor activity, anxiety-related behavior, social exploration, and object recognition memory. In the dark-light and object recognition tests, CCL17(-/-) mice even covered longer distances than WT mice. These data demonstrate a mechanistic or developmental role of CCR4 in the regulation of locomotor and exploratory behaviors, whereas the ligand CCL17 appears not to be involved in the behaviors measured here. Thus, either CCL17 and the alternative ligand CCL22 may be redundant, or CCL22 is the main activator of CCR4 in these processes. Taken together, these findings contribute to the growing evidence regarding the involvement of chemokines and their receptors in the regulation of behavior. PMID:27469058

  8. Association of haemolytic uraemic syndrome with dysregulation of chemokine receptor expression in circulating monocytes.

    Science.gov (United States)

    Ramos, Maria Victoria; Ruggieri, Matias; Panek, Analia Cecilia; Mejias, Maria Pilar; Fernandez-Brando, Romina Jimena; Abrey-Recalde, Maria Jimena; Exeni, Andrea; Barilari, Catalina; Exeni, Ramon; Palermo, Marina Sandra

    2015-08-01

    Haemolytic uraemic syndrome (HUS) is the major complication of Escherichia coli gastrointestinal infections that are Shiga toxin (Stx) producing. Monocytes contribute to HUS evolution by producing cytokines that sensitize endothelial cells to Stx action and migration to the injured kidney. As CC chemokine receptors (CCRs) are involved in monocyte recruitment to injured tissue, we analysed the contribution of these receptors to the pathogenesis of HUS. We analysed CCR1, CCR2 and CCR5 expression in peripheral monocytes from HUS patients during the acute period, with healthy children as controls. We observed an increased expression of CCRs per cell in monocytes from HUS patients, accompanied by an increase in the absolute number of monocytes CCR1+, CCR2+ and CCR5+. It is interesting that prospective analysis confirmed that CCR1 expression positively correlated with HUS severity. The evaluation of chemokine levels in plasma showed that regulated on activation of normal T-cell-expressed and -secreted (RANTES) protein was reduced in plasma from patients with severe HUS, and this decrease correlated with thrombocytopenia. Finally, the expression of the higher CCRs was accompanied by a loss of functionality which could be due to a mechanism for desensitization to compensate for altered receptor expression. The increase in CCR expression correlates with HUS severity, suggesting that the dysregulation of these receptors might contribute to an increased risk of renal damage. Activated monocytes could be recruited by chemokines and then receptors could be dysregulated. The dysregulation of CCRs and their ligands observed during the acute period suggests that a chemokine pathway would participate in HUS development.

  9. Comparison of aqueous humor cytokine and chemokine levels in diabetic patients with and without retinopathy

    OpenAIRE

    Cheung, Chui Ming Gemmy; Vania, Maya; Ang, Marcus; Chee, Soon Phaik; Li, Jing

    2012-01-01

    Purpose To compare the aqueous humor levels of proinflammatory and angiogenic factors of diabetic patients with and without retinopathy. Methods Aqueous humor was collected at the start of cataract surgery from diabetic subjects and non-diabetic controls. The presence and severity of diabetic retinopathy were graded with fundus examination. Levels of 22 different inflammatory and angiogenic cytokines and chemokines were compared. Results Aqueous humor samples from 47 diabetic patients (20 wit...

  10. Interferon-inducible CXC chemokines directly contribute to host defense against inhalational anthrax in a murine model of infection.

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    Matthew A Crawford

    Full Text Available Chemokines have been found to exert direct, defensin-like antimicrobial activity in vitro, suggesting that, in addition to orchestrating cellular accumulation and activation, chemokines may contribute directly to the innate host response against infection. No observations have been made, however, demonstrating direct chemokine-mediated promotion of host defense in vivo. Here, we show that the murine interferon-inducible CXC chemokines CXCL9, CXCL10, and CXCL11 each exert direct antimicrobial effects in vitro against Bacillus anthracis Sterne strain spores and bacilli including disruptions in spore germination and marked reductions in spore and bacilli viability as assessed using CFU determination and a fluorometric assay of metabolic activity. Similar chemokine-mediated antimicrobial activity was also observed against fully virulent Ames strain spores and encapsulated bacilli. Moreover, antibody-mediated neutralization of these CXC chemokines in vivo was found to significantly increase host susceptibility to pulmonary B. anthracis infection in a murine model of inhalational anthrax with disease progression characterized by systemic bacterial dissemination, toxemia, and host death. Neutralization of the shared chemokine receptor CXCR3, responsible for mediating cellular recruitment in response to CXCL9, CXCL10, and CXCL11, was not found to increase host susceptibility to inhalational anthrax. Taken together, our data demonstrate a novel, receptor-independent antimicrobial role for the interferon-inducible CXC chemokines in pulmonary innate immunity in vivo. These data also support an immunomodulatory approach for effectively treating and/or preventing pulmonary B. anthracis infection, as well as infections caused by pathogenic and potentially, multi-drug resistant bacteria including other spore-forming organisms.

  11. Cytokine & chemokine response in the lungs, pleural fluid and serum in thoracic surgery using one-lung ventilation

    OpenAIRE

    Breunig Andreas; Gambazzi Franco; Beck-Schimmer Beatrice; Tamm Michael; Lardinois Didier; Oertli Daniel; Zingg Urs

    2011-01-01

    Abstract Background Thoracic surgery mandates usually a one-lung ventilation (OLV) strategy with the collapse of the operated lung and ventilation of the non-operated lung. These procedures trigger a substantial inflammatory response. The aim of this study was to analyze the cytokine and chemokine reaction in both lungs, pleural space and blood in patients undergoing lung resection with OLV with special interest in the chemokine growth-regulated peptide alpha (GROα) which is the human equival...

  12. Helicobacter pylori water soluble surface proteins prime human neutrophils for enhanced production of reactive oxygen species and stimulate chemokine production

    OpenAIRE

    Shimoyama, T.; Fukuda, S.; Liu, Q.; Nakaji, S; Fukuda, Y.; Sugawara, K

    2003-01-01

    Backgrounds/Aims: Chronic gastritis induced by Helicobacter pylori is characterised by considerable neutrophil infiltration into the gastric mucosa without mucosal invasion of bacteria. Bacteria have different characteristics with respect to their ability to stimulate human neutrophils to produce reactive oxygen species and chemokines. The aim of this study was to examine the effects of H pylori water extracts on the oxidative burst and chemokine production of human neutrophils.

  13. B Cell, Th17, and Neutrophil Related Cerebrospinal Fluid Cytokine/Chemokines Are Elevated in MOG Antibody Associated Demyelination.

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    Kavitha Kothur

    Full Text Available Myelin oligodendrocyte glycoprotein antibody (MOG Ab associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination.To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS and -negative (NEG groups.We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8, transverse myelitis (TM = 2 n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9 demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls.The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19 as well as some of Th17 related cytokines (IL-6 AND G-CSF compared to MOG Ab NEG group (all p<0.01. In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies.Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.

  14. Impact of HIV co-infection on plasma level of cytokines and chemokines of pulmonary tuberculosis patients

    OpenAIRE

    Mihret, Adane; Abebe, Markos; Bekele, Yonas; Aseffa, Abraham; Walzl, Gerhard; Howe, Rawleigh

    2014-01-01

    Background The immunologic environment during HIV/M. tuberculosis co-infection is characterized by cytokine and chemokine irregularities that have been shown to increase immune activation, viral replication, and T cell dysfunction. Methods We analysed ex vivo plasma samples from 17 HIV negative and 16 HIV pulmonary tuberculosis co infected cases using Luminex assay to see impact of HIV co-infection on plasma level of cytokines and chemokines of pulmonary tuberculosis patients before and after...

  15. Comprehensive analysis of serum cytokines/chemokines in febrile children with primary human herpes virus-6B infection.

    Science.gov (United States)

    Nagasaka, Miwako; Morioka, Ichiro; Kawabata, Akiko; Yamagishi, Yoshiaki; Iwatani, Sota; Taniguchi-Ikeda, Mariko; Ishida, Akihito; Iijima, Kazumoto; Mori, Yasuko

    2016-09-01

    Cytokines and chemokines induced by primary human herpes virus (HHV)-6B infection may play a critical role in the clinical manifestations of infection. In this study, we analyzed 40 cytokines/chemokines in febrile children with primary HHV-6B infection. Blood samples from 233 febrile and 36 afebrile patients 0-3 years of age were used for this study. In febrile patients, primary HHV-6B infection was determined by detection of HHV-6B DNA without anti-HHV-6 immunoglobulin G in the blood (HHV-6B group). Infection by other pathogens was assumed when HHV-6B DNA was not detected in the blood (non-HHV-6B group). Of the 233 febrile patients, 30 patients (13%) were diagnosed with primary HHV-6B infection. To analyze serum cytokines/chemokines, patients were randomly chosen from the HHV-6B (n = 25) and non-HHV-6B groups (n = 8). Sera from 25 afebrile patients were used as a control. When comparing the levels of 40 cytokines/chemokines between the HHV-6B and control groups, we found that four chemokines (chemokine [C-X-C motif] ligand [CXCL] 11, CXCL10, CXCL16, and chemokine [C-C motif] ligand [CCL] 2) were significantly upregulated in the HHV-6B group compared with those in the control. Of these, only CXCL11 levels were significantly higher in the HHV-6B group than in the non-HHV-6B group. Because the induction of CCL2 was already reported in an early study, we found, for the first time, the induction of three new chemokines, i.e., CXCL11, CXCL10, and CXCL16 in patients with primary HHV-6B infection. Importantly, we demonstrated that serum CXCL11 levels increased specifically in patients with HHV-6B infection. PMID:27346377

  16. The Role of Cytokines, Chemokines, and Growth Factors in the Pathogenesis of Pityriasis Rosea

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    Francesco Drago

    2015-01-01

    Full Text Available Introduction. Pityriasis rosea (PR is an exanthematous disease related to human herpesvirus- (HHV- 6/7 reactivation. The network of mediators involved in recruiting the infiltrating inflammatory cells has never been studied. Object. To investigate the levels of serum cytokines, growth factors, and chemokines in PR and healthy controls in order to elucidate the PR pathogenesis. Materials and Methods. Interleukin- (IL- 1, IL-6, IL-17, interferon- (IFN- γ, tumor necrosis factor- (TNF- α, vascular endothelial growth factor (VEGF, granulocyte colony stimulating factor (G-CSF, and chemokines, CXCL8 (IL-8 and CXCL10 (IP-10, were measured simultaneously by a multiplex assay in early acute PR patients’ sera and healthy controls. Subsequently, sera from PR patients were analysed at 3 different times (0, 15, and 30 days. Results and discussion. Serum levels of IL-17, IFN-γ, VEGF, and IP-10 resulted to be upregulated in PR patients compared to controls. IL-17 has a key role in host defense against pathogens stimulating the release of proinflammatory cytokines/chemokines. IFN-γ has a direct antiviral activity promoting NK cells and virus specific T cells cytotoxicity. VEGF stimulates vasculogenesis and angiogenesis. IP-10 can induce chemotaxis, apoptosis, cell growth, and angiogenesis. Conclusions. Our findings suggest that these inflammatory mediators may modulate PR pathogenesis in synergistic manner.

  17. [The role of CC-chemokine ligand 2 in the development of psychic dependence on methamphetamine].

    Science.gov (United States)

    Saika, Fumihiro; Kiguchi, Norikazu; Kishioka, Shiroh

    2015-10-01

    Addiction is described as a chronic neurological disorder associated with plasticity in the mesolimbic system. Recently, it has been suggested that neuroinflammation plays an important role in the induction of neuronal plasticity and the formation of pathogenesis in chronic neurological disorders. Therefore, we examined the role of CC-chemokine ligand 2 (CCL2), a proinflammatory chemokine, in the development of psychic dependence on methamphetamine. In mice treated with methamphetamine, CCL2 mRNA was significantly increased in prefrontal cortex and nucleus accumbens. Moreover, phosphorylated tyrosine hydroxylase serine40 (pTH Ser40) levels in the ventral tegmental area (VTA) were increased by methamphetamine. Similarly, pTH Ser40 levels in the VTA were also increased by the intracerebroventricular administration of recombinant CCL2. The increment of pTH Ser40 levels in the VTA by methamphetamine was attenuated by RS504393, a selective CC-chemokine receptor 2 (CCR2) antagonist, indicating that the increased CCL2 activates the brain reward system via CCR2 activation. In the conditioned place preference test, methamphetamine produced place preference in a dose-dependent manner, which was attenuated by RS504393. These results suggest that the activation of the brain reward system via CCL2-CCR2 pathway plays an important role in the development of psychic dependence on methamphetamine. PMID:26946780

  18. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis.

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    Ishan Roy

    Full Text Available Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites.

  19. Profile of Cytokines and Chemokines Triggered by Wild-Type Strains of Rabies Virus in Mice.

    Science.gov (United States)

    Appolinário, Camila Michele; Allendorf, Susan Dora; Peres, Marina Gea; Ribeiro, Bruna Devidé; Fonseca, Clóvis R; Vicente, Acácia Ferreira; Antunes, João Marcelo A de Paula; Megid, Jane

    2016-02-01

    Rabies is a lethal infectious disease that causes 55,000 human deaths per year and is transmitted by various mammalian species, such as dogs and bats. The host immune response is essential for avoiding viral progression and promoting viral clearance. Cytokines and chemokines are crucial in the development of an immediate antiviral response; the rabies virus (RABV) attempts to evade this immune response. The virus's capacity for evasion is correlated with its pathogenicity and the host's inflammatory response, with highly pathogenic strains being the most efficient at hijacking the host's defense mechanisms and thereby decreasing inflammation. The purpose of this study was to evaluate the expression of a set of cytokine and chemokine genes that are related to the immune response in the brains of mice inoculated intramuscularly or intracerebrally with two wild-type strains of RABV, one from dog and the other from vampire bat. The results demonstrated that the gene expression profile is intrinsic to the specific rabies variant. The prompt production of cytokines and chemokines seems to be more important than their levels of expression for surviving a rabies infection. PMID:26711511

  20. Nitric Oxide Donors Suppress Chemokine Production by Keratinocytes in Vitro and in Vivo

    Science.gov (United States)

    Giustizieri, Maria Laura; Albanesi, Cristina; Scarponi, Claudia; De Pità, Ornella; Girolomoni, Giampiero

    2002-01-01

    Nitric oxide (NO) is involved in the modulation of inflammatory responses. In psoriatic skin, NO is highly produced by epidermal keratinocytes in response to interferon-γ and tumor necrosis factor-α. In this study, we investigated whether the NO donors, S-nitrosoglutathione (GS-NO) and NOR-1, could regulate chemokine production by human keratinocytes activated with interferon-γ and tumor necrosis factor-α. In addition, we studied the effects of the topical application of a GS-NO ointment on chemokine expression in lesional psoriatic skin. NO donors diminished in a dose-dependent manner and at both mRNA and protein levels the IP-10, RANTES, and MCP-1 expression in keratinocytes cultured from healthy patients and psoriatic patients. In contrast, constitutive and induced interleukin-8 production was unchanged. GS-NO-treated psoriatic skin showed reduction of IP-10, RANTES, and MCP-1, but not interleukin-8 expression by keratinocytes. Moreover, the number of CD14+ and CD3+ cells infiltrating the epidermis and papillary dermis diminished significantly. NO donors also down-regulated ICAM-1 protein expression without affecting mRNA accumulation in vitro, and suppressed keratinocyte ICAM-1 in vivo. Finally, NO donors inhibited nuclear factor-κB and STAT-1, but not AP-1 activities in transiently transfected keratinocytes. These results define NO donors as negative regulators of chemokine production by keratinocytes. PMID:12368213

  1. Analysis of Chemokines and Receptors Expression Profile in the Myelin Mutant Taiep Rat

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    Guadalupe Soto-Rodriguez

    2015-01-01

    Full Text Available Taiep rat has a failure in myelination and remyelination processes leading to a state of hypomyelination throughout its life. Chemokines, which are known to play a role in inflammation, are also involved in the remyelination process. We aimed to demonstrate that remyelination-stimulating factors are altered in the brainstem of 1- and 6-month-old taiep rats. We used a Rat RT2 Profiler PCR Array to assess mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors. We also evaluated protein levels of CCL2, CCR1, CCR2, CCL5, CCR5, CCR8, CXCL1, CXCR2, CXCR4, FGF2, and VEGFA by ELISA. Sprague-Dawley rats were used as a control. PCR Array procedure showed that proinflammatory cytokines were not upregulated in the taiep rat. In contrast, some mRNA levels of beta and alpha chemokines were upregulated in 1-month-old rats, but CXCR4 was downregulated at their 6 months of age. ELISA results showed that CXCL1, CCL2, CCR2, CCR5, CCR8, and CXCR4 protein levels were decreased in brainstem at the age of 6 months. These results suggest the presence of a chronic neuroinflammation process with deficiency of remyelination-stimulating factors (CXCL1, CXCR2, and CXCR4, which might account for the demyelination in the taiep rat.

  2. Angiogenic CXC chemokine expression during differentiation of human mesenchymal stem cells towards the osteoblastic lineage.

    Science.gov (United States)

    Bischoff, D S; Zhu, J H; Makhijani, N S; Kumar, A; Yamaguchi, D T

    2008-02-15

    The potential role of ELR(+) CXC chemokines in early events in bone repair was studied using human mesenchymal stem cells (hMSCs). Inflammation, which occurs in the initial phase of tissue healing in general, is critical to bone repair. Release of cytokines from infiltrating immune cells and injured bone can lead to recruitment of MSCs to the region of repair. CXC chemokines bearing the Glu-Leu-Arg (ELR) motif are also released by inflammatory cells and serve as angiogenic factors stimulating chemotaxis and proliferation of endothelial cells. hMSCs, induced to differentiate with osteogenic medium (OGM) containing ascorbate, beta-glycerophosphate (beta-GP), and dexamethasone (DEX), showed an increase in mRNA and protein secretion of the ELR(+) CXC chemokines CXCL8 and CXCL1. CXCL8 mRNA half-life studies reveal an increase in mRNA stability upon OGM stimulation. Increased expression and secretion is a result of DEX in OGM and is dose-dependent. Inhibition of the glucocorticoid receptor with mifepristone only partially inhibits DEX-stimulated CXCL8 expression indicating both glucocorticoid receptor dependent and independent pathways. Treatment with signal transduction inhibitors demonstrate that this expression is due to activation of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways and is mediated through the G(alphai)-coupled receptors. Angiogenesis assays demonstrate that OGM-stimulated conditioned media containing secreted CXCL8 and CXCL1 can induce angiogenesis of human microvascular endothelial cells in an in vitro Matrigel assay.

  3. Application of chemokine receptor antagonist with stents reduces local inflammation and suppresses cancer growth.

    Science.gov (United States)

    Mao, Ai-Wu; Jiang, Ting-Hui; Sun, Xian-Jun; Peng, Jian

    2015-11-01

    Severe pain and obstructive jaundice resulting from invasive cholangiocarcinoma or pancreatic carcinoma can be alleviated by implantation of biliary and duodenal stents. However, stents may cause local inflammation to have an adverse effect on the patients' condition and survival. So far, no efficient approaches have been applied to prevent the occurrence of stents-related inflammation. Here, we reported significantly higher levels of serum stromal cell-derived factor 1 (SDF-1) in the patients that developed stents-associated inflammation. A higher number of inflammatory cells have been detected in the cancer close to stent in the patients with high serum SDF-1. Since chemokine plays a pivotal role in the development of inflammation, we implanted an Alzet osmotic pump with the stents to gradually release AMD3100, a specific inhibitor binding of SDF-1 and its receptor C-X-C chemokine receptor 4 (CXCR4), at the site of stents in mice that had developed pancreatic cancer. We found that AMD3100 significantly reduced local inflammation and significantly inhibited cancer cell growth, resulting in improved survival of the mice that bore cancer. Moreover, the suppression of cancer growth may be conducted through modulation of CyclinD1, p21, and p27 in the cancer cells. Together, these data suggest that inhibition of chemokine signaling at the site of stents may substantially improve survival through suppression of stent-related inflammation and tumor growth.

  4. Critical roles of chemokine receptor CCR5 in regulating glioblastoma proliferation and invasion.

    Science.gov (United States)

    Zhao, Lanfu; Wang, Yuan; Xue, Yafei; Lv, Wenhai; Zhang, Yufu; He, Shiming

    2015-11-01

    Glioblastoma (GBM) is the most prevalent malignant primary brain tumor in adults and exhibits a spectrum of aberrantly aggressive phenotype. Tumor cell proliferation and invasion are critically regulated by chemokines and their receptors. Recent studies have shown that the chemokine CCL5 and its receptor CCR5 play important roles in tumor invasion and metastasis. Nonetheless, the roles of the CCR5 in GBM still remain unclear. The present study provides the evidence that the chemokine receptor CCR5 is highly expressed and associated with poor prognosis in human GBM. Mechanistically, CCL5-CCR5 mediates activation of Akt, and subsequently induces proliferation and invasive responses in U87 and U251 cells. Moreover, down-regulation of CCR5 significantly inhibited the growth of glioma in U87 tumor xenograft mouse model. Finally, high CCR5 expression in GBM is correlated with increased p-Akt expression in patient samples. Together, these findings suggest that the CCR5 is a critical molecular event associated with gliomagenesis.

  5. Enhanced Chemokine Receptor Expression on Leukocytes of Patients with Alzheimer's Disease.

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    David Goldeck

    Full Text Available Although primarily a neurological complaint, systemic inflammation is present in Alzheimer's Disease, with higher than normal levels of proinflammatory cytokines and chemokines in the periphery as well as the brain. A gradient of these factors may enhance recruitment of activated immune cells into the brain via chemotaxis. Here, we investigated the phenotypes of circulating immune cells in AD patients with multi-colour flow cytometry to determine whether their expression of chemokine receptors is consistent with this hypothesis. In this study, we confirmed our previously reported data on the shift of early- to late-differentiated CD4+ T-cells in AD patients. The percentage of cells expressing CD25, a marker of acute T-cell activation, was higher in patients than in age-matched controls, and percentages of CCR6+ cells were elevated. This chemokine receptor is primarily expressed on pro-inflammatory memory cells and Th17 cells. The proportion of cells expressing CCR4 (expressed on Th2 cells and CCR5 (Th1 cells and dendritic cells was also greater in patients, and was more pronounced on CD4+ than CD8+ T-cells. These findings allow a more detailed insight into the systemic immune status of patients with Alzheimer's disease and suggest possible novel targets for immune therapy.

  6. Exploring a model of human chemokine receptor CCR2 in presence of TAK779: A membrane based molecular dynamics study

    Science.gov (United States)

    Balupuri, Anand; Sobhia, M. Elizabeth

    2014-04-01

    Chemokine receptor 2 (CCR2) is a G-protein coupled receptor (GPCR) and a crucial target for various inflammation-driven diseases. In the present study, molecular docking and molecular dynamics simulations were performed on a CCR2 homology model. This work includes the comparative MD simulations of uncomplexed and ‘antagonist-complexed’ CCR2 models. These simulations yield insights into the binding mechanism of antagonist TAK779 and improve the understanding of various structural changes induced by the ligand in the CCR2 protein. Here, one 20 ns MD simulation was carried out on the uncomplexed CCR2 model in lipid bilayer to explore the effects of lipid membrane on the protein. Another 20 ns MD simulation was performed under the similar conditions on the docked CCR2-TAK779 complex. An alteration in the position and orientation of the ligand in binding site was observed after the simulation. Examination of protein-ligand complex suggested that TAK779 produced a greater structural change on the TM-III, TM-IV, TM-V and TM-VI than TM-I, TM-II and TM-VII. Interaction networks involving the conserved residues of uncomplexed and ‘antagonist-complexed’ CCR2 models were also examined. The major difference was observed to be the role of conserved residues of the DRY motif of TM-III and the NPxxY motif of TM-VII of CCR2.

  7. Inhibition of Epithelial CC-Family Chemokine Synthesis by the Synthetic Chalcone DMPF-1 via Disruption of NF-κB Nuclear Translocation and Suppression of Experimental Asthma in Mice

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    Revathee Rajajendram

    2015-01-01

    Full Text Available Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The interaction between airway epithelium and inflammatory mediators plays a key role in the pathogenesis of asthma. In vitro studies evaluated the inhibitory effects of 3-(2,5-dimethoxyphenyl-1-(5-methylfuran-2-ylprop-2-en-1-one (DMPF-1, a synthetic chalcone analogue, upon inflammation in the A549 lung epithelial cell line. DMPF-1 selectively inhibited TNF-α-stimulated CC chemokine secretion (RANTES, eotaxin-1, and MCP-1 without any effect upon CXC chemokine (GRO-α and IL-8 secretion. Western blot analysis further demonstrated that the inhibitory activity resulted from disruption of p65NF-κB nuclear translocation without any effects on the mitogen-activated protein kinase (MAPK pathway. Treatment of ovalbumin-sensitized and ovalbumin-challenged BALB/c mice with DMPF-1 (0.2–100 mg/kg demonstrated significant reduction in the secretion and gene expression of CC chemokines (RANTES, eotaxin-1, and MCP-1 and Th2 cytokines (IL-4, IL-5, and IL-13. Furthermore, DMPF-1 treatment inhibited eosinophilia, goblet cell hyperplasia, peripheral blood total IgE, and airway hyperresponsiveness in ovalbumin-sensitized and ovalbumin-challenged mice. In conclusion, these findings demonstrate the potential of DMPF-1, a nonsteroidal compound, as an antiasthmatic agent for further pharmacological evaluation.

  8. Tumor-Promoting Circuits That Regulate a Cancer-Related Chemokine Cluster: Dominance of Inflammatory Mediators Over Oncogenic Alterations

    International Nuclear Information System (INIS)

    Here, we investigated the relative contribution of genetic/signaling components versus microenvironmental factors to the malignancy phenotype. In this system, we took advantage of non-transformed fibroblasts that carried defined oncogenic modifications in Ras and/or p53. These cells were exposed to microenvironmental pressures, and the expression of a cancer-related chemokine cluster was used as readout for the malignancy potential (CCL2, CCL5, CXCL8, CXCL10). In cells kept in-culture, synergism between Ras hyper-activation and p53 dysfunction was required to up-regulate the expression of the chemokine cluster. The in vivo passage of RasHigh/p53Low-modified cells has led to tumor formation, accompanied by potentiation of chemokine release, implicating a powerful role for the tumor microenvironment in up-regulating the chemokine cluster. Indeed, we found that inflammatory mediators which are prevalent in tumor sites, such as TNFα and IL-1β, had a predominant impact on the release of the chemokines, which was substantially higher than that obtained by the oncogenic modifications alone, possibly acting through the transcription factors AP-1 and NF-κB. Together, our results propose that in the unbiased model system that we were using, inflammatory mediators of the tumor milieu have dominating roles over oncogenic modifications in dictating the expression of a pro-malignancy chemokine readout

  9. The effective impacts of Angi- Pars on Expression of Some CXC Chemokines Group in STZ-Induced Diabetic Rats

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    mm Taghavi

    2013-09-01

    Full Text Available Abstract Background & aim: Diabetes mellitus (DM has destructive tissue effects via inducing oxidative stress. The aim of this study was to evaluate the Angi Pars effects on the expression of some CXC group of streptozotocin-induced diabetic rats. Methods: This experimental study was conducted on 48 male rats. Induced diabetic rats were done by 50 mg/ kg of Streptozotocin. 56 days after induction of diabetes, rats were randomly divided into 4 groups including control, untreated diabetic, insulin-treated diabetic and diabetic treated with insulin and Angipars. 24 h after the last injection the animals were bled and the expression of cxc Chemokines groups were measured by western blotting. Data were analyzed by t test. Results: Showed that CXCL10 was reduced in the treatment group and the treatment group receiving insulin in combination with angi - pars decreased significantly (P<0.05. The total concentration of CXCL12 chemokine showed that the concentration of the different groups did not change compared to the control group (P<0.05. The study showed that CXCL1 levels in the group receiving insulin in combination with angi-pars the chemokine concentration was significantly lower than the control group (P<0.05. Conclusion: Since, Angi-Pars consists of two major phenolic compound groups, 7 - hydroxy coumarin and flavonoids, has antioxidant, and controls the inflammatory effects of chemokine increase and balances between chemokines its effectiveness in angiogenesis can be maintain. Key words: Diabetes, Angi- Pars, Chemokines

  10. Tumor-Promoting Circuits That Regulate a Cancer-Related Chemokine Cluster: Dominance of Inflammatory Mediators Over Oncogenic Alterations

    Energy Technology Data Exchange (ETDEWEB)

    Leibovich-Rivkin, Tal [Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978 (Israel); Buganim, Yosef; Solomon, Hilla [Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100 (Israel); Meshel, Tsipi [Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978 (Israel); Rotter, Varda [Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100 (Israel); Ben-Baruch, Adit, E-mail: aditbb@tauex.tau.ac.il [Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978 (Israel)

    2012-01-20

    Here, we investigated the relative contribution of genetic/signaling components versus microenvironmental factors to the malignancy phenotype. In this system, we took advantage of non-transformed fibroblasts that carried defined oncogenic modifications in Ras and/or p53. These cells were exposed to microenvironmental pressures, and the expression of a cancer-related chemokine cluster was used as readout for the malignancy potential (CCL2, CCL5, CXCL8, CXCL10). In cells kept in-culture, synergism between Ras hyper-activation and p53 dysfunction was required to up-regulate the expression of the chemokine cluster. The in vivo passage of Ras{sup High}/p53{sup Low}-modified cells has led to tumor formation, accompanied by potentiation of chemokine release, implicating a powerful role for the tumor microenvironment in up-regulating the chemokine cluster. Indeed, we found that inflammatory mediators which are prevalent in tumor sites, such as TNFα and IL-1β, had a predominant impact on the release of the chemokines, which was substantially higher than that obtained by the oncogenic modifications alone, possibly acting through the transcription factors AP-1 and NF-κB. Together, our results propose that in the unbiased model system that we were using, inflammatory mediators of the tumor milieu have dominating roles over oncogenic modifications in dictating the expression of a pro-malignancy chemokine readout.

  11. Selective loss of chemokine receptor expression on leukocytes after cell isolation.

    Directory of Open Access Journals (Sweden)

    Juan C Nieto

    Full Text Available Chemokine receptors are distinctively exposed on cells to characterize their migration pattern. However, little is known about factors that may regulate their expression. To determine the optimal conditions for an accurate analysis of chemokine receptors, we compared the expression of CCR2, CCR4, CCR5, CCR6, CXCR3 and CXCR4 on different leukocyte subsets using whole blood (WB plus erythrocyte lysis and density gradient isolation (Ficoll. Most WB monocytes were CCR2+ (93.5 ± 2.9% whereas 32.8 ± 6.0% of monocytes from Ficoll-PBMC expressed CCR2 (p<0.001. Significant reductions of CCR6 and CXCR3 on monocytes were also observed after Ficoll isolation (WB: 46.4 ± 7.5% and 57.1 ± 5.5%; Ficoll: 29.5 ± 2.2% and 5.4 ± 4.3% respectively (p<0.01. Although comparable percentages of WB and Ficoll-PBMC monocytes expressed CCR4, CCR5 and CXCR4, Ficoll isolation significantly reduced the levels of CXCR4 (WB: MFI 5 ± 0.4 and Ficoll: MFI 3.3 ± 0.1 (p<0.05. Similarly to monocytes, CCR2, CXCR3 and CXCR4 were also reduced on lymphocytes. In addition, Ficoll isolation significantly reduced the percentage of CCR4 positive lymphocytes (WB: 90.2 ± 4.5% and Ficoll: 55 ± 4.1% (p<0.01. The loss of expression of chemokine receptors after isolation of monocytes was not dependent on either the anticoagulant or the density gradient method. It was irreversible and could not be restored by LPS activation or in vitro macrophage differentiation. Experiments tagged with anti-CCR2 antibodies prior to density gradient isolation demonstrated that Ficoll internalized chemokine receptors. The method for cell isolation may alter not only the expression of certain chemokine receptors but also the respective functional migration assay. The final choice to analyze their expression should therefore depend on the receptor to be measured.

  12. CXC-chemokine regulation and neutrophil trafficking in hepatic ischemia-reperfusion injury in P-selectin/ICAM-1 deficient mice

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    Crockett Elahé T

    2007-05-01

    Full Text Available Abstract Background Neutrophil adhesion and migration are critical in hepatic ischemia and reperfusion injury (I/R. P-selectin and the intercellular adhesion molecule (ICAM-1 can mediate neutrophil-endothelial cell interactions, neutrophil migration, and the interactions of neutrophils with hepatocytes in the liver. Despite very strong preclinical data, recent clinical trials failed to show a protective effect of anti-adhesion therapy in reperfusion injury, indicating that the length of injury might be a critical factor in neutrophil infiltration. Therefore, the aim of this study was to assess the role of P-selectin and ICAM-1 in neutrophil infiltration and liver injury during early and late phases of liver I/R. Methods Adult male wild-type and P-selectin/ICAM-1-deficient (P/I null mice underwent 90 minutes of partial liver ischemia followed by various periods of reperfusion (6, 15 h, and a survival study. Liver injury was assessed by plasma level of alanine aminotransferase (ALT and histopathology. The plasma cytokines, TNF-α, IL-6, MIP-2 and KC, were measured by ELISA. Results Reperfusion caused significant hepatocellular injury in both wild-type and P/I null mice as was determined by plasma ALT levels and liver histopathology. The injury was associated with a marked neutrophil infiltration into the ischemic livers of both wild-type and P/I null mice. Although the levels of ALT and neutrophil infiltration were slightly lower in the P/I null mice compared with the wild-type mice the differences were not statistically significant. The plasma cytokine data of TNF-α and IL-6 followed a similar pattern to ALT data, and no significant difference was found between the wild-type and P/I null groups. In contrast, a significant difference in KC and MIP-2 chemokine levels was observed between the wild-type and P/I null mice. Additionally, the survival study showed a trend towards increased survival in the P/I null group. Conclusion While ICAM-1 and P

  13. Doxycycline and Benznidazole Reduce the Profile of Th1, Th2, and Th17 Chemokines and Chemokine Receptors in Cardiac Tissue from Chronic Trypanosoma cruzi-Infected Dogs

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    Guilherme de Paula Costa

    2016-01-01

    Full Text Available Chemokines (CKs and chemokine receptors (CKR promote leukocyte recruitment into cardiac tissue infected by the Trypanosoma cruzi. This study investigated the long-term treatment with subantimicrobial doses of doxycycline (Dox in association, or not, with benznidazole (Bz on the expression of CK and CKR in cardiac tissue. Thirty mongrel dogs were infected, or not, with the Berenice-78 strain of T. cruzi and grouped according their treatments: (i two months after infection, Dox (50 mg/kg 2x/day for 12 months; (ii nine months after infection, Bz (3,5 mg/kg 2x/day for 60 days; (iii Dox + Bz; and (iv vehicle. After 14 months of infection, hearts were excised and processed for qPCR analysis of Th1 (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL11, Th2 (CCL1, CCL17, CCL24, and CCL26, Th17 (CCL20 CKs, Th1 (CCR5, CCR6, and CXCR3, and Th2/Th17 (CCR3, CCR4, and CCR8 CKR, as well as IL-17. T. cruzi infection increases CCL1, CCL2, CCL4, CCL5, CCL17, CXCL10, and CCR5 expression in the heart. Dox, Bz, or Dox + Bz treatments cause a reversal of CK and CKR and reduce the expression of CCL20, IL-17, CCR6, and CXCR3. Our data reveal an immune modulatory effect of Dox with Bz, during the chronic phase of infection suggesting a promising therapy for cardiac protection.

  14. A bioplex analysis of cytokines and chemokines in first trimester maternal plasma to screen for predictors of miscarriage.

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    Natalie J Hannan

    Full Text Available BACKGROUND: We have previously shown in two independent cohorts that circulating first trimester Macrophage Inhibitory Cytokine-1 (MIC-1 levels are lower in women in early pregnancy who are destined to miscarriage. While promising, the diagnostic performance of measuring MIC-1 alone was not sufficient for it to be a useful predictive test for miscarriage. Besides MIC-1, there are other cytokines, as well as chemokines, involved in facilitating early pregnancy. We reasoned that screening these factors in maternal plasma could uncover other predictive markers of miscarriage. METHODS: This was a nested case control study, of 78 women from a prospective study of 462 attending the Early Pregnancy Assessment Unit in the first trimester (EPAU with a threatened miscarriage; 34 of these subsequently miscarried (cases and 44 went on to have a normal delivery (controls Cytokines IL-1β, IL-6 and IL-10, and the chemokines, CXCL8, CCL2, CCL5, CCL7 and CX3CL1 were measured in plasma from our cohort. RESULTS: The cytokines IL-1β, IL-6, IL-10 and the chemokine CXCL8 were not detectable in first trimester plasma. The chemokines CCL2, CCL5, CCL7 and CX3CL1 were detectable in all samples but levels did not vary across 5-12 weeks of gestation among controls. Plasma levels of these chemokines were no different in the miscarriage cohort compared to controls. CONCLUSION: The chemokines CCL2, CCL5, CCL7 and CX3CL1 were detectable in plasma during the first trimester while IL-1β, IL-6, IL-10 and CXCL8 were not. However, none of the cytokines and chemokines screened were different in maternal plasma in cases or controls. These therefore do not appear to have potential for application as predictive biomarkers of miscarriage.

  15. Soluble M3 proteins of murine gammaherpesviruses 68 and 72 expressed in Escherichia coli: analysis of chemokine-binding properties.

    Science.gov (United States)

    Matúšková, R; Pančík, P; Štibrániová, I; Belvončíková, P; Režuchová, I; Kúdelová, M

    2015-12-01

    M3 protein of murine gammaherpesvirus 68 (MHV-68) was identified as a viral chemokine-binding protein 3 (vCKBP-3) capable to bind a broad spectrum of chemokines and their receptors. During both acute and latent infection MHV-68 M3 protein provides a selective advantage for the virus by inhibiting the antiviral and inflammatory response. A unique mutation Asp307Gly was identified in the M3 protein of murine gammaherpesvirus 72 (MHV-72), localized near chemokine-binding domain. Study on chemokine-binding properties of MHV-72 M3 protein purified from medium of infected cells implied reduced binding to some chemokines when compared to MHV-68 M3 protein. It was suggested that the mutation in the M3 protein might be involved in the attenuation of immune response to infection with MHV-72. Recently, Escherichia coli cells were used to prepare native recombinant M3 proteins of murine gammaherpesviruses 68 and 72 (Pančík et al., 2013). In this study, we assessed the chemokine-binding properties of three M3 proteins prepared in E. coli Rosetta-gami 2 (DE3) cells, the full length M3 protein of both MHV-68 and MHV-72 and MHV-68 M3 protein truncated in the signal sequence (the first 24 aa). They all displayed binding activity to human chemokines CCL5 (RANTES), CXCL8 (IL-8), and CCL3 (MIP-1α). The truncated MHV-68 M3 protein had more than twenty times reduced binding activity to CCL5, but only about five and three times reduced binding to CXCL8 and CCL3 when compared to its full length counterpart. Binding of the full length MHV-72 M3 protein to all chemokines was reduced when compared to MHV-68 M3 protein. Its binding to CCL5 and CCL3 was reduced over ten and seven times. However, its binding to CXCL8 was only slightly reduced (64.8 vs 91.8%). These data implied the significance of the signal sequence and also of a single mutation (at aa 307) for efficient M3 protein binding to some chemokines.

  16. Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression.

    Science.gov (United States)

    Shen, Zhe; Liu, Yan; Dewidar, Bedair; Hu, Junhao; Park, Ogyi; Feng, Teng; Xu, Chengfu; Yu, Chaohui; Li, Qi; Meyer, Christoph; Ilkavets, Iryna; Müller, Alexandra; Stump-Guthier, Carolin; Munker, Stefan; Liebe, Roman; Zimmer, Vincent; Lammert, Frank; Mertens, Peter R; Li, Hai; Ten Dijke, Peter; Augustin, Hellmut G; Li, Jun; Gao, Bin; Ebert, Matthias P; Dooley, Steven; Li, Youming; Weng, Hong-Lei

    2016-07-01

    Disrupting Notch signaling ameliorates experimental liver fibrosis. However, the role of individual Notch ligands in liver damage is unknown. We investigated the effects of Delta-like ligand 4 (Dll4) in liver disease. DLL4 expression was measured in 31 human liver tissues by immunohistochemistry. Dll4 function was examined in carbon tetrachloride- and bile duct ligation-challenged mouse models in vivo and evaluated in hepatic stellate cells, hepatocytes, and Kupffer cells in vitro. DLL4 was expressed in patients' Kupffer and liver sinusoidal endothelial cells. Recombinant Dll4 protein (rDll4) ameliorated hepatocyte apoptosis, inflammation, and fibrosis in mice after carbon tetrachloride challenge. In vitro, rDll4 significantly decreased lipopolysaccharide-dependent chemokine expression in both Kupffer and hepatic stellate cells. In bile duct ligation mice, rDll4 induced massive hepatic necrosis, resulting in the death of all animals within 1 week. Inflammatory cell infiltration and chemokine ligand 2 (Ccl2) expression were significantly reduced in rDll4-receiving bile duct ligation mice. Recombinant Ccl2 rescued bile duct ligation mice from rDll4-mediated death. In patients with acute-on-chronic liver failure, DLL4 expression was inversely associated with CCL2 abundance. Mechanistically, Dll4 regulated Ccl2 expression via NF-κB. Taken together, Dll4 modulates liver inflammatory response by down-regulating chemokine expression. rDll4 application results in opposing outcomes in two models of liver damage. Loss of DLL4 may be associated with CCL2-mediated cytokine storm in patients with acute-on-chronic liver failure. PMID:27171900

  17. Regulation of MMP-3 expression and secretion by the chemokine eotaxin-1 in human chondrocytes

    Directory of Open Access Journals (Sweden)

    Chao Pin-Zhir

    2011-11-01

    Full Text Available Abstract Background Osteoarthritis (OA is characterized by the degradation of articular cartilage, marked by the breakdown of matrix proteins. Studies demonstrated the involvement of chemokines in this process, and some may potentially serve as diagnostic markers and therapeutic targets; however, the underlying signal transductions are not well understood. Methods We investigated the effects of the CC chemokine eotaxin-1 (CCL11 on the matrix metalloproteinase (MMP expression and secretion in the human chondrocyte cell line SW1353 and primary chondrocytes. Results Eotaxin-1 significantly induced MMP-3 mRNA expression in a dose-dependent manner. Inhibitors of extracellular signal-regulated kinase (ERK and p38 kinase were able to repress eotaxin-1-induced MMP-3 expression. On the contrary, Rp-adenosine-3',5'-cyclic monophosphorothioate (Rp-cAMPs, a competitive cAMP antagonist for cAMP receptors, and H-89, a protein kinase A (PKA inhibitor, markedly enhanced eotaxin-1-induced MMP-3 expression. These results suggest that MMP-3 expression is specifically mediated by the G protein-coupled eotaxin-1 receptor activities. Interestingly, little amount of MMP-3 protein was detected in the cell lysates of eotaxin-1-treated SW1353 cells, and most of MMP-3 protein was in the culture media. Furthermore we found that the eotaxin-1-dependent MMP-3 protein secretion was regulated by phospholipase C (PLC-protein kinase C (PKC cascade and c-Jun N-terminal kinase (JNK/mitogen-activated protein (MAP kinase pathways. These data indicate a specific regulation of MMP-3 secretion also by eotaxin-1 receptor activities. Conclusions Eotaxin-1 not only induces MMP-3 gene expression but also promotes MMP-3 protein secretion through G protein-coupled eotaxin-1 receptor activities. Chemokines, such as eotaxin-1, could be a potential candidate in the diagnosis and treatment of arthritis.

  18. Chemokine-mediated distribution of dendritic cell subsets in renal cell carcinoma

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    Meyer Werner

    2010-10-01

    Full Text Available Abstract Background Renal cell carcinoma (RCC represents one of the most immunoresponsive cancers. Antigen-specific vaccination with dendritic cells (DCs in patients with metastatic RCC has been shown to induce cytotoxic T-cell responses associated with objective clinical responses. Thus, clinical trials utilizing DCs for immunotherapy of advanced RCCs appear to be promising; however, detailed analyses concerning the distribution and function of DC subsets in RCCs are lacking. Methods We characterized the distribution of the different immature and mature myeloid DC subsets in RCC tumour tissue and the corresponding normal kidney tissues. In further analyses, the expression of various chemokines and chemokine receptors controlling the migration of DC subsets was investigated. Results The highest numbers of immature CD1a+ DCs were found within RCC tumour tissue. In contrast, the accumulation of mature CD83+/DC-LAMP+ DCs were restricted to the invasive margin of the RCCs. The mature DCs formed clusters with proliferating T-cells. Furthermore, a close association was observed between MIP-3α-producing tumour cells and immature CCR6+ DC recruitment to the tumour bed. Conversely, MIP-3β and SLC expression was only detected at the tumour border, where CCR7-expressing T-cells and mature DCs formed clusters. Conclusion Increased numbers of immature DCs were observed within the tumour tissue of RCCs, whereas mature DCs were found in increased numbers at the tumour margin. Our results strongly implicate that the distribution of DC subsets is controlled by local lymphoid chemokine expression. Thus, increased expression of MIP-3α favours recruitment of immature DCs to the tumour bed, whereas de novo local expression of SLC and MIP-3β induces accumulation of mature DCs at the tumour margin forming clusters with proliferating T-cells reflecting a local anti-tumour immune response.

  19. Expression of the chemokine receptor CXCR4 on lymphocytes of leprosy patients

    Directory of Open Access Journals (Sweden)

    V.A. Mendonça

    2011-12-01

    Full Text Available Leprosy is caused by Mycobacterium leprae, which induces chronic granulomatous infection of the skin and peripheral nerves. The disease ranges from the tuberculoid to the lepromatous forms, depending on the cellular immune response of the host. Chemokines are thought to be involved in the immunopathogenesis of leprosy, but few studies have investigated the expression of chemokine receptors on leukocytes of leprosy patients. In the present study, we evaluated 21 leprosy patients (M/F: 16/5 with a new diagnosis from the Dermatology Outpatient Clinic of the University Hospital, Federal University of Minas Gerais. The control group was composed of 20 healthy members (M/F: 15/5 of the community recruited by means of announcements. The expression of CCR2, CCR3, CCR5, and CXCR4 was investigated by flow cytometry on the surface of peripheral blood lymphocytes. There was a decrease in percentage of CD3+CXCR4+ and CD4+CXCR4+ lymphocytes in the peripheral blood of leprosy patients (median [range], 17.6 [2.7-41.9] and 65.3 [3.9-91.9], respectively compared to the control group (median [range], 43.0 [3.7-61.3] and 77.2 [43.6-93.5], respectively. The percentage of CD4+CXCR4+ was significantly lower in patients with the tuberculoid form (median [range], 45.7 [0.0-83.1] of the disease, but not in lepromatous patients (median [range], 81.5 [44.9-91.9]. The CXCR4 chemokine receptor may play a role in leprosy immunopathogenesis, probably directing cell migration to tissue lesions in tuberculoid leprosy patients.

  20. Expressions of chemokine receptor CXCR4 and its ligand CXCL12 in salivary adenoid cystic carcinoma

    Institute of Scientific and Technical Information of China (English)

    徐晓刚; 吕春堂; 周中华

    2004-01-01

    Objective: To examine expressions of chemokine receptor CXCR4 and its ligand CXCL12 in primary focus and lymphogenous metastasis of salivary adenoid cystic carcinoma (ACC) with lung metastasis. Methods: Using immunohistochemical hypersensitivity catalyzed signal amplification (CSA), expressions of chemokine receptor CXCR4 and ligand CXCL12 were detected in tissue specimens from 20 cases of primary cancer focus and lymphogenous metastasis of salivary adenoid cystic carcinoma, of which 7 cases were associated with lung metastasis and 3 with lympogenons metastasis. Twenty cases of tongue carcinoma (including 10 cases with lymphogenous metastasis) and 15 cases of mucoepidermoid carcinoma (including 5 cases with lymphogenous metastasis) were used as the malignant control group; and salivary mixed tumor ( n =10), tongue leukoceratosis ( n = 10) and cervical lymph node reactive hyperplasia ( n = 10) were used as the benign control group. Results: Expression of CXCR4 in the tissues and lymph metastases of oral and maxillofacial salivary ACC, mucoepidermoid carcinoma and tongue carcinoma was significantly higher than that of the benign control group ( P < 0.05); expression of CXCR4 in the primary focus of ACC was significantly higher than that of the malignant control group; and expression of CXCR4 in the ACC with lung metastasis was 87.1% (6/7), significantly higher than that without lung metastasis( P <0.01 ). There was evident positive expression of CXCL12 in endotheliocytes of microvessels within cancer and paracancer tissues and significantly high expression of CXCL12 in lymphogenous metastasis( P < 0.05). Conclusion: Chemokine receptor CXCR4 and its ligand CXCL12 may be associated with local invasion and lymphogenous metastasis of oral and maxillofacial cancer, especially with lung metastasis of salivary ACC.

  1. Antimycotics suppress the Malassezia extract-induced production of CXC chemokine ligand 10 in human keratinocytes.

    Science.gov (United States)

    Hau, Carren S; Kanda, Naoko; Makimura, Koichi; Watanabe, Shinichi

    2014-02-01

    Malassezia, a lipophilic yeast, exacerbates atopic dermatitis. Malassezia products can penetrate the disintegrated stratum corneum and encounter subcorneal keratinocytes in the skin of atopic dermatitis patients. Type 1 helper T (Th1) cells infiltrate chronic lesions with atopic dermatitis, and antimycotic agents improve its symptoms. We aimed to identify Malassezia-induced chemokines in keratinocytes and examine whether antimycotics suppressed this induction. Normal human keratinocytes were incubated with a Malassezia restricta extract and antimycotics. Chemokine expression was analyzed by enzyme-linked immunosorbent assays and real-time polymerase chain reaction. Signal transducer and activator of transcription (STAT)1 activity was examined by luciferase assays. The tyrosine-phosphorylation of STAT1 was analyzed by western blotting. The M. restricta extract increased the mRNA and protein expression of Th1-attracting CXC chemokine ligand (CXCL)10 and STAT1 activity and phosphorylation in keratinocytes, which was suppressed by a Janus kinase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine suppressed M. restricta extract-induced CXCL10 mRNA and protein expression and STAT1 activity and phosphorylation. These effects were similarly induced by 15-deoxy-Δ-(12,14) -prostaglandin J2 (15d-PGJ2 ), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes. The antimycotic-induced suppression of CXCL10 production and STAT1 activity was counteracted by a lipocalin-type prostaglandin D synthase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine may suppress the M. restricta-induced production of CXCL10 by inhibiting STAT1 through an increase in 15d-PGJ2 production in keratinocytes. These antimycotics may block the Th1-mediated inflammation triggered by Malassezia in the chronic phase of atopic dermatitis. PMID

  2. Chemokine biomarkers in central nervous system tissue and cerebrospinal fluid in the Theiler's virus model mirror those in multiple sclerosis.

    Science.gov (United States)

    Pachner, Andrew R; Li, Libin; Gilli, Francesca

    2015-12-01

    Chemokines have increasingly been implicated in inflammatory and infectious disease of the central nervous system, both as biomarkers and as molecules important in pathogenesis. Multiple sclerosis is a disabling disease of unknown etiology, and recently chemokines have been identified as being upregulated molecules in the disease. We were interested in how the chemokine expression patterns in the central nervous system of a viral model of multiple sclerosis, Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), compared to that in humans with multiple sclerosis. Cerebrospinal fluid and spinal cord tissue were analyzed for expression of a range of cytokines and chemokines. Three chemokines, CXCL10, CXCL9, and CCL5 were strongly and specifically upregulated in both the cerebrospinal fluid and spinal cord in chronic disease, a pattern identical to that in multiple sclerosis. These data, the first study of cytokines in central nervous system tissue and cerebrospinal fluid in TMEV-IDD, support the hypothesis that multiple sclerosis is caused by chronic infection with an as-yet unidentified pathogen, possibly a picornavirus.

  3. A chemokine targets the nucleus: Cxcl12-gamma isoform localizes to the nucleolus in adult mouse heart.

    Directory of Open Access Journals (Sweden)

    Raul Torres

    Full Text Available Chemokines are extracellular mediators of complex regulatory circuits involved principally in cell-to-cell communication. Most studies to date of the essential chemokine Cxcl12 (Sdf-1 have focused on the ubiquitously expressed secreted isoforms alpha and beta. Here we show that, unlike these isoforms and all other known chemokines, the alternatively transcribed gamma isoform is an intracellular protein that localizes to the nucleolus in differentiated mouse Cardiac tissue. Our results demonstrate that nucleolar transportation is encoded by a nucleolar-localization signal in the unique carboxy-terminal region of Sdf-1gamma, and is competent both in vivo and in vitro. The molecular mechanism underlying these unusual chemokine properties involves cardiac-specific transcription of an mRNA containing a unique short-leader sequence lacking the signal peptide and translation from a non-canonical CUG codon. Our results provide an example of genome economy even for essential and highly conserved genes such as Cxcl12, and suggest that chemokines can exert tissue specific functions unrelated to cell-to-cell communication.

  4. Genetic characterization of the chemokine receptor CXCR4 gene in lagomorphs: comparison between the families Ochotonidae and Leporidae.

    Science.gov (United States)

    Abrantes, J; Esteves, P J; Carmo, C R; Müller, A; Thompson, G; van der Loo, W

    2008-04-01

    Chemokines receptors are transmembrane proteins that bind chemokines. Chemokines and their receptors are known to play a crucial role in the immune system and in pathogen entry. There is evidence that myxoma virus, the causative agent of myxomatosis, can use the chemokine receptor CXCR4 to infect cells. This virus causes a benign disease in its natural host, Sylvilagus, but in the European rabbit (Oryctolagus cuniculus) it causes a highly fatal and infectious disease known as myxomatosis. We have characterized the chemokine receptor CXCR4 gene in five genera of the order Lagomorpha, Ochotona (Ochotonidae), and Oryctolagus, Lepus, Bunolagus and Sylvilagus (Leporidae). In lagomorphs, the CXCR4 is highly conserved, with most of the protein diversity found at surface regions. Five amino acid replacements were observed, two in the intracellular loops, one in the transmembrane domain and two in the extracellular loops. Oryctolagus features unique amino acid changes at the intracellular domains, putting this genus apart of all other lagomorphs. Furthermore, in the 37 European rabbits analysed, which included healthy rabbits and rabbits with clinical symptoms of myxomatosis, 14 nucleotide substitutions were obtained but no amino acid differences were observed. PMID:18205827

  5. Gamma Interferon Signaling in Macrophage Lineage Cells Regulates Central Nervous System Inflammation and Chemokine Production ▿

    OpenAIRE

    Lin, Adora A.; Tripathi, Pulak K.; Sholl, Allyson; Jordan, Michael B.; Hildeman, David A.

    2009-01-01

    Intracranial (i.c.) infection of mice with lymphocytic choriomeningitis virus (LCMV) results in anorexic weight loss, mediated by T cells and gamma interferon (IFN-γ). Here, we assessed the role of CD4+ T cells and IFN-γ on immune cell recruitment and proinflammatory cytokine/chemokine production in the central nervous system (CNS) after i.c. LCMV infection. We found that T-cell-depleted mice had decreased recruitment of hematopoietic cells to the CNS and diminished levels of IFN-γ, CCL2 (MCP...

  6. Chemokine receptor CCR8 is required for lipopolysaccharide-triggered cytokine production in mouse peritoneal macrophages.

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    Tomoyuki Oshio

    Full Text Available Chemokine (C-C motif receptor 8 (CCR8, the chemokine receptor for chemokine (C-C motif ligand 1 (CCL1, is expressed in T-helper type-2 lymphocytes and peritoneal macrophages (PMφ and is involved in various pathological conditions, including peritoneal adhesions. However, the role of CCR8 in inflammatory responses is not fully elucidated. To investigate the function of CCR8 in macrophages, we compared cytokine secretion from mouse PMφ or bone marrow-derived macrophages (BMMφ stimulated with various Toll-like receptor (TLR ligands in CCR8 deficient (CCR8-/- and wild-type (WT mice. We found that CCR8-/- PMφ demonstrated attenuated secretion of tumor necrosis factor (TNF-α, interleukin (IL-6, and IL-10 when stimulated with lipopolysaccharide (LPS. In particular, LPS-induced IL-10 production absolutely required CCR8. CCR8-dependent cytokine secretion was characteristic of PMφ but not BMMφ. To further investigate this result, we selected the small molecule compound R243 from a library of compounds with CCR8-antagonistic effects on CCL1-induced Ca2+ flux and CCL1-driven PMφ aggregation. Similar to CCR8-/- PMφ, R243 attenuated secretion of TNF-α, IL-6, and most strikingly IL-10 from WT PMφ, but not BMMφ. CCR8-/- PMφ and R243-treated WT PMφ both showed suppressed c-jun N-terminal kinase activity and nuclear factor-κB signaling after LPS treatment when compared with WT PMφ. A c-Jun signaling pathway inhibitor also produced an inhibitory effect on LPS-induced cytokine secretion that was similar to that of CCR8 deficiency or R243 treatment. As seen in CCR8-/- mice, administration of R243 attenuated peritoneal adhesions in vivo. R243 also prevented hapten-induced colitis. These results are indicative of cross talk between signaling pathways downstream of CCR8 and TLR-4 that induces cytokine production by PMφ. Through use of CCR8-/- mice and the new CCR8 inhibitor, R243, we identified a novel macrophage innate immune response pathway that

  7. The Role of chemokine receptor CXCR4 in breast cancer metastasis

    OpenAIRE

    Mukherjee, Debarati; Zhao, Jihe

    2013-01-01

    Breast cancer is one of the leading causes of cancer related deaths worldwide. Breast cancer-related mortality is associated with the development of metastatic potential of primary tumor lesions. The chemokine receptor CXCR4 has been found to be a prognostic marker in various types of cancer, including breast cancer. Recent advances in the field of cancer biology has pointed to the critical role that CXCR4 receptor and its ligand CXCL12 play in the metastasis of various types of cancer, inclu...

  8. Two selective novel triterpene glycosides from sea cucumber, Telenata ananas: Inhibitors of chemokine receptor-5

    Digital Repository Service at National Institute of Oceanography (India)

    Hegde, V.R.; Chan, T.-M.; Pu, H.; Gullo, V.P.; Patel, M.G.; Das, P.; Wagner, N.; Parameswaran, P.S.; Naik, C.G.

    . Kitagawa, I.; Kobayashi, M.; Kyogoku, Y. Chem. Pharm. Bull. 1982, 30, 2045. 12. A screening assay utilizing a membrane-binding assay was developed to identify antagonists of the ligand RANTES binding to the CCR5 receptor. Cell membranes were prepared from... CHO cells (BioSignal Inc.) transduced to express the human CCR5 chemokine receptor. These membrane prepara- tions were incubated with 125 I-RANTESin the presence or absenceofcompoundforonehourat25 C14 C.Compounds were serially diluted over a range of 0...

  9. Identification and Profiling of Novel α1A-Adrenoceptor-CXC Chemokine Receptor 2 Heteromer*

    OpenAIRE

    Mustafa, Sanam; Heng B See; Seeber, Ruth M.; Armstrong, Stephen P.; White, Carl W; Ventura, Sabatino; Ayoub, Mohammed Akli; Pfleger, Kevin D.G.

    2012-01-01

    We have provided the first evidence for specific heteromerization between the α1A-adrenoceptor (α1AAR) and CXC chemokine receptor 2 (CXCR2) in live cells. α1AAR and CXCR2 are both expressed in areas such as the stromal smooth muscle layer of the prostate. By utilizing the G protein-coupled receptor (GPCR) heteromer identification technology on the live cell-based bioluminescence resonance energy transfer (BRET) assay platform, our studies in human embryonic kidney 293 cells have identified no...

  10. Production of Interferons and β-Chemokines by Placental Trophoblasts of HIV-1-Infected Women

    OpenAIRE

    Reuben, James M.; Shearer, William T; Mary Paul; Claudia Kozinetz; Stanley Cron; Popek, Edwina J; Hunter Hammill; Bang-Ning Lee

    2001-01-01

    Objective: The mechanism whereby the placental cells of a human immunodeficiency virus (HIV)-1-infected mother protect the fetus from HIV-1 infection is unclear. Interferons (IFNs) inhibit the replication of viruses by acting at various stages of the life cycle and may play a role in protecting against vertical transmission of HIV-1. In addition the β-chemokines RANTES (regulated on activation T cell expressed and secreted), macrophage inflammatory protein-1-α (MIP-1α), and MIP-1β can block H...

  11. Differential modulation of retinal degeneration by Ccl2 and Cx3cr1 chemokine signalling.

    Science.gov (United States)

    Luhmann, Ulrich F O; Lange, Clemens A; Robbie, Scott; Munro, Peter M G; Cowing, Jill A; Armer, Hannah E J; Luong, Vy; Carvalho, Livia S; MacLaren, Robert E; Fitzke, Frederick W; Bainbridge, James W B; Ali, Robin R

    2012-01-01

    Microglia and macrophages are recruited to sites of retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to retinal telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2(-/-)/Crb1(Rd8/RD8), Cx3cr1(-/-)/Crb1(Rd8/RD8) and CCl2(-/-)/Cx3cr1(-/-)/Crb1(Rd8/RD8) mice, we observed a differential modulation of the retinal phenotype by genetic background and both chemokine signalling pathways. These findings

  12. Pseudogenization of the MCP-2/CCL8 chemokine gene in European rabbit (genus Oryctolagus, but not in species of Cottontail rabbit (Sylvilagus and Hare (Lepus

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    van der Loo Wessel

    2012-08-01

    Full Text Available Abstract Background Recent studies in human have highlighted the importance of the monocyte chemotactic proteins (MCP in leukocyte trafficking and their effects in inflammatory processes, tumor progression, and HIV-1 infection. In European rabbit (Oryctolagus cuniculus one of the prime MCP targets, the chemokine receptor CCR5 underwent a unique structural alteration. Until now, no homologue of MCP-2/CCL8a, MCP-3/CCL7 or MCP-4/CCL13 genes have been reported for this species. This is interesting, because at least the first two genes are expressed in most, if not all, mammals studied, and appear to be implicated in a variety of important chemokine ligand-receptor interactions. By assessing the Rabbit Whole Genome Sequence (WGS data we have searched for orthologs of the mammalian genes of the MCP-Eotaxin cluster. Results We have localized the orthologs of these chemokine genes in the genome of European rabbit and compared them to those of leporid genera which do (i.e. Oryctolagus and Bunolagus or do not share the CCR5 alteration with European rabbit (i.e. Lepus and Sylvilagus. Of the Rabbit orthologs of the CCL8, CCL7, and CCL13 genes only the last two were potentially functional, although showing some structural anomalies at the protein level. The ortholog of MCP-2/CCL8 appeared to be pseudogenized by deleterious nucleotide substitutions affecting exon1 and exon2. By analyzing both genomic and cDNA products, these studies were extended to wild specimens of four genera of the Leporidae family: Oryctolagus, Bunolagus, Lepus, and Sylvilagus. It appeared that the anomalies of the MCP-3/CCL7 and MCP-4/CCL13 proteins are shared among the different species of leporids. In contrast, whereas MCP-2/CCL8 was pseudogenized in every studied specimen of the Oryctolagus - Bunolagus lineage, this gene was intact in species of the Lepus - Sylvilagus lineage, and was, at least in Lepus, correctly transcribed. Conclusion The biological function of a gene was often

  13. Interleukin-4 induction of the CC chemokine TARC (CCL17 in murine macrophages is mediated by multiple STAT6 sites in the TARC gene promoter

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    Glass Christopher K

    2006-11-01

    Full Text Available Abstract Background Macrophages (Mθ play a central role in the innate immune response and in the pathology of chronic inflammatory diseases. Macrophages treated with Th2-type cytokines such as Interleukin-4 (IL-4 and Interleukin-13 (IL-13 exhibit an altered phenotype and such alternatively activated macrophages are important in the pathology of diseases characterised by allergic inflammation including asthma and atopic dermatitis. The CC chemokine Thymus and Activation-Regulated Chemokine (TARC/CCL17 and its murine homologue (mTARC/ABCD-2 bind to the chemokine receptor CCR4, and direct T-cell and macrophage recruitment into areas of allergic inflammation. Delineating the molecular mechanisms responsible for the IL-4 induction of TARC expression will be important for a better understanding of the role of Th2 cytokines in allergic disease. Results We demonstrate that mTARC mRNA and protein are potently induced by the Th2 cytokine, Interleukin-4 (IL-4, and inhibited by Interferon-γ (IFN-γ in primary macrophages (Mθ. IL-4 induction of mTARC occurs in the presence of PI3 kinase pathway and translation inhibitors, but not in the absence of STAT6 transcription factor, suggesting a direct-acting STAT6-mediated pathway of mTARC transcriptional activation. We have functionally characterised eleven putative STAT6 sites identified in the mTARC proximal promoter and determined that five of these contribute to the IL-4 induction of mTARC. By in vitro binding assays and transient transfection of isolated sites into the RAW 264.7 Mθ cell-line, we demonstrate that these sites have widely different capacities for binding and activation by STAT6. Site-directed mutagenesis of these sites within the context of the mTARC proximal promoter revealed that the two most proximal sites, conserved between the human and mouse genes, are important mediators of the IL-4 response. Conclusion The induction of mTARC by IL-4 results from cooperative interactions between STAT6

  14. Vascular Stem/Progenitor Cell Migration Induced by Smooth Muscle Cell-Derived Chemokine (C-C Motif) Ligand 2 and Chemokine (C-X-C motif) Ligand 1 Contributes to Neointima Formation.

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    Yu, Baoqi; Wong, Mei Mei; Potter, Claire M F; Simpson, Russell M L; Karamariti, Eirini; Zhang, Zhongyi; Zeng, Lingfang; Warren, Derek; Hu, Yanhua; Wang, Wen; Xu, Qingbo

    2016-09-01

    Recent studies have shown that Sca-1(+) (stem cell antigen-1) stem/progenitor cells within blood vessel walls may contribute to neointima formation, but the mechanism behind their recruitment has not been explored. In this work Sca-1(+) progenitor cells were cultivated from mouse vein graft tissue and found to exhibit increased migration when cocultured with smooth muscle cells (SMCs) or when treated with SMC-derived conditioned medium. This migration was associated with elevated levels of chemokines, CCL2 (chemokine (C-C motif) ligand 2) and CXCL1 (chemokine (C-X-C motif) ligand 1), and their corresponding receptors on Sca-1(+) progenitors, CCR2 (chemokine (C-C motif) receptor 2) and CXCR2 (chemokine (C-X-C motif) receptor 2), which were also upregulated following SMC conditioned medium treatment. Knockdown of either receptor in Sca-1(+) progenitors significantly inhibited cell migration. The GTPases Cdc42 and Rac1 were activated by both CCL2 and CXCL1 stimulation and p38 phosphorylation was increased. However, only Rac1 inhibition significantly reduced migration and p38 phosphorylation. After Sca-1(+) progenitors labeled with green fluorescent protein (GFP) were applied to the adventitial side of wire-injured mouse femoral arteries, a large proportion of GFP-Sca-1(+) -cells were observed in neointimal lesions, and a marked increase in neointimal lesion formation was seen 1 week post-operation. Interestingly, Sca-1(+) progenitor migration from the adventitia to the neointima was abrogated and neointima formation diminished in a wire injury model using CCL2(-/-) mice. These findings suggest vascular stem/progenitor cell migration from the adventitia to the neointima can be induced by SMC release of chemokines which act via CCR2/Rac1/p38 and CXCR2/Rac1/p38 signaling pathways. Stem Cells 2016;34:2368-2380.

  15. The role of cytokines and chemokines in the T-cell-mediated autoimmune process in alopecia areata.

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    Ito, Taisuke; Tokura, Yoshiki

    2014-11-01

    The aetiology of alopecia areata (AA) is still not fully understood. However, recent clinical and experimental studies have provided insights into the pathomechanisms of AA and revealed that it is an organ-specific and cell-mediated autoimmune disease. Some triggers, such as viral infections, trauma, hormones and emotional/physical stressors, may cause activation of autoreactive T cells that target hair follicle (HF) autoantigens. In these immunological responses, cytokines and chemokines are regarded as key players that mediate the autoimmune inflammation. This results in the collapse of HF immune privilege, which is central to the pathogenesis of AA. This essay will focus on how cytokines and chemokines contribute to the immunological aspects of AA. The management of AA often remains difficult in a number of cases. Our review suggests that novel therapies for AA may involve targeting cytokines and chemokines. PMID:25040075

  16. Inflammatory cytokines regulate secretion of VEGF and chemokines by human conjunctival fibroblasts: Role in dysfunctional tear syndrome.

    Science.gov (United States)

    Nagineni, Chandrasekharam N; William, Abitha; Cherukuri, Aswini; Samuel, William; Hooks, John J; Detrick, Barbara

    2016-02-01

    Ocular surface inflammation is one of the primary mechanisms associated with dysfunctional tear syndrome (DTS), also known as dry eye disease. DTS, more prevalent in older populations, causes ocular discomfort and visual disturbance due to dryness on the surface layer in the eye. We used human conjunctival fibroblast cultures (HCJVF) to investigate the effects of inflammatory cytokines IFN-γ, TNF-α and IL-1β (ITI) on the secretions of VEGF and chemokines. Our results demonstrate the elevated secretion of angiogenic VEGF molecules by ITI without affecting anti-angiogenic molecules, PEDF, endostatin, thrombospondin and sVEGF-R1. The secretion of interferon-γ inducible chemokines, CXCL9, -10, -11 by HCJVF were significantly enhanced by ITI. Our in vitro study supports previously reported observations of elevated VEGF and chemokines in tear fluids of DTS patients, reiterating the role of inflammatory reactions in DTS. PMID:26615568

  17. The role of cytokines and chemokines in the T-cell-mediated autoimmune process in alopecia areata.

    Science.gov (United States)

    Ito, Taisuke; Tokura, Yoshiki

    2014-11-01

    The aetiology of alopecia areata (AA) is still not fully understood. However, recent clinical and experimental studies have provided insights into the pathomechanisms of AA and revealed that it is an organ-specific and cell-mediated autoimmune disease. Some triggers, such as viral infections, trauma, hormones and emotional/physical stressors, may cause activation of autoreactive T cells that target hair follicle (HF) autoantigens. In these immunological responses, cytokines and chemokines are regarded as key players that mediate the autoimmune inflammation. This results in the collapse of HF immune privilege, which is central to the pathogenesis of AA. This essay will focus on how cytokines and chemokines contribute to the immunological aspects of AA. The management of AA often remains difficult in a number of cases. Our review suggests that novel therapies for AA may involve targeting cytokines and chemokines.

  18. Thiazolidinediones inhibit airway smooth muscle release of the chemokine CXCL10: in vitro comparison with current asthma therapies

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    Seidel Petra

    2012-10-01

    Full Text Available Abstract Background Activated mast cells are present within airway smooth muscle (ASM bundles in eosinophilic asthma. ASM production of the chemokine CXCL10 plays a role in their recruitment. Thus the effects of glucocorticoids (fluticasone, budesonide, long-acting β2-agonists (salmeterol, formoterol and thiazolidinediones (ciglitazone, rosiglitazone on CXCL10 production by ASM cells (ASMC from people with and without asthma were investigated in vitro. Methods Confluent serum-deprived cells were treated with the agents before and during cytokine stimulation for 0-24 h. CXCL10 protein/mRNA, IκB-α levels and p65 activity were measured using ELISA, RT PCR, immunoblotting and p65 activity assays respectively. Data were analysed using ANOVA followed by Fisher’s post-hoc test. Results Fluticasone and/or salmeterol at 1 and 100 nM inhibited CXCL10 release induced by IL-1β and TNF-α, but not IFNγ or all three cytokines (cytomix. The latter was also not affected by budesonide and formoterol. In asthmatic ASMC low salmeterol, but not formoterol, concentrations increased cytomix-induced CXCL10 release and at 0.01 nM enhanced NF-κB activity. Salmeterol 0.1nM together with fluticasone 0.1 and 10 nM still increased CXCL10 release. The thiazolidinediones ciglitazone and rosiglitazone (at 25 and 100 μM inhibited cytomix-induced CXCL10 release but these inhibitory effects were not prevented by the PPAR-g antagonist GW9662. Ciglitazone did not affect early NF-κB activity and CXCL10 mRNA production. Conclusions Thus the thiazolidinediones inhibited asthmatic ASMC CXCL10 release under conditions when common asthma therapies were ineffective or enhanced it. They may provide an alternative strategy to reduce mast cell-ASM interactions and restore normal airway physiology in asthma.

  19. Disruption of mTORC1 in Macrophages Decreases Chemokine Gene Expression and Atherosclerosis

    Science.gov (United States)

    Ai, Ding; Jiang, Hongfeng; Westerterp, Marit; Murphy, Andrew J.; Wang, Mi; Ganda, Anjali; Abramowicz, Sandra; Welch, Carrie; Almazan, Felicidad; Zhu, Yi; Miller, Yury I; Tall, Alan R.

    2014-01-01

    Rationale The mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin, has been shown to decrease atherosclerosis, even while increasing plasma LDL levels. This suggests an anti-atherogenic effect possibly mediated by modulation of inflammatory responses in atherosclerotic plaques. Objective To assess the role of macrophage mTORC1 in atherogenesis. Methods and Results We transplanted bone marrow from mice in which a key mTORC1 adaptor, Raptor, was deleted in macrophages by Cre/loxP recombination (Mac-RapKO mice) into Ldlr-/- mice and then fed them the Western-type diet (WTD). Atherosclerotic lesions from Mac-RapKO mice showed decreased infiltration of macrophages, lesion size and chemokine gene expression compared with control mice. Treatment of macrophages with minimally modified LDL (mmLDL) resulted in increased levels of chemokine mRNAs and STAT3 phosphorylation; these effects were reduced in Mac-RapKO macrophages. While wild-type and Mac-RapKO macrophages showed similar STAT3 phosphorylation on Tyr705, Mac-RapKO macrophages showed decreased STAT3 Ser727 phosphorylation in response to mmLDL treatment and decreased Ccl2 promoter binding of STAT3. Conclusions The results demonstrate cross-talk between nutritionally-induced mTORC1 signaling and mmLDL-mediated inflammatory signaling via combinatorial phosphorylation of STAT3 in macrophages, leading to increased STAT3 activity on the CCL2 (MCP-1)promoter with pro-atherogenic consequences. PMID:24687132

  20. Lipopolysaccharide Biosynthesis Genes of Yersinia pseudotuberculosis Promote Resistance to Antimicrobial Chemokines

    Science.gov (United States)

    Erickson, David L.; Lew, Cynthia S.; Kartchner, Brittany; Porter, Nathan T.; McDaniel, S. Wade; Jones, Nathan M.; Mason, Sara; Wu, Erin; Wilson, Eric

    2016-01-01

    Antimicrobial chemokines (AMCs) are a recently described family of host defense peptides that play an important role in protecting a wide variety of organisms from bacterial infection. Very little is known about the bacterial targets of AMCs or factors that influence bacterial susceptibility to AMCs. In an effort to understand how bacterial pathogens resist killing by AMCs, we screened Yersinia pseudotuberculosis transposon mutants for those with increased binding to the AMCs CCL28 and CCL25. Mutants exhibiting increased binding to AMCs were subjected to AMC killing assays, which revealed their increased sensitivity to chemokine-mediated cell death. The majority of the mutants exhibiting increased binding to AMCs contained transposon insertions in genes related to lipopolysaccharide biosynthesis. A particularly strong effect on susceptibility to AMC mediated killing was observed by disruption of the hldD/waaF/waaC operon, necessary for ADP-L-glycero-D-manno-heptose synthesis and a complete lipopolysaccharide core oligosaccharide. Periodate oxidation of surface carbohydrates also enhanced AMC binding, whereas enzymatic removal of surface proteins significantly reduced binding. These results suggest that the structure of Y. pseudotuberculosis LPS greatly affects the antimicrobial activity of AMCs by shielding a protein ligand on the bacterial cell surface. PMID:27275606

  1. UNBS5162, a Novel Naphthalimide That Decreases CXCL Chemokine Expression in Experimental Prostate Cancers

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    Tatjana Mijatovic

    2008-06-01

    Full Text Available Several naphthalimides have been evaluated clinically as potential anticancer agents. UNBS3157, a naphthalimide that belongs to the same class as amonafide, was designed to avoid the specific activating metabolism that induces amonafide’s hematotoxicity. The current study shows that UNBS3157 rapidly and irreversibly hydrolyzes to UNBS5162 without generating amonafide. In vivo UNBS5162 after repeat administration significantly increased survival in orthotopic human prostate cancer models. Results obtained by the National Cancer Institute (NCI using UNBS3157 and UNBS5162 against the NCI 60 cell line panel did not show a correlation with any other compound present in the NCI database, including amonafide, thereby suggesting a unique mechanism of action for these two novel naphthalimides. Affymetrix genome-wide microarray analysis and enzyme-linked immunosorbent assay revealed that in vitro exposure of PC-3 cells to UNBS5162 (1 μM for 5 successive days dramatically decreased the expression of the proangiogenic CXCL chemokines. Histopathology additionally revealed antiangiogenic properties in vivo for UNBS5162 in the orthotopic PC-3 model. In conclusion, the present study reveals UNBS5162 to be a pan-antagonist of CXCL chemokine expression, with the compound displaying antitumor effects in experimental models of human refractory prostate cancer when administered alone and found to enhance the activity of taxol when coadministered with the taxoid.

  2. Molecular cloning and characterization of orange-spotted grouper (Epinephelus coioides) CXC chemokine ligand 12.

    Science.gov (United States)

    Wu, Chen-Shiou; Wang, Ting-Yu; Liu, Chin-Feng; Lin, Hao-Ping; Chen, Young-Mao; Chen, Tzong-Yueh

    2015-12-01

    Chemokines are a family of soluble peptides that can recruit a wide range of immune cells to sites of infection and disease. The CXCL12 is a chemokine that binds to its cognate receptor CXCR4 and thus involved in multiple physiological and pathophysiological processes. In this study, we cloned and characterized CXCL12 from Epinephelus coioides (osgCXCL12). We found that the open reading frame of osgCXCL12 consists of 98 amino acid residues with the small cytokine C-X-C domain located between residues 29 and 87. Higher expression levels for osgCXCL12 were detected at the kitting stage, compared with the prolarva and larva shape stages. The expression patterns revealed that osgCXCL12 may play a key role in early grouper development. We detected mRNA transcripts for osgCXCL12 in healthy tissues and found the highest osgCXCL12 expression in the head kidney. Furthermore, a time-course analysis revealed significantly increased osgCXCL12 and osgCXCR4 expression levels after the nervous necrosis virus (NNV) challenge. In addition, expression of osgCXCL12 was affected by injection with microbial mimics [LPS and poly(I:C)]. These results suggest that osgCXCL12 is associated with inflammatory and developmental processes in the grouper.

  3. CC Chemokine Receptor 5: The Interface of Host Immunity and Cancer

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    Carlos Eduardo Coral de Oliveira

    2014-01-01

    Full Text Available Solid tumors are embedded in a stromal microenvironment consisting of immune cells, such as macrophages and lymphocytes, as well as nonimmune cells, such as endothelial cells and fibroblasts. Chemokines are a type of small secreted chemotactic cytokine and together with their receptors play key roles in the immune defense. Critically, they regulate cancer cellular migration and also contribute to their proliferation and survival. The CCR5 chemokine receptor is involved in leucocytes chemotaxis to sites of inflammation and plays an important role in the macrophages, T cells, and monocytes recruitment. Additionally, CCR5 may have an indirect effect on cancer progression by controlling the antitumor immune response, since it has been demonstrated that its expression could promote tumor growth and contribute to tumor metastasis, in different types of malignant tumors. Furthermore, it was demonstrated that a CCR5 antagonist may inhibit tumor growth, consisting of a possible therapeutic target. In this context, the present review focuses on the establishment of CCR5 within the interface of host immunity, tumor microenvironment, and its potential as a targeting to immunotherapy.

  4. Chemokine-Targeted Mouse Models of Human Primary and Metastatic Colorectal Cancer

    Science.gov (United States)

    Chen, Huanhuan Joyce; Sun, Jian; Huang, Zhiliang; Hou, Harry; Arcilla, Myra; Rakhilin, Nikolai; Joe, Daniel J.; Choi, Jiahn; Gadamsetty, Poornima; Milsom, Jeff; Nandakumar, Govind; Longman, Randy; Zhou, Xi Kathy; Edwards, Robert; Chen, Jonlin; Chen, Kai Yuan; Bu, Pengcheng; Wang, Lihua; Xu, Yitian; Munroe, Robert; Abratte, Christian; Miller, Andrew D.; Gümüş, Zeynep H.; Shuler, Michael; Nishimura, Nozomi; Edelmann, Winfried; Shen, Xiling; Lipkin, Steven M.

    2015-01-01

    Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired sub-cutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening. PMID:26006007

  5. Abrogation of CC chemokine receptor 9 ameliorates ventricular remodeling in mice after myocardial infarction.

    Science.gov (United States)

    Huang, Yan; Wang, Dandan; Wang, Xin; Zhang, Yijie; Liu, Tao; Chen, Yuting; Tang, Yanhong; Wang, Teng; Hu, Dan; Huang, Congxin

    2016-01-01

    CC chemokine receptor 9 (CCR9), which is a unique receptor for CC chemokine ligand (CCL25), is mainly expressed on lymphocytes, dendritic cells (DCs) and monocytes/macrophages. CCR9 mediates the chemotaxis of inflammatory cells and participates in the pathological progression of inflammatory diseases. However, the role of CCR9 in the pathological process of myocardial infarction (MI) remains unexplored; inflammation plays a key role in this process. Here, we used CCR9 knockout mice to determine the functional significance of CCR9 in regulating post-MI cardiac remodeling and its underlying mechanism. MI was induced by surgical ligation of the left anterior descending coronary artery in CCR9 knockout mice and their CCR9+/+ littermates. Our results showed that the CCR9 expression levels were up-regulated in the hearts of the MI mice. Abrogation of CCR9 improved the post-MI survival rate and left ventricular (LV) dysfunction and decreased the infarct size. In addition, the CCR9 knockout mice exhibited attenuated inflammation, apoptosis, structural and electrical remodeling compared with the CCR9+/+ MI mice. Mechanistically, CCR9 mainly regulated the pathological response by interfering with the NF-κB and MAPK signaling pathways. In conclusion, the data reveal that CCR9 serves as a novel modulator of pathological progression following MI through NF-κB and MAPK signaling.

  6. Humoral Immune Pressure Selects for HIV-1 CXC-chemokine Receptor 4-using Variants.

    Science.gov (United States)

    Lin, Nina; Gonzalez, Oscar A; Registre, Ludy; Becerril, Carlos; Etemad, Behzad; Lu, Hong; Wu, Xueling; Lockman, Shahin; Essex, Myron; Moyo, Sikhulile; Kuritzkes, Daniel R; Sagar, Manish

    2016-06-01

    Although both C-C chemokine receptor 5 (CCR5)- and CXC chemokine receptor 4 (CXCR4)-using HIV-1 strains cause AIDS, the emergence of CXCR4-utilizing variants is associated with an accelerated decline in CD4+ T cells. It remains uncertain if CXCR4-using viruses hasten disease or if these variants only emerge after profound immunological damage. We show that exclusively CXCR4- as compared to cocirculating CCR5-utilizing variants are less sensitive to neutralization by both contemporaneous autologous plasma and plasma pools from individuals that harbor only CCR5-using HIV-1. The CXCR4-utilizing variants, however, do not have a global antigenic change because they remain equivalently susceptible to antibodies that do not target coreceptor binding domains. Studies with envelope V3 loop directed antibodies and chimeric envelopes suggest that the neutralization susceptibility differences are potentially influenced by the V3 loop. In vitro passage of a neutralization sensitive CCR5-using virus in the presence of autologous plasma and activated CD4+ T cells led to the emergence of a CXCR4-utilizing virus in 1 of 3 cases. These results suggest that in some but not necessarily all HIV-1 infected individuals humoral immune pressure against the autologous virus selects for CXCR4-using variants, which potentially accelerates disease progression. Our observations have implications for using antibodies for HIV-1 immune therapy. PMID:27428434

  7. Humoral Immune Pressure Selects for HIV-1 CXC-chemokine Receptor 4-using Variants

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    Nina Lin

    2016-06-01

    Full Text Available Although both C-C chemokine receptor 5 (CCR5- and CXC chemokine receptor 4 (CXCR4-using HIV-1 strains cause AIDS, the emergence of CXCR4-utilizing variants is associated with an accelerated decline in CD4+ T cells. It remains uncertain if CXCR4-using viruses hasten disease or if these variants only emerge after profound immunological damage. We show that exclusively CXCR4- as compared to cocirculating CCR5-utilizing variants are less sensitive to neutralization by both contemporaneous autologous plasma and plasma pools from individuals that harbor only CCR5-using HIV-1. The CXCR4-utilizing variants, however, do not have a global antigenic change because they remain equivalently susceptible to antibodies that do not target coreceptor binding domains. Studies with envelope V3 loop directed antibodies and chimeric envelopes suggest that the neutralization susceptibility differences are potentially influenced by the V3 loop. In vitro passage of a neutralization sensitive CCR5-using virus in the presence of autologous plasma and activated CD4+ T cells led to the emergence of a CXCR4-utilizing virus in 1 of 3 cases. These results suggest that in some but not necessarily all HIV-1 infected individuals humoral immune pressure against the autologous virus selects for CXCR4-using variants, which potentially accelerates disease progression. Our observations have implications for using antibodies for HIV-1 immune therapy.

  8. Breast cancer lung metastasis requires expression of chemokine receptor CCR4 and regulatory T cells.

    Science.gov (United States)

    Olkhanud, Purevdorj B; Baatar, Dolgor; Bodogai, Monica; Hakim, Fran; Gress, Ronald; Anderson, Robin L; Deng, Jie; Xu, Mai; Briest, Susanne; Biragyn, Arya

    2009-07-15

    Cancer metastasis is a leading cause of cancer morbidity and mortality. More needs to be learned about mechanisms that control this process. In particular, the role of chemokine receptors in metastasis remains controversial. Here, using a highly metastatic breast cancer (4T1) model, we show that lung metastasis is a feature of only a proportion of the tumor cells that express CCR4. Moreover, the primary tumor growing in mammary pads activates remotely the expression of TARC/CCL17 and MDC/CCL22 in the lungs. These chemokines acting through CCR4 attract both tumor and immune cells. However, CCR4-mediated chemotaxis was not sufficient to produce metastasis, as tumor cells in the lung were efficiently eliminated by natural killer (NK) cells. Lung metastasis required CCR4(+) regulatory T cells (Treg), which directly killed NK cells using beta-galactoside-binding protein. Thus, strategies that abrogate any part of this process should improve the outcome through activation of effector cells and prevention of tumor cell migration. We confirm this prediction by killing CCR4(+) cells through delivery of TARC-fused toxins or depleting Tregs and preventing lung metastasis. PMID:19567680

  9. CXCR4 Chemokine Receptor Mediates Prostate Tumor Cell Adhesion through α5 and β3 Integrins

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    Tobias Engl

    2006-04-01

    Full Text Available The mechanisms leading to prostate cancer metastasis are not understood completely. Although there is evidence that the CXC chemokine receptor (CXCR 4 and its ligand CXCL12 may regulate tumor dissemination, their role in prostate cancer is controversial. We examined CXCR4 expression and functionality, and explored CXCL12-triggered adhesion of prostate tumor cells to human endothelium or to extracellular matrix proteins laminin, collagen, and fibronectin. Although little CXCR4 was expressed on LNCaP and DU-145 prostate tumor cells, CXCR4 was still active, enabling the cells to migrate toward a CXCL12 gradient. CXCL12 induced elevated adhesion to the endothelial cell monolayer and to immobilized fibronectin, laminin, and collagen. Anti-CXCR4 antibodies or CXCR4 knock out significantly impaired CXCL 12-triggered tumor cell binding. The effects observed did not depend on CXCR4 surface expression level. Rather, CXCR4-mediated adhesion was established by α5 and β3 integrin subunits and took place in the presence of reduced p38 and p38 phosphorylation. These data show that chemoattractive mechanisms are involved in adhesion processes of prostate cancer cells, and that binding of CXCL12 to its receptor leads to enhanced expression of α5 and β3. The findings provide a link between chemokine receptor expression and integrin-triggered tumor dissemination.

  10. Chemokine Receptor CXCR4 Is a Novel Marker for the Progression of Cutaneous Malignant Melanomas

    International Nuclear Information System (INIS)

    The CXCR4/CXCL12 pathway has recently been reported to be involved in stimulating the metastasis of many different neoplasms, in which CXCR4 activates various phenomena such as chemotaxis, invasion, angiogenesis and proliferation. The purpose of this study was to analyze a possible association between the expression of chemokine receptors CXCR4, CCR6 and CCR7 with the clinicopathological features of cutaneous malignant melanoma, and to assess the usefulness of these chemokine receptors for diagnosis and prognosis. In our study, a percentage of immunoexpression of both CXCR4 and its ligands CXCL12 was associated with high clinical risk. In contrast, the patients with a low immunoexpression of CXCR4 and CXCL12 had low clinical risk. CCR6 and CCR7 immunoexpressions were also correlated with some clinical parameters, but seemed no more useful than CXCR4. These data suggest that the assessment of CXCR4 immunoexpression is a novel tool for predicting tumor aggressiveness in malignant melanomas, and in particular, a high immunoexpression percentage of CXCR4 and CXCL12 might be a sign of a poor prognosis

  11. Lipopolysaccharide Biosynthesis Genes of Yersinia pseudotuberculosis Promote Resistance to Antimicrobial Chemokines.

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    David L Erickson

    Full Text Available Antimicrobial chemokines (AMCs are a recently described family of host defense peptides that play an important role in protecting a wide variety of organisms from bacterial infection. Very little is known about the bacterial targets of AMCs or factors that influence bacterial susceptibility to AMCs. In an effort to understand how bacterial pathogens resist killing by AMCs, we screened Yersinia pseudotuberculosis transposon mutants for those with increased binding to the AMCs CCL28 and CCL25. Mutants exhibiting increased binding to AMCs were subjected to AMC killing assays, which revealed their increased sensitivity to chemokine-mediated cell death. The majority of the mutants exhibiting increased binding to AMCs contained transposon insertions in genes related to lipopolysaccharide biosynthesis. A particularly strong effect on susceptibility to AMC mediated killing was observed by disruption of the hldD/waaF/waaC operon, necessary for ADP-L-glycero-D-manno-heptose synthesis and a complete lipopolysaccharide core oligosaccharide. Periodate oxidation of surface carbohydrates also enhanced AMC binding, whereas enzymatic removal of surface proteins significantly reduced binding. These results suggest that the structure of Y. pseudotuberculosis LPS greatly affects the antimicrobial activity of AMCs by shielding a protein ligand on the bacterial cell surface.

  12. A novel role for β2-microglobulin: a precursor of antibacterial chemokine in respiratory epithelial cells.

    Science.gov (United States)

    Chiou, Shean-Jaw; Wang, Chan-Chi; Tseng, Yan-Shen; Lee, Yen-Jung; Chen, Shih-Chieh; Chou, Chi-Hsien; Chuang, Lea-Yea; Hong, Yi-Ren; Lu, Chi-Yu; Chiu, Chien-Chih; Chignard, Michel

    2016-01-01

    We analyzed a panel of cationic molecules secreted in the culture medium of human respiratory epithelial cells (REC) upon activation by IL-1β and different pathogen-associated molecular patterns. A 9 kDa fragment derived from β2-microglobulin (B2M) was identified and named shed 9 kDa B2M (sB2M-9). The primary structure of sB2M-9 was revealed to increase its pI value that potentially could play an important role in innate defense. sB2M-9 exhibits antibacterial activity against Gram positive Staphylococcus aureus (SA) but not against Gram negative Klebsiella pneumonia (KP). Upon its binding to SA, sB2M-9 induces clumps, a phenomenon not observed with B2M. Migration of THP-1 monocytes exposed to SA clumps was significantly greater than that to SA without clumps. sB2M-9 binds to SA, more likely as a chemokine, to facilitate THP-1 migration. As a whole, we demonstrated that REC release a novel chemokine with antibacterial activity that is shed from B2M to facilitate THP-1 migration. PMID:27503241

  13. Role of cytokines and chemokines in non-alcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Vincent Braunersreuther; Giorgio Luciano Viviani; Fran(c)ois Mach; Fabrizio Montecucco

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) includes a variety of histological conditions (ranging from liver steatosis and steatohepatitis,to fibrosis and hepatocarcinoma) that are characterized by an increased fat content within the liver.The accumulation/deposition of fat within the liver is essential for diagnosis of NAFLD and might be associated with alterations in the hepatic and systemic inflammatory state.Although it is still unclear if each histological entity represents a different disease or rather steps of the same disease,inflammatory processes in NAFLD might influence its pathophysiology and prognosis.In particular,nonalcoholic steatohepatitis (the most inflamed condition in NAFLDs,which more frequently evolves towards chronic and serious liver diseases) is characterized by a marked activation of inflammatory cells and the upregulation of several soluble inflammatory mediators.Among several mediators,cytokines and chemokines might play a pivotal active role in NAFLD and are considered as potential therapeutic targets.In this review,we will update evidence from both basic research and clinical studies on the potential role of cytokines and chemokines in the pathophysiology of NAFLD.

  14. Up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver.

    Science.gov (United States)

    Zhang, Shuai; Li, Tao-Sheng; Soyama, Akihiko; Tanaka, Takayuki; Yan, Chen; Sakai, Yusuke; Hidaka, Masaaki; Kinoshita, Ayaka; Natsuda, Koji; Fujii, Mio; Kugiyama, Tota; Baimakhanov, Zhassulan; Kuroki, Tamotsu; Gu, Weili; Eguchi, Susumu

    2016-01-01

    Although the healthy liver is known to have high regenerative potential, poor liver regeneration under pathological conditions remains a substantial problem. We investigated the key molecules that impair the regeneration of cholestatic liver. C57BL/6 mice were randomly subjected to partial hepatectomy and bile duct ligation (PH+BDL group, n = 16), partial hepatectomy only (PH group, n = 16), or sham operation (Sham group, n = 16). The liver sizes and histological findings were similar in the PH and sham groups 14 days after operation. However, compared with those in the sham group, the livers in mice in the PH+BDL group had a smaller size, a lower cell proliferative activity, and more fibrotic tissue 14 days after the operation, suggesting the insufficient regeneration of the cholestatic liver. Pathway-focused array analysis showed that many genes were up- or down-regulated over 1.5-fold in both PH+BDL and PH groups at 1, 3, 7, and 14 days after treatment. Interestingly, more genes that were functionally related to the extracellular matrix and inflammatory chemokines were found in the PH+BDL group than in the PH group at 7 and 14 days after treatment. Our data suggest that up-regulated extracellular matrix components and inflammatory chemokines may impair the regeneration of cholestatic liver.

  15. The relevance of chemokine signalling in modulating inherited and age-related retinal degenerations.

    Science.gov (United States)

    Luhmann, Ulrich Fo; Robbie, Scott J; Bainbridge, James Wb; Ali, Robin R

    2014-01-01

    Systemic monocytes, tissue resident macrophages, dendritic cells and microglia have specific roles in immune surveillance and maintenance of tissue homeostasis and are key regulator and effector cells of the local immune response to acute and chronic tissue injury.Two major signalling pathways that differentially define trafficking behaviour and activation of systemic and local myeloid cell populations in response to exogenous and endogenous inflammatory stimuli are the Ccl2-Ccr2 and the Cx3cl1-Cx3cr1 chemokine pathways.Alterations in these pathways have been implicated in controlling myeloid cell activation during normal ageing and in age-related retinal degenerations, including age-related macular degeneration (AMD).We review the evidence for how altered chemokine signalling in acute and chronic inflammatory conditions regulate local and systemic myeloid cell responses in the retina and how this may contribute to or attenuate pathology in inherited and age-related retinal diseases. We discuss the role of environmental factors (e.g. light exposure) and the influence of genetic factors on the manifestation of pathology in experimental models and in human patients and how we envisage harnessing this knowledge for the development of targeted, more broadly applicable anti-inflammatory treatment strategies for a wide range of retinal degenerations.

  16. Pathway-selective suppression of chemokine receptor signaling in B cells by LPS through downregulation of PLC-β2.

    Science.gov (United States)

    Shirakawa, Aiko-Konno; Liao, Fang; Zhang, Hongwei H; Hedrick, Michael N; Singh, Satya P; Wu, Dianqing; Farber, Joshua M

    2010-11-01

    Lymphocyte activation leads to changes in chemokine receptor expression. There are limited data, however, on how lymphocyte activators can alter chemokine signaling by affecting downstream pathways. We hypothesized that B cell-activating agents might alter chemokine responses by affecting downstream signal transducers, and that such effects might differ depending on the activator. We found that activating mouse B cells using either anti-IgM or lipopolysaccharide (LPS) increased the surface expression of CCR6 and CCR7 with large increases in chemotaxis to their cognate ligands. By contrast, while anti-IgM also led to enhanced calcium responses, LPS-treated cells showed only small changes in calcium signaling as compared with cells that were freshly isolated. Of particular interest, we found that LPS caused a reduction in the level of B-cell phospholipase C (PLC)-β2 mRNA and protein. Data obtained using PLC-β2(-/-) mice showed that the β2 isoform mediates close to one-half the chemokine-induced calcium signal in resting and anti-IgM-activated B cells, and we found that calcium signals in the LPS-treated cells were boosted by increasing the level of PLC-β2 using transfection, consistent with a functional effect of downregulating PLC-β2. Together, our results show activator-specific effects on responses through B-cell chemokine receptors that are mediated by quantitative changes in a downstream signal-transducing protein, revealing an activity for LPS as a downregulator of PLC-β2, and a novel mechanism for controlling chemokine-induced signals in lymphocytes.

  17. Cloning of Encoding Sequences for Chemokine Receptors CXCR4 and CCR5 from a Chinese Lymphocyte cDNAs

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    @@ It has been known recently that cofactors, which belong to the family of seven-transmembrane GTP-binding protein-coupled receptors, are necessary for the entry of HIV-1 into CD4+cells. The CXC chemokine receptor 4(CXCR4) was first found to act as the coreceptor for the infection of T cell line-tropic HIV-1 strains to T helper cells in 1996. Keeping in step with this find the CC chemokine receptor 5(CCR5)was also identified as a coreceptor for macrophage-tropic virus. Both of the coreceptors could be used in basic research and application design for AIDS.

  18. Selective elimination of high constitutive activity or chemokine binding in the human herpesvirus 8 encoded seven transmembrane oncogene ORF74

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Kledal, T N; Holst, Peter Johannes;

    2000-01-01

    Open reading frame 74 (ORF74) encoded by human herpesvirus 8 is a highly constitutively active seven transmembrane (7TM) receptor stimulated by angiogenic chemokines, e.g. growth-related oncogene-alpha, and inhibited by angiostatic chemokines e.g. interferon-gamma-inducible protein. Transgenic mice...... either agonist or inverse agonist modulation as well as high constitutive activity of the virally encoded oncogene ORF74 and that these mutant forms presumably can be used in transgenic animals to identify the molecular mechanism of its transforming activity....

  19. Evaluation of chemokines in gingival crevicular fluid in children with band and loop space maintainers: A clinico-biochemical study

    OpenAIRE

    Kumar, Naveen Kommineni; Reddy, Veera Kishore Kasa; Padakandla, Prathyusha; Togaru, Harshini; Kalagatla, Swathi; Vinay Chand M Reddy

    2016-01-01

    Background: Chemokines are pro-inflammatory cells that can be induced during an immune response to recruit cells of the immune system to a site of infection. Aim: This study was conducted to detect the presence of chemokines, macrophage inflammatory protein-1α (MIP-1α), and 1β (MIP-1β) and estimate their levels in gingival crevicular fluid (GCF) in children with band and loop space maintainers. Materials and Methods: MIP-1α and MIP-1β levels were estimated in GCF samples from twenty healthy c...

  20. Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes

    NARCIS (Netherlands)

    Pfleger, C; Kaas, A; Hansen, L; Alizadeh, B; Hougaard, P; Holl, R; Kolb, H; Roep, B O; Mortensen, H B; Schloot, N C

    2008-01-01

    Th1 related chemokines CCL3 and CCL5 and Th2 related CCL4 as ligands of the receptor CCR5 contribute to disease development in animal models of type 1 diabetes. In humans, no data are available addressing the role of these chemokines regarding disease progression and remission. We investigated longi

  1. Rescue from acute neuroinflammation by pharmacological chemokine-mediated deviation of leukocytes

    Directory of Open Access Journals (Sweden)

    Berghmans Nele

    2012-10-01

    Full Text Available Abstract Background Neutrophil influx is an important sign of hyperacute neuroinflammation, whereas the entry of activated lymphocytes into the brain parenchyma is a hallmark of chronic inflammatory processes, as observed in multiple sclerosis (MS and its animal models of experimental autoimmune encephalomyelitis (EAE. Clinically approved or experimental therapies for neuroinflammation act by blocking leukocyte penetration of the blood brain barrier. However, in view of unsatisfactory results and severe side effects, complementary therapies are needed. We have examined the effect of chlorite-oxidized oxyamylose (COAM, a potent antiviral polycarboxylic acid on EAE. Methods EAE was induced in SJL/J mice by immunization with spinal cord homogenate (SCH or in IFN-γ-deficient BALB/c (KO mice with myelin oligodendrocyte glycoprotein peptide (MOG35-55. Mice were treated intraperitoneally (i.p. with COAM or saline at different time points after immunization. Clinical disease and histopathology were compared between both groups. IFN expression was analyzed in COAM-treated MEF cell cultures and in sera and peritoneal fluids of COAM-treated animals by quantitative PCR, ELISA and a bioassay on L929 cells. Populations of immune cell subsets in the periphery and the central nervous system (CNS were quantified at different stages of disease development by flow cytometry and differential cell count analysis. Expression levels of selected chemokine genes in the CNS were determined by quantitative PCR. Results We discovered that COAM (2 mg i.p. per mouse on days 0 and 7 protects significantly against hyperacute SCH-induced EAE in SJL/J mice and MOG35-55-induced EAE in IFN-γ KO mice. COAM deviated leukocyte trafficking from the CNS into the periphery. In the CNS, COAM reduced four-fold the expression levels of the neutrophil CXC chemokines KC/CXCL1 and MIP-2/CXCL2. Whereas the effects of COAM on circulating blood and splenic leukocytes were limited, significant

  2. Similar activation of signal transduction pathways by the herpesvirus-encoded chemokine receptors US28 and ORF74

    DEFF Research Database (Denmark)

    McLean, Katherine A; Holst, Peter J; Martini, Lene;

    2004-01-01

    The virally encoded chemokine receptors US28 from human cytomegalovirus and ORF74 from human herpesvirus 8 are both constitutively active. We show that both receptors constitutively activate the transcription factors nuclear factor of activated T cells (NFAT) and cAMP response element binding pro...

  3. Dose Ramadan Fasting Affects Inflammatory Responses: Evidences for Modulatory Roles of This Unique Nutritional Status via Chemokine Network

    Directory of Open Access Journals (Sweden)

    Fateme Akrami Mohajeri

    2013-12-01

    The results of this study may reveal that Ramadan fasting is quite safe for normal healthy adults and so very useful in reduction of cholesterol and triglycerides in relation with dyslipidemia. It is also possible to conclude that fasting is important in controlling of inflammation via chemokines.

  4. Recombinant human interleukin-1 receptor antagonist promotes M1 microglia biased cytokines and chemokines following human traumatic brain injury.

    Science.gov (United States)

    Helmy, Adel; Guilfoyle, Mathew R; Carpenter, Keri Lh; Pickard, John D; Menon, David K; Hutchinson, Peter J

    2016-08-01

    Interleukin-1 receptor antagonist (IL1ra) has demonstrated efficacy in a wide range of animal models of neuronal injury. We have previously published a randomised controlled study of IL1ra in human severe TBI, with concomitant microdialysis and plasma sampling of 42 cytokines and chemokines. In this study, we have used partial least squares discriminant analysis to model the effects of drug administration and time following injury on the cytokine milieu within the injured brain. We demonstrate that treatment with rhIL1ra causes a brain-specific modification of the cytokine and chemokine response to injury, particularly in samples from the first 48 h following injury. The magnitude of this response is dependent on the concentration of IL1ra achieved in the brain extracellular space. Chemokines related to recruitment of macrophages from the plasma compartment (MCP-1) and biasing towards a M1 microglial phenotype (GM-CSF, IL1) are increased in patient samples in the rhIL1ra-treated patients. In control patients, cytokines and chemokines biased to a M2 microglia phenotype (IL4, IL10, MDC) are relatively increased. This pattern of response suggests that a simple classification of IL1ra as an 'anti-inflammatory' cytokine may not be appropriate and highlights the importance of the microglial response to injury. PMID:26661249

  5. Profiles of cytokine and chemokine gene expression in human pulmonary epithelial cells induced by human and avian influenza viruses

    Directory of Open Access Journals (Sweden)

    Chan Paul KS

    2010-11-01

    Full Text Available Abstract Influenza pandemic remains a serious threat to human health. In this study, the repertoire of host cellular cytokine and chemokine responses to infections with highly pathogenic avian influenza H5N1, low pathogenicity avian influenza H9N2 and seasonal human influenza H1N1 were compared using an in vitro system based on human pulmonary epithelial cells. The results showed that H5N1 was more potent than H9N2 and H1N1 in inducing CXCL-10/IP-10, TNF-alpha and CCL-5/RANTES. The cytokine/chemokine profiles for H9N2, in general, resembled those of H1N1. Of interest, only H1N1, but none of the avian subtypes examined could induce a persistent elevation of the immune-regulatory cytokine - TGF-β2. The differential expression of cytokines/chemokines following infection with different influenza viruses could be a key determinant for clinical outcome. The potential of using these cytokines/chemokines as prognostic markers or targets of therapy is worth exploring.

  6. Expressed gene sequence and bioactivity of the IFN-gamma-response chemokine CXCL11 of swine and cattle

    Science.gov (United States)

    This report describes the cloning and characterization of expressed gene sequences of the swine and bovine interferon-gamma inducible chemokine CXCL11, or I-TAC, associated with T helper 1-type immune responses, and affirmation of bioactivity of their yeast expressed protein products. The coding reg...

  7. Chemokine Expression in Retinal Pigment Epithelial ARPE-19 Cells in Response to Coculture with Activated T Cells

    DEFF Research Database (Denmark)

    Juel, Helene Bæk; Faber, Carsten; Udsen, Maja;

    2012-01-01

    Purpose. To investigate the effects of T-cell–derived cytokines on gene and protein expression of chemokines in a human RPE cell line (ARPE-19). Methods. We used an in vitro coculture system in which the RPE and CD3/CD28–activated T-cells were separated by a membrane. RPE cell expression of chemo...

  8. Treatment of hypertriglyceridemia and HIV: fenofibrate-induced changes in the expression of chemokine genes in circulating leukocytes

    OpenAIRE

    Alegret Josep M; Camps Jordi; Rull Anna; Fernández-Sender Laura; Beltrán-Debón Raúl; Aragonès Gerard; Alonso-Villaverde Carlos; Joven Jorge

    2009-01-01

    Abstract Fenofibrate changed the expression of chemokine genes in circulating leukocytes of HIV-infected patients with hypertriglyceridemia. The data suggest that fenofibrate when effective in the treatment of lipoprotein abnormalities, may act as a modulator of systemic inflammation. This particular action, therefore, may also influence the clinical course of the disease.

  9. Evaluation of serum enzymes polypeptide, chemokine levels and peripheral blood immune cells contents in children with bronchial asthma

    Institute of Scientific and Technical Information of China (English)

    Zhong-Yong Xie; Wei-Ming Chen; Wei-Zhong Zhang; Shang-Hong Tang

    2015-01-01

    Objective:To evaluate serum enzymes polypeptide, chemokine levels and peripheral blood immune cells contents of children with bronchial asthma.Methods:150 bronchial asthma children were enrolled as observation group, 120 healthy children received physical examination in our hospital over the same period were enrolled as control group. Then serum enzymes polypeptide, chemokine levels and peripheral blood immune cells contents were detected.Results:(1) Enzyme polypeptide: serum Cat K, MMP1, MMP2, MMP9 contents of observation group were significant higher than those of the control group; but TIMP1 content was lower than that of control group; (2)Chemokine: serum Eotaxin, MCP-1, MCP-4, MDC and IL-8 contents of observation group were higher than those of the control group; (3) Immune cell: Th1 cell, CD4+CD25+T cell and CD8+CD28+T cell contents of observation group were significant lower than those of the control; but Th2 cells and Th17 cells were higher than those of control group.Conclusions:Serum enzymes polypeptide and chemokine levels of children with bronchial asthma abnormally increase with presence of peripheral blood T cell subsets contents disorder, which is correlated with airway remodeling and inflammatory cell infiltration process.

  10. Modulation of Chemokine Gene Expression in CD133 Cord Blood-Derived Human Mast Cells by Cyclosporin A and Dexamethasone

    DEFF Research Database (Denmark)

    Holm, Mette; Kvistgaard, Helene; Dahl, Christine;

    2006-01-01

    dexamethasone prior to mast cell activation. Finally, we demonstrate that the same modulators added after mast cell activation can differentially quench ongoing chemokine gene induction. Thus, considering the vast yields of mast cells, our protocol is valuable not only for studying regulation of gene expression...

  11. Selective suppression of chemokine receptor CXCR3 expression by interferon-beta1a in multiple sclerosis

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Sellebjerg, F

    2002-01-01

    We studied the expression of chemokine receptors CCR1, CCR2, CCR3, CCR5, and CXCR3 on CD4 and CD8 positive T cells, and on CD14 positive monocytes in blood from 10 patients with relapsing-remitting multiple sclerosis (MS) at initiation of interferon (IFN)-beta treatment, after 1 month and after 3...

  12. GluVII:06--a highly conserved and selective anchor point for non-peptide ligands in chemokine receptors

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Schwartz, Thue W

    2006-01-01

    to be crucially important for the binding and action of a number of non-peptide ligands in for example the CCR1, CCR2 and CCR5 receptors. It is proposed that in chemokine receptors in general GluVII:06 serves as a selective anchor point for the centrally located, positively charged nitrogen of the small molecule...

  13. Chemokine Signaling Enhances CD36 Responsiveness toward Oxidized Low-Density Lipoproteins and Accelerates Foam Cell Formation

    Directory of Open Access Journals (Sweden)

    Harikesh S. Wong

    2016-03-01

    Full Text Available Excessive uptake of oxidized low-density lipoproteins (oxLDL by macrophages is a fundamental characteristic of atherosclerosis. However, signals regulating the engagement of these ligands remain elusive. Using single-molecule imaging, we discovered a mechanism whereby chemokine signaling enhanced binding of oxLDL to the scavenger receptor, CD36. By activating the Rap1-GTPase, chemokines promoted integrin-mediated adhesion of macrophages to the substratum. As a result, cells exhibited pronounced remodeling of the cortical actin cytoskeleton that increased CD36 clustering. Remarkably, CD36 clusters formed predominantly within actin-poor regions of the cortex, and these regions were primed to engage oxLDL. In accordance with enhanced ligand engagement, prolonged exposure of macrophages to chemokines amplified the accumulation of esterified cholesterol, thereby accentuating the foam cell phenotype. These findings imply that the activation of integrins by chemokine signaling exerts feedforward control over receptor clustering and effectively alters the threshold for cells to engage ligands.

  14. The Role of Chemokine Receptor CXCR4 in the Biologic Behavior of Human Soft Tissue Sarcoma

    Directory of Open Access Journals (Sweden)

    Roger H. Kim

    2011-01-01

    Full Text Available The molecular basis of sarcoma remains poorly understood. However, recent studies have begun to uncover some of the molecular pathways involved in sarcomagenesis. The chemokine receptor CXCR4 has been implicated in sarcoma development and has been found to be a prognostic marker for poor clinical outcome. There is growing evidence that overexpression of CXCR4 plays a significant role in development of metastatic disease, especially in directing tumor cells towards the preferential sites of metastases in sarcoma, lung and bone. Although further investigation is necessary to validate these pathways, there is potential for clinical application, particularly in the use of pharmacologic inhibitors of CXCR4 as means of preventing sarcoma metastasis.

  15. Retinoid X receptor alpha controls innate inflammatory responses through the up-regulation of chemokine expression.

    Science.gov (United States)

    Núñez, Vanessa; Alameda, Daniel; Rico, Daniel; Mota, Rubén; Gonzalo, Pilar; Cedenilla, Marta; Fischer, Thierry; Boscá, Lisardo; Glass, Christopher K; Arroyo, Alicia G; Ricote, Mercedes

    2010-06-01

    The retinoid X receptor alpha (RXRalpha) plays a central role in the regulation of many intracellular receptor signaling pathways and can mediate ligand-dependent transcription by forming homodimers or heterodimers with other nuclear receptors. Although several members of the nuclear hormone receptor superfamily have emerged as important regulators of macrophage gene expression, the existence in vivo of an RXR signaling pathway in macrophages has not been established. Here, we provide evidence that RXRalpha regulates the transcription of the chemokines Ccl6 and Ccl9 in macrophages independently of heterodimeric partners. Mice lacking RXRalpha in myeloid cells exhibit reduced levels of CCL6 and CCL9, impaired recruitment of leukocytes to sites of inflammation, and lower susceptibility to sepsis. These studies demonstrate that macrophage RXRalpha plays key roles in the regulation of innate immunity and represents a potential target for immunotherapy of sepsis.

  16. Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS

    DEFF Research Database (Denmark)

    Sellebjerg, F; Börnsen, L; Khademi, M;

    2009-01-01

    ), and noninflammatory neurologic disease control subjects. Some patients with RRMS were studied before and after treatment with methylprednisolone or natalizumab. RESULTS: In CSF, concentrations of CXCL13, but not CXCL12, were higher in patients with CIS, RRMS, SPMS, and PPMS than in controls. CSF concentrations...... of CXCL13 correlated with the CSF B-cell count, with markers of immune activation, and with disease activity in patients with CIS and RRMS. CSF concentrations of CXCL13 decreased after treatment with high-dose methylprednisolone and natalizumab. High CSF concentrations of CXCL13 correlated with low...... expression of messenger RNA encoding the immunoregulatory cytokines interleukin 10 and transforming growth factor beta1, but not with the expression of T-helper type 1 (Th1) and Th17 factors. CONCLUSION: The chemokine CXCL13 may play a major role in recruitment of B cells and T-cell subsets expressing...

  17. Respiratory dysfunction and proinflammatory chemokines in the pneumonia virus of mice (PVM) model of viral bronchiolitis.

    Science.gov (United States)

    Bonville, Cynthia A; Bennett, Nicholas J; Koehnlein, Melissa; Haines, Deborah M; Ellis, John A; DelVecchio, Alfred M; Rosenberg, Helene F; Domachowske, Joseph B

    2006-05-25

    We explore relationships linking clinical symptoms, respiratory dysfunction, and local production of proinflammatory chemokines in the pneumonia virus of mice (PVM) model of viral bronchiolitis. With a reduced inoculum of this natural rodent pathogen, we observe virus clearance by day 9, while clinical symptoms and respiratory dysfunction persist through days 14 and 17 postinoculation, respectively. Via microarray and ELISA, we identify expression profiles of proinflammatory mediators MIP-1alpha, MCP-1, and MIP-2 that correlate with persistent respiratory dysfunction. MIP-1alpha is localized in bronchial epithelium, which is also the major site of PVM replication. Interferon-gamma was detected in lung tissue, but at levels that do not correlate with respiratory dysfunction. Taken together, we present a modification of our pneumovirus infection model that results in improved survival and data that stand in support of a connection between local production of specific mediators and persistent respiratory dysfunction in the setting of acute viral bronchiolitis.

  18. Efficient T-cell surveillance of the CNS requires expression of the CXC chemokine receptor 3

    DEFF Research Database (Denmark)

    Christensen, Jeanette Erbo; Nansen, Anneline; Moos, Torben;

    2004-01-01

    T-cells play an important role in controlling viral infections inside the CNS. To study the role of the chemokine receptor CXCR3 in the migration and positioning of virus-specific effector T-cells within the brain, CXCR3-deficient mice were infected intracerebrally with lymphocytic choriomeningitis......-cell-mediated immunopathology. Quantitative analysis of the cellular infiltrate in CSF of infected mice revealed modest, if any, decrease in the number of mononuclear cells recruited to the meninges in the absence of CXCR3. However, immunohistological analysis disclosed a striking impairment of CD8+ T-cells from CXCR3......-deficient mice to migrate from the meninges into the outer layers of the brain parenchyma despite similar localization of virus-infected target cells. Reconstitution of CXCR3-deficient mice with wild-type CD8+ T-cells completely restored susceptibility to LCMV-induced meningitis. Thus, taken together, our...

  19. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array

    Directory of Open Access Journals (Sweden)

    Bekő Gabriella

    2010-12-01

    Full Text Available Abstract Background Preeclampsia is a severe complication of pregnancy characterized by an excessive maternal systemic inflammatory response with activation of both the innate and adaptive arms of the immune system. Cytokines, chemokines and adhesion molecules are central to innate and adaptive immune processes. The purpose of this study was to determine circulating levels of cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia in a comprehensive manner, and to investigate their relationship to the clinical features and laboratory parameters of the study participants, including markers of overall inflammation (C-reactive protein, endothelial activation (von Willebrand factor antigen and endothelial injury (fibronectin, oxidative stress (malondialdehyde and trophoblast debris (cell-free fetal DNA. Results Serum levels of interleukin (IL-1beta, IL-1 receptor antagonist (IL-1ra, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-18, interferon (IFN-gamma, tumor necrosis factor (TNF-alpha, transforming growth factor (TGF-beta1, interferon-gamma-inducible protein (IP-10, monocyte chemotactic protein (MCP-1, intercellular adhesion molecule (ICAM-1 and vascular cell adhesion molecule (VCAM-1 were measured in 60 preeclamptic patients, 60 healthy pregnant women and 59 healthy non-pregnant women by multiplex suspension array and ELISA. In normal pregnancy, the relative abundance of circulating IL-18 over IL-12p70 and the relative deficiency of the bioactive IL-12p70 in relation to IL-12p40 might favour Th2-type immunity. Although decreased IL-1ra, TNF-alpha and MCP-1 concentrations of healthy pregnant relative to non-pregnant women reflect anti-inflammatory changes in circulating cytokine profile, their decreased serum IL-10 and increased IP-10 levels might drive pro-inflammatory responses. In addition to a shift towards Th1-type immunity (expressed by the increased IL-2/IL-4 and IFN-gamma/IL-4 ratios, circulating levels of

  20. Chemokines CXCL10 and CCL2: differential involvement in intrathecal inflammation in multiple sclerosis

    DEFF Research Database (Denmark)

    Sørensen, T.L.; Sellebjerg, F; Jensen, C.V.;

    2001-01-01

    . Chemokine concentrations were measured by enzyme linked immunosorbent assay (ELISA) in CSF obtained at baseline and after 3 weeks, and were compared with other measures of intrathecal inflammation. At baseline CSF concentrations of CCL2 were significantly lower in the patient group than in controls....... The levels of CXCL10 were higher in the patient group than in controls but two outliers in the control group also had high CSF concentrations of CXCL10. The CSF concentrations of CXCL10 did not change over time or after treatment. The CSF concentration of CXCL10 was positively correlated with the CSF...... and IgG synthesis levels. CXCL10 may be involved in the maintenance of intrathecal inflammation whereas CCL2 correlates negatively with measures of inflammation, suggesting differential involvement of CXCL10 and CCL2 in CNS inflammation...

  1. Chemokine-like factor 1, a novel cytokine, contributes to airway damage, remodeling and pulmonary fibrosis

    Institute of Scientific and Technical Information of China (English)

    谭亚夏; 韩文玲; 陈英玉; 欧阳能太; 唐岩; 李枫; 丁培国; 任筱兰; 曾广翘; 丁静; 朱彤; 马大龙; 钟南山

    2004-01-01

    Background Chemokine-like factor 1 (CKLF1) was recently identified as a novel cytokine. The full-length CKLF1 cDNA contains 530 bp encoding 99 amino acid residues with a CC motif similar to that of other CC family chemokines. Recombinant CKLF1 exhibits chemotactic activity on leucocytes and stimulates proliferation of murine skeletal muscle cells. We questioned whether CKLF1 could be involved in the pathogenesis of inflammation and proliferation in the lung. Therefore we used efficient in vivo gene delivery method to investigate the biological effect of CKLF1 in the murine lung.Methods CKLF1-expressing plasmid, pCDI-CKLF1, was constructed and injected into the skeletal muscles followed by electroporation. Lung tissues were obtained at the end of week 1,2,3 and 4 respectively after injection. The pathological changes in the lungs were observed by light microscope.Results A single intramuscular injection of CKLF1 plasmid DNA into BALB/c mice caused dramatic pathological changes in the lungs of treated mice. These changes included peribronchial leukocyte infiltration, epithelial shedding, collagen deposition, proliferation of bronchial smooth muscle cells and fibrosis of the lung. Conclusions The sustained morphological abnormalities of the bronchial and bronchiolar wall, the acute pneumonitis and interstitial pulmonary fibrosis induced by CKLF1 were similar to phenomena observed in chronic persistent asthma, acute respiratory distress syndrome and severe acute respiratory syndrome. These data suggest that CKLF1 may play an important role in the pathogenesis of these important diseases and the study also implies that gene electro-transfer in vivo could serve as a valuable approach for evaluating the function of a novel gene in animals.

  2. Carnosol and Related Substances Modulate Chemokine and Cytokine Production in Macrophages and Chondrocytes

    Directory of Open Access Journals (Sweden)

    Joseph Schwager

    2016-04-01

    Full Text Available Phenolic diterpenes present in Rosmarinus officinalis and Salvia officinalis have anti-inflammatory and chemoprotective effects. We investigated the in vitro effects of carnosol (CL, carnosic acid (CA, carnosic acid-12-methylether (CAME, 20-deoxocarnosol and abieta-8,11,13-triene-11,12,20-triol (ABTT in murine macrophages (RAW264.7 cells and human chondrocytes. The substances concentration-dependently reduced nitric oxide (NO and prostaglandin E2 (PGE2 production in LPS-stimulated macrophages (i.e., acute inflammation. They significantly blunted gene expression levels of iNOS, cytokines/interleukins (IL-1α, IL-6 and chemokines including CCL5/RANTES, CXCL10/IP-10. The substances modulated the expression of catabolic and anabolic genes in chondrosarcoma cell line SW1353 and in primary human chondrocytes that were stimulated by IL-1β (i.e., chronic inflammation In SW1353, catabolic genes like MMP-13 and ADAMTS-4 that contribute to cartilage erosion were down-regulated, while expression of anabolic genes including Col2A1 and aggrecan were shifted towards pre-pathophysiological homeostasis. CL had the strongest overall effect on inflammatory mediators, as well as on macrophage and chondrocyte gene expression. Conversely, CAME mainly affected catabolic gene expression, whereas ABTT had a more selectively altered interleukin and chemokine gene exprssion. CL inhibited the IL-1β induced nuclear translocation of NF-κBp65, suggesting that it primarily regulated via the NF-κB signalling pathway. Collectively, CL had the strongest effects on inflammatory mediators and chondrocyte gene expression. The data show that the phenolic diterpenes altered activity pattern of genes that regulate acute and chronic inflammatory processes. Since the substances affected catabolic and anabolic gene expression in cartilage cells in vitro, they may beneficially act on the aetiology of osteoarthritis.

  3. Thymus and activation-regulated chemokine as a clinical biomarker in atopic dermatitis.

    Science.gov (United States)

    Kataoka, Yoko

    2014-03-01

    Thymus and activation-regulated chemokine (TARC/CCL17) is a member of the T-helper 2 chemokine family. In Japan, serum TARC level has been commercially measured since 2008. After years of experience, we realized that TARC is an extremely useful clinical biomarker for atopic dermatitis (AD) treatment. Usually, physicians conduct a visual examination to determine whether their treatment has been successful; however, the visual examination results may not always be accurate; in such cases, serum TARC levels should be measured to eliminate any ambiguity regarding the treatment outcome. When the waning and waxing of eczema and fluctuations in the serum TARC levels were considered, we frequently found that AD does not follow a natural course but follows non-regulated inflammatory floating caused by insufficient intermittent topical treatment. Serum TARC is a promising biomarker for remission and can be used for accurately monitoring proactive treatment for long-term control. Abnormally high serum TARC levels indicate accelerated pathogenesis of cutaneous inflammation. Rapid normalization and maintaining normal serum TARC levels using appropriate topical treatment is a reasonable strategy for alleviating inflammation without upregulating cytokine expression. Observing serum TARC levels during early intervention for severe infantile AD is worthwhile to determine initial disease activity and evaluate treatment efficacy. Appropriate control of severe early-onset infantile AD is important for improving prognosis of eczema and for preventing food allergies. Additionally, this biomarker is useful for improving patient adherence. Dermatologists will be able to make great progress in treating AD by adopting biomarkers such as TARC for accurately assessing non-visible subclinical disorders. PMID:24628072

  4. Chemokine receptor CXCR3 in turbot (Scophthalmus maximus): cloning, characterization and its responses to lipopolysaccharide.

    Science.gov (United States)

    Chen, Yadong; Zhou, Shuhong; Jiang, Zhiqiang; Wang, Xiuli; Liu, Yang

    2016-04-01

    Chemokine (C-X-C motif) receptor 3, a member of the G protein-coupled receptors superfamily, regulates the responses of many immune responses. In this experiment, we cloned and characterized the cDNA of CXCR3 in Scophthalmus maximus (turbot). A 5'-UTR of 216-bp, a 259-bp 3'-UTR with a poly (A) tail and a 1089-bp CDS encoding 362 amino acids form the cDNA of CXCR3, which is 1564-bp long. Phylogenetic analyses indicated that turbot CXCR3 shared a high similarity with other CXCR3s and shared more similarity with CXCR5 than the other subfamilies of chemokines. The CXCR3 protein in turbot showed the highest similarity with the CXCR3b from rainbow trout (44.5%), which indicated that this CXCR3 gene/protein may be a CXCR3b isoform. Quantitative real-time PCR analysis showed that CXCR3 transcripts were constitutively expressed in all the tissues of the non-injected turbot used in this study, with the highest expression occurring in blood. Several immune-related tissues of fish, such as the spleen, head kidney, liver and blood, tissues, which were abundant of lymphocyte, were investigated in this study. CXCR3 gene was expressed at the highest level in blood than the other tested tissues. The injection experiment suggested that the CXCR3 expression level after LPS injection was significantly up-regulated in all immune-related tissues in turbot. These results improve our understanding of the functions of CXCR3 in the turbot immune response. PMID:26585996

  5. Carnosol and Related Substances Modulate Chemokine and Cytokine Production in Macrophages and Chondrocytes.

    Science.gov (United States)

    Schwager, Joseph; Richard, Nathalie; Fowler, Ann; Seifert, Nicole; Raederstorff, Daniel

    2016-01-01

    Phenolic diterpenes present in Rosmarinus officinalis and Salvia officinalis have anti-inflammatory and chemoprotective effects. We investigated the in vitro effects of carnosol (CL), carnosic acid (CA), carnosic acid-12-methylether (CAME), 20-deoxocarnosol and abieta-8,11,13-triene-11,12,20-triol (ABTT) in murine macrophages (RAW264.7 cells) and human chondrocytes. The substances concentration-dependently reduced nitric oxide (NO) and prostaglandin E₂ (PGE₂) production in LPS-stimulated macrophages (i.e., acute inflammation). They significantly blunted gene expression levels of iNOS, cytokines/interleukins (IL-1α, IL-6) and chemokines including CCL5/RANTES, CXCL10/IP-10. The substances modulated the expression of catabolic and anabolic genes in chondrosarcoma cell line SW1353 and in primary human chondrocytes that were stimulated by IL-1β (i.e., chronic inflammation In SW1353, catabolic genes like MMP-13 and ADAMTS-4 that contribute to cartilage erosion were down-regulated, while expression of anabolic genes including Col2A1 and aggrecan were shifted towards pre-pathophysiological homeostasis. CL had the strongest overall effect on inflammatory mediators, as well as on macrophage and chondrocyte gene expression. Conversely, CAME mainly affected catabolic gene expression, whereas ABTT had a more selectively altered interleukin and chemokine gene exprssion. CL inhibited the IL-1β induced nuclear translocation of NF-κBp65, suggesting that it primarily regulated via the NF-κB signalling pathway. Collectively, CL had the strongest effects on inflammatory mediators and chondrocyte gene expression. The data show that the phenolic diterpenes altered activity pattern of genes that regulate acute and chronic inflammatory processes. Since the substances affected catabolic and anabolic gene expression in cartilage cells in vitro, they may beneficially act on the aetiology of osteoarthritis. PMID:27070563

  6. Plasmid Transduction Using Bacteriophage Φadh for Expression of CC Chemokines by Lactobacillus gasseri ADH▿

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    Damelin, Leonard H.; Mavri-Damelin, Demetra; Klaenhammer, Todd R.; Tiemessen, Caroline T.

    2010-01-01

    Vaginal mucosal microfloras are typically dominated by Gram-positive Lactobacillus species, and colonization of vaginal mucosa by exogenous microbicide-secreting Lactobacillus strains has been proposed as a means of enhancing this natural mucosal barrier against human immunodeficiency virus (HIV) infection. We asked whether an alternative strategy could be utilized whereby anti-HIV molecules are expressed within the cervicovaginal milieu by endogenous vaginal Lactobacillus populations which have been engineered in situ via transduction. In this study, we therefore investigated the feasibility of utilizing transduction for the expression of two HIV coreceptor antagonists, the CC chemokines CCL5 and CCL3, in a predominant vaginal Lactobacillus species, Lactobacillus gasseri. Modifying a previously established transduction model, which utilizes L. gasseri ADH and its prophage Φadh, we show that mitomycin C induction of L. gasseri ADH transformants containing pGK12-based plasmids with CCL5 and CCL3 expression and secretion cassettes (under the control of promoters P6 and P59, respectively) and a 232-bp Φadh cos site fragment results in the production of transducing particles which contain 8 to 9 copies of concatemeric plasmid DNA. High-frequency transduction for these particles (almost 6 orders of magnitude greater than that for pGK12 alone) was observed, and transductants were found to contain recircularized expression plasmids upon subsequent culture. Importantly, transductants produced CC chemokines at levels comparable to those produced by electroporation-derived transformants. Our findings therefore lend support to the potential use of transduction in vaginal Lactobacillus species as a novel strategy for the prevention of HIV infection across mucosal membranes. PMID:20418431

  7. Plasmid transduction using bacteriophage Phi(adh) for expression of CC chemokines by Lactobacillus gasseri ADH.

    Science.gov (United States)

    Damelin, Leonard H; Mavri-Damelin, Demetra; Klaenhammer, Todd R; Tiemessen, Caroline T

    2010-06-01

    Vaginal mucosal microfloras are typically dominated by Gram-positive Lactobacillus species, and colonization of vaginal mucosa by exogenous microbicide-secreting Lactobacillus strains has been proposed as a means of enhancing this natural mucosal barrier against human immunodeficiency virus (HIV) infection. We asked whether an alternative strategy could be utilized whereby anti-HIV molecules are expressed within the cervicovaginal milieu by endogenous vaginal Lactobacillus populations which have been engineered in situ via transduction. In this study, we therefore investigated the feasibility of utilizing transduction for the expression of two HIV coreceptor antagonists, the CC chemokines CCL5 and CCL3, in a predominant vaginal Lactobacillus species, Lactobacillus gasseri. Modifying a previously established transduction model, which utilizes L. gasseri ADH and its prophage Phiadh, we show that mitomycin C induction of L. gasseri ADH transformants containing pGK12-based plasmids with CCL5 and CCL3 expression and secretion cassettes (under the control of promoters P6 and P59, respectively) and a 232-bp Phiadh cos site fragment results in the production of transducing particles which contain 8 to 9 copies of concatemeric plasmid DNA. High-frequency transduction for these particles (almost 6 orders of magnitude greater than that for pGK12 alone) was observed, and transductants were found to contain recircularized expression plasmids upon subsequent culture. Importantly, transductants produced CC chemokines at levels comparable to those produced by electroporation-derived transformants. Our findings therefore lend support to the potential use of transduction in vaginal Lactobacillus species as a novel strategy for the prevention of HIV infection across mucosal membranes.

  8. Estrogen, SNP-Dependent Chemokine Expression and Selective Estrogen Receptor Modulator Regulation.

    Science.gov (United States)

    Ho, Ming-Fen; Bongartz, Tim; Liu, Mohan; Kalari, Krishna R; Goss, Paul E; Shepherd, Lois E; Goetz, Matthew P; Kubo, Michiaki; Ingle, James N; Wang, Liewei; Weinshilboum, Richard M

    2016-03-01

    We previously reported, on the basis of a genome-wide association study for aromatase inhibitor-induced musculoskeletal symptoms, that single-nucleotide polymorphisms (SNPs) near the T-cell leukemia/lymphoma 1A (TCL1A) gene were associated with aromatase inhibitor-induced musculoskeletal pain and with estradiol (E2)-induced TCL1A expression. Furthermore, variation in TCL1A expression influenced the downstream expression of proinflammatory cytokines and cytokine receptors. Specifically, the top hit genome-wide association study SNP, rs11849538, created a functional estrogen response element (ERE) that displayed estrogen receptor (ER) binding and increased E2 induction of TCL1A expression only for the variant SNP genotype. In the present study, we pursued mechanisms underlying the E2-SNP-dependent regulation of TCL1A expression and, in parallel, our subsequent observations that SNPs at a distance from EREs can regulate ERα binding and that ER antagonists can reverse phenotypes associated with those SNPs. Specifically, we performed a series of functional genomic studies using a large panel of lymphoblastoid cell lines with dense genomic data that demonstrated that TCL1A SNPs at a distance from EREs can modulate ERα binding and expression of TCL1A as well as the expression of downstream immune mediators. Furthermore, 4-hydroxytamoxifen or fulvestrant could reverse these SNP-genotype effects. Similar results were found for SNPs in the IL17A cytokine and CCR6 chemokine receptor genes. These observations greatly expand our previous results and support the existence of a novel molecular mechanism that contributes to the complex interplay between estrogens and immune systems. They also raise the possibility of the pharmacological manipulation of the expression of proinflammatory cytokines and chemokines in a SNP genotype-dependent fashion. PMID:26866883

  9. COPD promotes migration of A549 lung cancer cells: the role of chemokine CCL21

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    Kuźnar-Kamińska B

    2016-05-01

    Full Text Available Barbara Kuźnar-Kamińska,1 Justyna Mikuła-Pietrasik,2 Patrycja Sosińska,2 Krzysztof Książek,2 Halina Batura-Gabryel1 1Department of Pulmonology, Allergology and Respiratory Oncology, 2Department of Pathophysiology, Poznań University of Medical Sciences, Poznań, Poland Abstract: Patients with COPD develop lung cancer more frequently than healthy smokers. At the same time, molecular mediators promoting various aspects of cancer cell progression are still elusive. In this report, we examined whether COPD can be coupled with increased migration of non-small-cell lung cancer cells A549 and, if so, whether this effect may be related to altered production and activity of chemokines CCL21, CXCL5, and CXCL12. The study showed that the migration of A549 cells through the polycarbonate membrane and basement membrane extract toward a chemotactic gradient elicited by serum from patients with COPD was markedly higher as compared with serum from healthy donors. The concentration of CCL21 and CXCL12, but not CXCL5, in serum from patients with COPD was also increased. Experiments in which CCL21- and CXCL12-dependent signaling was blocked revealed that increased migration of the cancer cells upon treatment with serum from patients with COPD was mediated exclusively by CCL21. Collectively, our results indicate that COPD may contribute to the progression of lung cancer via CCL21-dependent intensification of cancer cell migration. Keywords: chemokines, COPD, lung cancer, migration

  10. Increased abscess formation and defective chemokine regulation in CREB transgenic mice.

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    Andy Y Wen

    Full Text Available Cyclic AMP-response element-binding protein (CREB is a transcription factor implicated in growth factor-dependent cell proliferation and survival, glucose homeostasis, spermatogenesis, circadian rhythms, and synaptic plasticity associated with memory. To study the phenotype of CREB overexpression in vivo, we generated CREB transgenic (TG mice in which a myeloid specific hMRP8 promoter drives CREB expression. CREB TG mice developed spontaneous skin abscesses more frequently than wild type (WT mice. To understand the role of CREB in myeloid function and innate immunity, chemokine expression in bone marrow derived macrophages (BMDMs from CREB TG mice were compared with BMDMs from WT mice. Our results demonstrated decreased Keratinocyte-derived cytokine (KC in CREB TG BMDMs but not TNFα protein production in response to lipid A (LPA. In addition, mRNA expression of KC and IL-1β (Interleukin-1β was decreased in CREB TG BMDMs; however, there was no difference in the mRNA expression of TNFα, MCP-1, IL-6 and IL-12p40. The mRNA expression of IL-1RA and IL-10 was decreased in response to LPA. Nuclear factor kappa B (NFκB expression and a subset of its target genes were upregulated in CREB TG mouse BMDMs. Although neutrophil migration was the same in both CREB TG and WT mice, Nicotinamide adenine dinucleotide phosphate (NADPH oxidase activity was significantly increased in neutrophils from CREB TG mice. Taken together, CREB overexpression in myeloid cells results in increased abscess formation in vivo and aberrant cytokine and chemokine response, and neutrophil function in vitro.

  11. Fractalkine receptor chemokine (CX3CR1 influences on cervical and lumbar disc herniation

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    In-Soo Oh

    2015-01-01

    of CX3CL1 and CX3CR1 in the disc degeneration and to compare between cervical and lumbar HNP. Materials and Methods: The mRNA concentrations of CX3CL1/CX3CR1 chemokine were analyzed in the surgically obtained disc specimens from C-HNP (n = 13 and L-HNP (n = 13 by real-time polymerase chain reaction (PCR. The localization of CX3CL1/CX3CR1 chemokine in the disc of C-HNP and L-HNP patients was determined using immunohistochemical study. Blood samples from patients with C-HNP and L-HNP patients were stained for CX3CR1 with flow cytometric analysis. Results: The CX3CL1 positive cell ratio in the discs was observed in both groups by immunohistochemical study. CX3CR1 was strongly expressed on endothelial cells in C-spine disc, but sparely expressed in L-spine disc. There was greater CX3CR1 mRNA expression in C-HNP patients than in L-HNP patients as quantified by reversal transcription-PCR (P = 0.010. CX3CR1 positive cell frequencies and CX3CR1 expression levels were increased in CD4 (+ T-cells and natural killer (NK cells from patients with C-HNP (P = 0.210 and P = 0.040. Conclusions: This study identified that increases in CX3CL1 and CX3CR1-expressing cells are significantly related to pathomechanism of HNP for the first time. Especially, CD4 (+ T-cells and NK cells expressing CX3CR1 may play an important role in developing C-HNP.

  12. Cytokine and Chemokine Expression in Kidneys during Chronic Leptospirosis in Reservoir and Susceptible Animal Models.

    Science.gov (United States)

    Matsui, Mariko; Roche, Louise; Geroult, Sophie; Soupé-Gilbert, Marie-Estelle; Monchy, Didier; Huerre, Michel; Goarant, Cyrille

    2016-01-01

    Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. Humans can be infected after exposure to contaminated urine of reservoir animals, usually rodents, regarded as typical asymptomatic carriers of leptospires. In contrast, accidental hosts may present an acute form of leptospirosis with a range of clinical symptoms including the development of Acute Kidney Injury (AKI). Chronic Kidney Disease (CKD) is considered as a possible AKI-residual sequela but little is known about the renal pathophysiology consequent to leptospirosis infection. Herein, we studied the renal morphological alterations in relation with the regulation of inflammatory cytokines and chemokines, comparing two experimental models of chronic leptospirosis, the golden Syrian hamster that survived the infection, becoming carrier of virulent leptospires, and the OF1 mouse, a usual reservoir of the bacteria. Animals were monitored until 28 days after injection with a virulent L. borgpetersenii serogroup Ballum to assess chronic infection. Hamsters developed morphological alterations in the kidneys with tubulointerstitial nephritis and fibrosis. Grading of lesions revealed higher scores in hamsters compared to the slight alterations observed in the mouse kidneys, irrespective of the bacterial load. Interestingly, pro-fibrotic TGF-β was downregulated in mouse kidneys. Moreover, cytokines IL-1β and IL-10, and chemokines MIP-1α/CCL3 and IP-10/CXCL-10 were significantly upregulated in hamster kidneys compared to mice. These results suggest a possible maintenance of inflammatory processes in the hamster kidneys with the infiltration of inflammatory cells in response to bacterial carriage, resulting in alterations of renal tissues. In contrast, lower expression levels in mouse kidneys indicated a better regulation of the inflammatory response and possible resolution processes likely related to resistance mechanisms. PMID:27219334

  13. Cytokine and Chemokine Profile in Amicrobial Pustulosis of the Folds: Evidence for Autoinflammation.

    Science.gov (United States)

    Marzano, Angelo V; Tavecchio, Simona; Berti, Emilio; Gelmetti, Carlo; Cugno, Massimo

    2015-12-01

    Autoinflammation has recently been suggested in the pathogenesis of neutrophilic dermatoses but systematic studies on their cytokine profile are lacking. Notably, amicrobial pustulosis of the folds (APF), classified among neutrophilic dermatoses, has been studied only in small case series. In our University Hospital, we conducted an observational study on 15 APF patients, analyzing their clinical and laboratory features with a follow-up of 9 months to 20 years. Skin cytokine pattern of 9 of them was compared to that of 6 normal controls. In all patients, primary lesions were pustules symmetrically involving the skin folds and anogenital region with a chronic-relapsing course and responding to corticosteroids. Dapsone, cyclosporine, and tumor necrosis factor blockers were effective in refractory cases. In skin samples, the expressions of interleukin (IL)-1β, pivotal cytokine in autoinflammation, and its receptors I and II were significantly higher in APF (P = 0.005, 0.018, and 0.034, respectively) than in controls. Chemokines responsible for neutrophil recruitment such as IL-8 (P = 0.003), CXCL 1/2/3 (C-X-C motif ligand 1/2/3) (P = 0.010), CXCL 16 (P = 0.045), and RANTES (regulated on activation, normal T cell expressed and secreted) (P = 0.034) were overexpressed. Molecules involved in tissue damage like matrix metalloproteinase-2 (MMP-2) (P = 0.010) and MMP-9 (P = 0.003) were increased. APF is a pustular neutrophilic dermatosis with a typical distribution in all patients. The disorder may coexist with an underlying autoimmune/dysimmune disease but is often associated only with a few autoantibodies without a clear autoimmunity. The overexpression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that APF has an important autoinflammatory component. PMID:26683967

  14. Cytokine, chemokine, and growth factor profile of platelet-rich plasma.

    Science.gov (United States)

    Mussano, F; Genova, T; Munaron, L; Petrillo, S; Erovigni, F; Carossa, S

    2016-07-01

    During wound healing, biologically active molecules are released from platelets. The rationale of using platelet-rich plasma (PRP) relies on the concentration of bioactive molecules and subsequent delivery to healing sites. These bioactive molecules have been seldom simultaneously quantified within the same PRP preparation. In the present study, the flexible Bio-Plex system was employed to assess the concentration of a large range of cytokines, chemokines, and growth factors in 16 healthy volunteers so as to determine whether significant baseline differences may be found. Besides IL-1b, IL-1ra, IL-4, IL-6, IL-8, IL-12, IL-13, IL-17, INF-γ, TNF-α, MCP-1, MIP-1a, RANTES, bFGF, PDGF, and VEGF that were already quantified elsewhere, the authors reported also on the presence of IL-2, IL-5, IL-7, IL-9, IL-10, IL-15 G-CSF, GM-CSF, Eotaxin, CXCL10 chemokine (IP-10), and MIP 1b. Among the most interesting results, it is convenient to mention the high concentrations of the HIV-suppressive and inflammatory cytokine RANTES and a statistically significant difference between males and females in the content of PDGF-BB. These data are consistent with previous reports pointing out that gender, diet, and test system affect the results of platelet function in healthy subjects, but seem contradictory when compared to other quantification assays in serum and plasma. The inconsistencies affecting the experimental results found in literature, along with the variability found in the content of bioactive molecules, urge further research, hopefully in form of randomized controlled clinical trials, in order to find definitive evidence of the efficacy of PRP treatment in various pathologic and regenerative conditions. PMID:26950533

  15. Cytokine and Chemokine Expression in Kidneys during Chronic Leptospirosis in Reservoir and Susceptible Animal Models.

    Directory of Open Access Journals (Sweden)

    Mariko Matsui

    Full Text Available Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. Humans can be infected after exposure to contaminated urine of reservoir animals, usually rodents, regarded as typical asymptomatic carriers of leptospires. In contrast, accidental hosts may present an acute form of leptospirosis with a range of clinical symptoms including the development of Acute Kidney Injury (AKI. Chronic Kidney Disease (CKD is considered as a possible AKI-residual sequela but little is known about the renal pathophysiology consequent to leptospirosis infection. Herein, we studied the renal morphological alterations in relation with the regulation of inflammatory cytokines and chemokines, comparing two experimental models of chronic leptospirosis, the golden Syrian hamster that survived the infection, becoming carrier of virulent leptospires, and the OF1 mouse, a usual reservoir of the bacteria. Animals were monitored until 28 days after injection with a virulent L. borgpetersenii serogroup Ballum to assess chronic infection. Hamsters developed morphological alterations in the kidneys with tubulointerstitial nephritis and fibrosis. Grading of lesions revealed higher scores in hamsters compared to the slight alterations observed in the mouse kidneys, irrespective of the bacterial load. Interestingly, pro-fibrotic TGF-β was downregulated in mouse kidneys. Moreover, cytokines IL-1β and IL-10, and chemokines MIP-1α/CCL3 and IP-10/CXCL-10 were significantly upregulated in hamster kidneys compared to mice. These results suggest a possible maintenance of inflammatory processes in the hamster kidneys with the infiltration of inflammatory cells in response to bacterial carriage, resulting in alterations of renal tissues. In contrast, lower expression levels in mouse kidneys indicated a better regulation of the inflammatory response and possible resolution processes likely related to resistance mechanisms.

  16. Elevated expression of the chemokine CCL18 in chronic rhinosinusitis with nasal polyps

    Science.gov (United States)

    Peterson, Sarah; Poposki, Julie A.; Nagarkar, Deepti R.; Chustz, Regina T.; Peters, Anju T.; Suh, Lydia A.; Carter, Roderick; Norton, James; Harris, Kathleen E.; Grammer, Leslie C.; Tan, Bruce K.; Chandra, Rakesh K.; Conley, David B.; Kern, Robert C.; Schleimer, Robert P.; Kato, Atsushi

    2011-01-01

    Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with Th2-dominant inflammation including eosinophilia, in contrast to non-polypoid CRS (CRSsNP). Chemokine CCL18/PARC (pulmonary and activation regulated chemokine) is known to recruit naïve T cells, B cells, and immature dendritic cells, as well as activate fibroblasts. CCL18is thought to be involved in Th2-related inflammatory diseases including asthma and atopic dermatitis. Objectives The objective of this study was to investigate the expression of CCL18 in patients with CRS. Methods Using nasal polyp tissue (NP) and uncinate tissue (UT) from controls and patients with CRS, we examined the expression of CCL18 mRNA by real-time PCR and measured CCL18 protein by ELISA, western blot and immunofluorescence. Results Compared to UT tissue in control subjects, CCL18 mRNA was significantly increased in NP (p<0.001) and UT (p<0.05) from patients with CRSwNP but not in UT from patients with CRSsNP. Similarly, CCL18 protein was elevated in NP and UT from CRSwNP and levels were even higher in Samter’s triad patients. Immunohistochemical analysis revealed CCL18 expression in inflammatory cells and CCL18+ cells were significantly increased in NP. Immunofluorescence data showed co-localization of CCL18 in CD68+/CD163+/macrophage mannose receptor+ M2 macrophages and tryptase+ mast cells in NP. Levels of CCL18 correlated with markers of M2 macrophages but not with tryptase, suggesting that M2 macrophages are a major CCL18-producing cells in NP. Conclusion Overproduction of CCL18 might contribute to the pathogenesis of CRSwNP through its known activities, which include recruitment of lymphocytes and dendritic cells, activation of fibroblasts, and initiation of local inflammation. PMID:21943944

  17. Up-regulation of the chemokine CCL21 in the skin of subjects exposed to irritants

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    Kuznitzky Raquel

    2004-04-01

    Full Text Available Abstract Background Expression of murine CCL21 by dermal lymphatic endothelial cells (LEC has been demonstrated to be one of the most important steps in Langerhans cell emigration from skin. Previously, our group and others have found that this chemokine is up-regulated in different human inflammatory skin diseases mediated by diverse specific immune responses. This study was carried out to investigate the involvement of CCL21 in human skin after challenge with irritant agents responsible for inducing Irritant Contact Dermatitis (ICD. Results Eleven normal individuals were challenged with different chemical or physical irritants. Two patients with Allergic Contact Dermatitis (ACD were also challenged with the relevant antigen in order to have a positive control for CCL21 expression. Macroscopic as well as microscopic responses were evaluated. We observed typical ICD responses with mostly mononuclear cells in perivascular areas, but a predominance of polymorphonuclear cells away from the inflamed blood vessels and in the epidermis at 24 hours. Immunohistochemical studies showed up-regulation of CCL21 by lymphatic endothelial cells in all the biopsies taken from ICD and ACD lesions compared to normal skin. Kinetic study at 10, 48, 96 and 168 hours after contact with a classical irritant (sodium lauryl sulphate showed that the expression of CCL21 was increased in lymphatic vessels at 10 hours, peaked at 48 hours, and then gradually declined. There was a strong correlation between CCL21 expression and the macroscopic response (r = 0.69; p = 0.0008, but not between CCL21 and the number of infiltrating cells in the lesions. Conclusions These results provide new evidence for the role of CCL21 in inflammatory processes. Since the up-regulation of this chemokine was observed in ICD and ACD, it is tempting to speculate that this mechanism operates independently of the type of dermal insult, facilitating the emigration of CCR7+ cells.

  18. Type 1 chemokine receptor expression in Chagas' disease correlates with morbidity in cardiac patients.

    Science.gov (United States)

    Gomes, Juliana A S; Bahia-Oliveira, Lilian M G; Rocha, Manoel Otávio C; Busek, Solange C U; Teixeira, Mauro M; Silva, João Santana; Correa-Oliveira, Rodrigo

    2005-12-01

    Chemokines and chemokine receptors (CKRs) control the migration of leukocytes during the inflammatory process and are important immunological markers of type 1 (CCR5 and CXCR3) and type 2 (CCR3 and CCR4) responses. The coexpression of CKRs (CCR2, CCR3, CCR5, CXCR3, and CXCR4) and intracellular cytokines (interleukin-10 [IL-10], IL-4, tumor necrosis factor alpha [TNF-alpha], and gamma interferon [IFN-gamma]) on T CD4+ and CD8+ peripheral cells from individuals with indeterminate (IND) or cardiac (CARD) clinical forms of Chagas' disease after in vitro stimulation with Trypanosoma cruzi antigens, were evaluated in this study. The percentage of T CD4+ and CD8+ cells coexpressing CCR5 and IFN-gamma, CXCR3 and IFN-gamma, and CXCR3 and TNF-alpha were higher in CARD than in IND individuals; on the other hand, the percentage of T CD4+ or CD8+ cells coexpressing CCR3 and IL-10 or coexpressing CCR3 and IL-4 were lower in CARD individuals than in IND individuals. In addition, a significant positive correlation between the expression of CCR5 or CXCR3 and IFN-gamma was observed in CARD individuals contrasting with a significant positive correlation between the expression of CCR3 and IL-4 and of CCR3 and IL-10 in IND patients. These results reinforce the hypothesis that a T. cruzi-exacerbated specific type 1 immune response developed by CARD chagasic patients is associated with the development of heart pathology.

  19. Cloning and functional characterization of the rabbit C-C chemokine receptor 2

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    Hamdouchi Chafiq

    2005-07-01

    Full Text Available Abstract Background CC-family chemokine receptor 2 (CCR2 is implicated in the trafficking of blood-borne monocytes to sites of inflammation and is implicated in the pathogenesis of several inflammatory diseases such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. The major challenge in the development of small molecule chemokine receptor antagonists is the lack of cross-species activity to the receptor in the preclinical species. Rabbit models have been widely used to study the role of various inflammatory molecules in the development of inflammatory processes. Therefore, in this study, we report the cloning and characterization of rabbit CCR2. Data regarding the activity of the CCR2 antagonist will provide valuable tools to perform toxicology and efficacy studies in the rabbit model. Results Sequence alignment indicated that rabbit CCR2 shares 80 % identity to human CCR2b. Tissue distribution indicated that rabbit CCR2 is abundantly expressed in spleen and lung. Recombinant rabbit CCR2 expressed as stable transfectants in U-937 cells binds radiolabeled 125I-mouse JE (murine MCP-1 with a calculated Kd of 0.1 nM. In competition binding assays, binding of radiolabeled mouse JE to rabbit CCR2 is differentially competed by human MCP-1, -2, -3 and -4, but not by RANTES, MIP-1α or MIP-1β. U-937/rabbit CCR2 stable transfectants undergo chemotaxis in response to both human MCP-1 and mouse JE with potencies comparable to those reported for human CCR2b. Finally, TAK-779, a dual CCR2/CCR5 antagonist effectively inhibits the binding of 125I-mouse JE (IC50 = 2.3 nM to rabbit CCR2 and effectively blocks CCR2-mediated chemotaxis. Conclusion In this study, we report the cloning of rabbit CCR2 and demonstrate that this receptor is a functional chemotactic receptor for MCP-1.

  20. Inhibition of oncogene-induced inflammatory chemokines using a farnesyltransferase inhibitor

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    Rothstein Jay L

    2008-02-01

    Full Text Available Abstract Background Farnesyltransferase inhibitors (FTI are small molecule agents originally formulated to inhibit the oncogenic functions of Ras. Although subsequent analysis of FTI activity revealed wider effects on other pathways, the drug has been demonstrated to reduce Ras signaling by direct measurements. The purpose of the current study was to determine if FTI could be used to inhibit the inflammatory activities of a known Ras-activating human oncoprotein, RET/PTC3. RET/PTC3 is a fusion oncoprotein expressed in the thyroid epithelium of patients afflicted with thyroid autoimmune disease and/or differentiated thyroid carcinoma. Previous studies have demonstrated that RET/PTC3 signals through Ras and can provoke nuclear translocation of NFκB and the downstream release of pro-inflammatory mediators from thyroid follicular cells in vitro and in vivo, making it an ideal target for studies using FTI. Methods For the studies described here, an in vitro assay was developed to measure FTI inhibition of RET/PTC3 pro-inflammatory effects. Rat thyrocytes transfected with RET/PTC3 or vector control cDNA were co-cultured with FTI and examined for inhibition of chemokine expression and secretion measured by RT-PCR and ELISA. Immunoblot analysis was used to confirm the level at which FTI acts on RET/PTC3-expressing cells, and Annexin V/PI staining of cells was used to assess cell death in RET/PTC3-expressing cells co-cultured with FTI. Results These analyses revealed significant mRNA and protein inhibition of chemokines Ccl2 and Cxcl1 with nanomolar doses of FTI. Neither RET/PTC3 protein expression nor apoptosis were affected at any dose of FTI investigated. Conclusion These data suggest that FTI may be applied as an effective inhibitor for RET/PTC3-oncogene induced pro-inflammatory mediators.

  1. Cytokine and Chemokine Expression in Kidneys during Chronic Leptospirosis in Reservoir and Susceptible Animal Models

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    Matsui, Mariko; Roche, Louise; Geroult, Sophie; Soupé-Gilbert, Marie-Estelle; Monchy, Didier; Huerre, Michel; Goarant, Cyrille

    2016-01-01

    Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. Humans can be infected after exposure to contaminated urine of reservoir animals, usually rodents, regarded as typical asymptomatic carriers of leptospires. In contrast, accidental hosts may present an acute form of leptospirosis with a range of clinical symptoms including the development of Acute Kidney Injury (AKI). Chronic Kidney Disease (CKD) is considered as a possible AKI-residual sequela but little is known about the renal pathophysiology consequent to leptospirosis infection. Herein, we studied the renal morphological alterations in relation with the regulation of inflammatory cytokines and chemokines, comparing two experimental models of chronic leptospirosis, the golden Syrian hamster that survived the infection, becoming carrier of virulent leptospires, and the OF1 mouse, a usual reservoir of the bacteria. Animals were monitored until 28 days after injection with a virulent L. borgpetersenii serogroup Ballum to assess chronic infection. Hamsters developed morphological alterations in the kidneys with tubulointerstitial nephritis and fibrosis. Grading of lesions revealed higher scores in hamsters compared to the slight alterations observed in the mouse kidneys, irrespective of the bacterial load. Interestingly, pro-fibrotic TGF-β was downregulated in mouse kidneys. Moreover, cytokines IL-1β and IL-10, and chemokines MIP-1α/CCL3 and IP-10/CXCL-10 were significantly upregulated in hamster kidneys compared to mice. These results suggest a possible maintenance of inflammatory processes in the hamster kidneys with the infiltration of inflammatory cells in response to bacterial carriage, resulting in alterations of renal tissues. In contrast, lower expression levels in mouse kidneys indicated a better regulation of the inflammatory response and possible resolution processes likely related to resistance mechanisms. PMID:27219334

  2. Matrix metalloproteinases and chemokines in the gingival crevicular fluid during orthodontic tooth movement.

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    Capelli, Jonas; Kantarci, Alpdogan; Haffajee, Anne; Teles, Ricardo Palmier; Fidel, Rivail; Figueredo, Carlos Marcelo

    2011-12-01

    Matrix metalloproteinases (MMPs) and monocyte chemoattractants are key modulators of the biological mechanisms triggered in the periodontium by mechanical forces. The gingival crevicular fluid (GCF) provides a non-invasive method to assess longitudinally the release of inflammatory mediators during orthodontic tooth movement. The goal of this study was to examine the GCF levels of MMP-3, MMP-9, and MMP-13 and of the chemokines macrophage inflammatory protein (MIP)-1β, monocyte chemoattractant protein (MCP)-1, and regulated on activation normal T cells expressed and secreted (RANTES) at different time points during orthodontic tooth movement. Fourteen subjects (three males and 11 females, 18.8 ± 4.8 years of age; range from 12 to 28 years) had their maxillary canines retracted. Thirty-second GCF samples were collected from the tension and pressure sides 7 days prior to the activation of the orthodontic appliance, on the day of activation, and after 1 and 24 hours, and 14, 21, and 80 days of constant force application. The volume of GCF was measured and samples analysed using a multiplexed bead immunoassay for the content of the six target molecules. Differences in the mean GFC volumes and mean level for each analyte over time were assessed using the Friedman test, and differences between the tension and pressure sides at each time point with the Mann-Whitney test. The mean levels of the three MMPs changed significantly over time but only at the compression side (P < 0.05, Friedman test). The GCF levels of the three chemokines were not affected by the application of mechanical stress. The levels of MMPs in GCF at the pressure side are modulated by the application of orthodontic force. PMID:21389074

  3. Different expression of chemokines in rheumatoid arthritis and osteoarthritis bone marrow

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    Kurowska, Weronika J.; Radzikowska, Anna; Massalska, Magdalena A.; Burakowski, Tomasz; Kontny, Ewa; Słowińska, Iwona; Gasik, Robert; Maśliński, Włodzimierz

    2016-01-01

    Objectives Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction. In addition to involvement of the joints, there is growing evidence that inflammatory/autoimmune processes take place in bone marrow, beginning the disease onset. Activated T and B cells accumulate in bone marrow, where also effective antigen presentation takes place. An increased number of activated T cells was observed in RA in comparison to osteoarthritis (OA) bone marrow. In the present study we analyzed the levels of chemokines that may be responsible for accumulation/retention of T-cells in the bone marrow of RA and OA patients. Material and methods Bone marrow samples were obtained from RA and OA patients during total hip replacement surgery, and bone marrow plasma was obtained by gradient centrifugation. Levels of the chemokines CX3CL1, CCL5, CCL2, CXCL12 and CXCL1 were measured in bone marrow plasma by specific ELISAs. Comparison between the groups of patients and statistical significance were analyzed by the two-tailed Mann-Whitney U test. Results Increased levels of CX3CL1 (818 ±431 pg/ml vs. 502 ±131 pg/ml, p < 0.0007) and CCL5 (5967 ±1680 pg/ml vs. 4878 ±2360 pg/ml, p < 0.05) respectively in bone marrow plasma from RA in comparison with OA patients were observed. In contrast, similar levels of CCL2, CXCL12 and CXCL1 in RA and OA bone marrow suggest that these cytokines do not play a significant role in the observed T cell accumulation in RA bone marrow. Conclusions CX3CL1 and CCL5 overproduced in RA bone marrow may contribute to the accumulation of T cells observed in RA bone marrow. PMID:27407279

  4. Localization of Distinct Peyer's Patch Dendritic Cell Subsets and Their Recruitment by Chemokines Macrophage Inflammatory Protein (Mip)-3α, Mip-3β, and Secondary Lymphoid Organ Chemokine

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    Iwasaki, Akiko; Kelsall, Brian L.

    2000-01-01

    We describe the anatomical localization of three distinct dendritic cell (DC) subsets in the murine Peyer's patch (PP) and explore the role of chemokines in their recruitment. By two-color in situ immunofluorescence, CD11b+ myeloid DCs were determined to be present in the subepithelial dome (SED) region, whereas CD8α+ lymphoid DCs are present in the T cell–rich interfollicular region (IFR). DCs that lack expression of CD8α or CD11b (double negative) are present in both the SED and IFR. By in situ hybridization, macrophage inflammatory protein (MIP)-3α mRNA was dramatically expressed only by the follicle-associated epithelium overlying the SED, while its receptor, CCR6, was concentrated in the SED. In contrast, CCR7 was expressed predominantly in the IFR. Consistent with these findings, reverse transcriptase polymerase chain reaction analysis and in vitro chemotaxis assays using freshly isolated DCs revealed that CCR6 was functionally expressed only by DC subsets present in the SED, while all subsets expressed functional CCR7. Moreover, none of the splenic DC subsets migrated toward MIP-3α. These data support a distinct role for MIP-3α/CCR6 in recruitment of CD11b+ DCs toward the mucosal surfaces and for MIP-3β/CCR7 in attraction of CD8α+ DCs to the T cell regions. Finally, we demonstrated that all DC subsets expressed an immature phenotype when freshly isolated and maintained expression of subset markers upon maturation in vitro. In contrast, CCR7 expression by myeloid PP DCs was enhanced with maturation in vitro. In addition, this subset disappeared from the SED and appeared in the IFR after microbial stimulation in vivo, suggesting that immature myeloid SED DCs capture antigens and migrate to IFR to initiate T cell responses after mucosal microbial infections. PMID:10770804

  5. The effect of combined polymorphisms in chemokines and chemokine receptors on the clinical course of HIV-1 infection in a Brazilian population

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    Valdimara Corrêa Vieira

    2011-06-01

    Full Text Available Polymorphisms in genes that encode chemokines or their receptors can modulate susceptibility to human immunodeficiency virus (HIV infection and disease progression. The objective of this study was to assess the frequency of polymorphisms CCR5-Δ32, CCR2-64I, CCR5-59029A and SDF1-3'A and their role in the course of HIV infection in a Southern Brazilian population. Clinical data were obtained from 249 patients for an average period of 6.4 years and genotypes were determined by standard polymerase chain reaction (PCR and PCR-restriction fragment length polymorphism. Survival analyses were conducted for three outcomes: CD4+ T-cell counts below 200 cells/µL, acquired immune deficiency syndrome (AIDS or death. The frequency of the polymorphisms CCR5-Δ32, CCR2-64I, CCR5-59029A and SDF1-3'A were 0.024, 0.113, 0.487 and 0.207, respectively. CCR5-Δ32 was associated with a reduction in the risk for CD4+ T-cell depletion and with an increased risk for death after AIDS diagnosis. CCR2-64I was associated with a reduction in the risk for developing AIDS. SDF1-3'A was also associated with decreased risk for AIDS, but its effect was only evident when CCR2-64I was present as well. These results highlight the possibility of using these markers as indicators for the prognosis of disease progression and provide evidence for the importance of analysing the effects of gene polymorphisms in a combined fashion.

  6. (+)-Nootkatone inhibits tumor necrosis factor α/interferon γ-induced production of chemokines in HaCaT cells.

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    Choi, Hyeon-Jae; Lee, Jin-Hwee; Jung, Yi-Sook

    2014-05-01

    Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD. PMID:24704449

  7. Therapeutic T cells induce tumor-directed chemotaxis of innate immune cells through tumor-specific secretion of chemokines and stimulation of B16BL6 melanoma to secrete chemokines

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    Fox Bernard A

    2007-11-01

    Full Text Available Abstract Background The mechanisms by which tumor-specific T cells induce regression of established metastases are not fully characterized. In using the poorly immunogenic B16BL6-D5 (D5 melanoma model we reported that T cell-mediated tumor regression can occur independently of perforin, IFN-γ or the combination of both. Characterization of regressing pulmonary metastases identified macrophages as a major component of the cells infiltrating the tumor after adoptive transfer of effector T cells. This led us to hypothesize that macrophages played a central role in tumor regression following T-cell transfer. Here, we sought to determine the factors responsible for the infiltration of macrophages at the tumor site. Methods These studies used the poorly immunogenic D5 melanoma model. Tumor-specific effector T cells, generated from tumor vaccine-draining lymph nodes (TVDLN, were used for adoptive immunotherapy and in vitro analysis of chemokine expression. Cellular infiltrates into pulmonary metastases were determined by immunohistochemistry. Chemokine expression by the D5 melanoma following co-culture with T cells, IFN-γ or TNF-α was determined by RT-PCR and ELISA. Functional activity of chemokines was confirmed using a macrophage migration assay. T cell activation of macrophages to release nitric oxide (NO was determined using GRIES reagent. Results We observed that tumor-specific T cells with a type 1 cytokine profile also expressed message for and secreted RANTES, MIP-1α and MIP-1β following stimulation with specific tumor. Unexpectedly, D5 melanoma cells cultured with IFN-γ or TNF-α, two type 1 cytokines expressed by therapeutic T cells, secreted Keratinocyte Chemoattractant (KC, MCP-1, IP-10 and RANTES and expressed mRNA for MIG. The chemokines released by T cells and cytokine-stimulated tumor cells were functional and induced migration of the DJ2PM macrophage cell line. Additionally, tumor-specific stimulation of wt or perforin

  8. Performance of multiplex commercial kits to quantify cytokine and chemokine responses in culture supernatants from Plasmodium falciparum stimulations.

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    Gemma Moncunill

    Full Text Available BACKGROUND: Cytokines and chemokines are relevant biomarkers of pathology and immunity to infectious diseases such as malaria. Several commercially available kits based on quantitative suspension array technologies allow the profiling of multiple cytokines and chemokines in small volumes of sample. However, kits are being continuously improved and information on their performance is lacking. METHODOLOGY/PRINCIPAL FINDINGS: Different cytokine/chemokine kits, two flow cytometry-based (eBioscience® FlowCytomix™ and BD™ Cytometric Bead Array Human Enhanced Sensitivity and four Luminex®-based (Invitrogen™ Human Cytokine 25-Plex Panel, Invitrogen™ Human Cytokine Magnetic 30-Plex Panel, Bio-Rad® Bio-Plex Pro™ Human Cytokine Plex Assay and Millipore™ MILLIPLEX® MAP Plex Kit were compared. Samples tested were supernatants of peripheral blood mononuclear cells of malaria-exposed children stimulated with Plasmodium falciparum parasite lysates. Number of responses in range that could be detected was determined and reproducibility of duplicates was evaluated by the Bland-Altman test. Luminex® kits performed better than flow cytometry kits in number of responses in range and reproducibility. Luminex® kits were more reproducible when magnetic beads were used. However, within each methodology overall performance depended on the analyte tested in each kit. Within the Luminex® kits, the Invitrogen™ with polystyrene beads had the poorer performance, whereas Invitrogen™ with magnetic beads had the higher percentage of cytokines/chemokines with both readings in range (40%, followed by Bio-Rad® with magnetic beads (35%. Regarding reproducibility, the Millipore™ kit had the highest percentage (60% of cytokines/chemokines with acceptable limits of agreement (<30%, followed by the Invitrogen™ with magnetic beads (40% that had tighter limits of agreement. CONCLUSIONS/SIGNIFICANCE: Currently available kits for cytokine and chemokine

  9. Chemokine Transfer by Liver Sinusoidal Endothelial Cells Contributes to the Recruitment of CD4+ T Cells into the Murine Liver.

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    Katrin Neumann

    Full Text Available Leukocyte adhesion and transmigration are central features governing immune surveillance and inflammatory reactions in body tissues. Within the liver sinusoids, chemokines initiate the first crucial step of T-cell migration into the hepatic tissue. We studied molecular mechanisms involved in endothelial chemokine supply during hepatic immune surveillance and liver inflammation and their impact on the recruitment of CD4(+ T cells into the liver. In the murine model of Concanavalin A-induced T cell-mediated hepatitis, we showed that hepatic expression of the inflammatory CXC chemokine ligands (CXCL9 and CXCL10 strongly increased whereas homeostatic CXCL12 significantly decreased. Consistently, CD4(+ T cells expressing the CXC chemokine receptor (CXCR3 accumulated within the inflamed liver tissue. In histology, CXCL9 was associated with liver sinusoidal endothelial cells (LSEC which represent the first contact site for T-cell immigration into the liver. LSEC actively transferred basolaterally internalized CXCL12, CXCL9 and CXCL10 via clathrin-coated vesicles to CD4(+ T cells leading to enhanced transmigration of CXCR4(+ total CD4(+ T cells and CXCR3(+ effector/memory CD4(+ T cells, respectively in vitro. LSEC-expressed CXCR4 mediated CXCL12 transport and blockage of endothelial CXCR4 inhibited CXCL12-dependent CD4(+ T-cell transmigration. In contrast, CXCR3 was not involved in the endothelial transport of its ligands CXCL9 and CXCL10. The clathrin-specific inhibitor chlorpromazine blocked endothelial chemokine internalization and CD4(+ T-cell transmigration in vitro as well as migration of CD4(+ T cells into the inflamed liver in vivo. Moreover, hepatic accumulation of CXCR3(+ CD4(+ T cells during T cell-mediated hepatitis was strongly reduced after administration of chlorpromazine. These data demonstrate that LSEC actively provide perivascularly expressed homeostatic and inflammatory chemokines by CXCR4- and clathrin-dependent intracellular

  10. Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis.

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    Takuya Matsushita

    Full Text Available BACKGROUND: Differences in cytokine/chemokine profiles among patients with neuromyelitis optica (NMO, relapsing remitting multiple sclerosis (RRMS, and primary progressive MS (PPMS, and the relationships of these profiles with clinical and neuroimaging features are unclear. A greater understanding of these profiles may help in differential diagnosis. METHODS/PRINCIPAL FINDINGS: We measured 27 cytokines/chemokines and growth factors in CSF collected from 20 patients with NMO, 26 with RRMS, nine with PPMS, and 18 with other non-inflammatory neurological diseases (OND by multiplexed fluorescent bead-based immunoassay. Interleukin (IL-17A, IL-6, CXCL8 and CXCL10 levels were significantly higher in NMO patients than in OND and RRMS patients at relapse, while granulocyte-colony stimulating factor (G-CSF and CCL4 levels were significantly higher in NMO patients than in OND patients. In NMO patients, IL-6 and CXCL8 levels were positively correlated with disability and CSF protein concentration while IL-6, CXCL8, G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF and IFN-γ were positively correlated with CSF neutrophil counts at the time of sample collection. In RRMS patients, IL-6 levels were significantly higher than in OND patients at the relapse phase while CSF cell counts were negatively correlated with the levels of CCL2. Correlation coefficients of cytokines/chemokines in the relapse phase were significantly different in three combinations, IL-6 and GM-CSF, G-CSF and GM-CSF, and GM-CSF and IFN-γ, between RRMS and NMO/NMOSD patients. In PPMS patients, CCL4 and CXCL10 levels were significantly higher than in OND patients. CONCLUSIONS: Our findings suggest distinct cytokine/chemokine alterations in CSF exist among NMO, RRMS and PPMS. In NMO, over-expression of a cluster of Th17- and Th1-related proinflammatory cytokines/chemokines is characteristic, while in PPMS, increased CCL4 and CXCL10 levels may reflect on-going low grade T cell

  11. (+)-Nootkatone inhibits tumor necrosis factor α/interferon γ-induced production of chemokines in HaCaT cells

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    Choi, Hyeon-Jae; Lee, Jin-Hwee [College of Pharmacy, Ajou University, Suwon 443-749 (Korea, Republic of); Jung, Yi-Sook, E-mail: yisjung@ajou.ac.kr [College of Pharmacy, Ajou University, Suwon 443-749 (Korea, Republic of); Research Institute of Pharmaceutical Sciences and Technology, Ajou University, Suwon 443-749 (Korea, Republic of)

    2014-05-02

    Highlights: • (+)-Nootkatone inhibits TNF-α/IFN-γ-induced TARC and MDC expression in HaCaT cells. • PKCζ, p38 MAPK, or NF-κB mediate TNF-α/IFN-γ-induced TARC and MDC expression. • (+)-Nootkatone inhibits TNF-α/IFN-γ-induced activation of PKCζ, p38 MAPK, or NF-κB. • (+)-Nootkatone suppresses chemokine expression by inhibiting of PKCζ and p38 pathways. - Abstract: Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD.

  12. Myocardial chemokine expression and intensity of myocarditis in Chagas cardiomyopathy are controlled by polymorphisms in CXCL9 and CXCL10.

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    Luciana Gabriel Nogueira

    Full Text Available BACKGROUND: Chronic Chagas cardiomyopathy (CCC, a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi. Even though the Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis, little is known about the factors controlling inflammatory cell migration to CCC myocardium. METHODS AND RESULTS: Using confocal immunofluorescence and quantitative PCR, we studied cell surface staining and gene expression of the CXCR3, CCR4, CCR5, CCR7, CCR8 receptors and their chemokine ligands in myocardial samples from end-stage CCC patients. CCR5+, CXCR3+, CCR4+, CCL5+ and CXCL9+ mononuclear cells were observed in CCC myocardium. mRNA expression of the chemokines CCL5, CXCL9, CXCL10, CCL17, CCL19 and their receptors was upregulated in CCC myocardium. CXCL9 mRNA expression directly correlated with the intensity of myocarditis, as well as with mRNA expression of CXCR3, CCR4, CCR5, CCR7, CCR8 and their ligands. We also analyzed single-nucleotide polymorphisms for genes encoding the most highly expressed chemokines and receptors in a cohort of Chagas disease patients. CCC patients with ventricular dysfunction displayed reduced genotypic frequencies of CXCL9 rs10336 CC, CXCL10 rs3921 GG, and increased CCR5 rs1799988CC as compared to those without dysfunction. Significantly, myocardial samples from CCC patients carrying the CXCL9/CXCL10 genotypes associated to a lower risk displayed a 2-6 fold reduction in mRNA expression of CXCL9, CXCL10, and other chemokines and receptors, along with reduced intensity of myocarditis, as compared to those with other CXCL9/CXCL10 genotypes. CONCLUSIONS: Results may indicate that genotypes associated to reduced risk in closely linked CXCL9 and CXCL10 genes may modulate local expression of the chemokines themselves, and simultaneously affect myocardial expression of other key chemokines as well as intensity of myocarditis. Taken together our

  13. (+)-Nootkatone inhibits tumor necrosis factor α/interferon γ-induced production of chemokines in HaCaT cells

    International Nuclear Information System (INIS)

    Highlights: • (+)-Nootkatone inhibits TNF-α/IFN-γ-induced TARC and MDC expression in HaCaT cells. • PKCζ, p38 MAPK, or NF-κB mediate TNF-α/IFN-γ-induced TARC and MDC expression. • (+)-Nootkatone inhibits TNF-α/IFN-γ-induced activation of PKCζ, p38 MAPK, or NF-κB. • (+)-Nootkatone suppresses chemokine expression by inhibiting of PKCζ and p38 pathways. - Abstract: Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well-known typical inflammatory chemokines involved in atopic dermatitis (AD). (+)-Nootkatone is the major component of Cyperus rotundus. (+)-Nootkatone has antiallergic, anti-inflammatory, and antiplatelet activities. The purpose of this study was to investigate the effect of (+)-nootkatone on tumor necrosis factor α (TNF-α)/interferon γ (IFN-γ)-induced expression of Th2 chemokines in HaCaT cells. We found that (+)-nootkatone inhibited the TNF-α/IFN-γ-induced expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells. It also significantly inhibited TNF-α/IFN-γ-induced activation of nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (MAPK), and protein kinase Cζ (PKCζ). Furthermore, we showed that PKCζ and p38 MAPK contributed to the inhibition of TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression by blocking IκBα degradation in HaCaT cells. Taken together, these results suggest that (+)-nootkatone may suppress TNF-α/IFN-γ-induced TARC/CCL17 and MDC/CCL22 expression in HaCaT cells by inhibiting of PKCζ and p38 MAPK signaling pathways that lead to activation of NF-κB. We propose that (+)-nootkatone may be a useful therapeutic candidate for inflammatory skin diseases such as AD

  14. Thymocyte migration: an affair of multiple cellular interactions?

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    Savino W.

    2003-01-01

    Full Text Available Cell migration is a crucial event in the general process of thymocyte differentiation. The cellular interactions involved in the control of this migration are beginning to be defined. At least chemokines and extracellular matrix proteins appear to be part of the game. Cells of the thymic microenvironment produce these two groups of molecules, whereas developing thymocytes express the corresponding receptors. Moreover, although chemokines and extracellular matrix can drive thymocyte migration per se, a combined role for these molecules appears to contribute to the resulting migration patterns of thymocytes in their various stages of differentiation. The dynamics of chemokine and extracellular matrix production and degradation is not yet well understood. However, matrix metalloproteinases are likely to play a role in the breakdown of intrathymic extracellular matrix contents. Thus, the physiological migration of thymocytes should be envisioned as a resulting vector of multiple, simultaneous and/or sequential stimuli involving chemokines, adhesive and de-adhesive extracellular matrix proteins, as well as matrix metalloproteinases. Accordingly, it is conceivable that any pathological change in any of these loops may result in the alteration of normal thymocyte migration. This seems to be the case in murine infection by the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas' disease. A better knowledge of the physiological mechanisms governing thymocyte migration will provide new clues for designing therapeutic strategies targeting developing T cells.

  15. Immunological role of C4 CC chemokine-1 from snakehead murrel Channa striatus.

    Science.gov (United States)

    Bhatt, Prasanth; Kumaresan, Venkatesh; Palanisamy, Rajesh; Chaurasia, Mukesh Kumar; Gnanam, Annie J; Pasupuleti, Mukesh; Arockiaraj, Jesu

    2014-02-01

    In this study, we have reported a cDNA sequence of C4 CC chemokine identified from snakehead murrel (also known as striped murrel) Channa striatus (named as CsCC-Chem-1) normalized cDNA library constructed by Genome Sequencing FLX™ Technology (GS-FLX™). CsCC-Chem-1 is 641 base pairs (bp) long that contain 438 bp open reading frame (ORF). The ORF encodes a polypeptide of 146 amino acids with a molecular mass of 15 kDa. The polypeptide contains a small cytokine domain at 30-88. The domain carries the CC motif at Cys(33)-Cys(34). In addition, CsCC-Chem-1 consists of another two cysteine residues at C(59) and C(73), which, together with C(33) and C(34), make CsCC-Chem-1 as a C4-CC chemokine. CsCC-Chem-1 also contains a 'TCCT' motif at 32-35 as CC signature motif; this new motif may represent new characteristic features, which may lead to some unknown function that needs to be further focused on. Phylogenitically, CsCC-Chem-1 clustered together with CC-Chem-1 from rock bream Oplegnathus fasciatus and European sea bass Dicentrarchus labrax. Significantly (P<0.05) highest gene expression was noticed in spleen and is up-regulated upon fungus (Aphanomyces invadans), bacteria (Aeromonas hydrophila) and virus (poly I:C) infection at various time points. The gene expression results indicate the influence of CsCC-Chem-1 in the immune system of murrel. Overall, the gene expression study showed that the CsCC-Chem-1 is a capable gene to increase the cellular response against various microbial infections. Further, we cloned the coding sequence of CsCC-Chem-1 in pMAL vector and purified the recombinant protein to study the functional properties. The cell proliferation activity of recombinant CsCC-Chem-1 protein showed a significant metabolic activity in a concentration dependent manner. Moreover, the chemotaxis assay showed the capability of recombinant CsCC-Chem-1 protein which can induce the migration of spleen leukocytes in C. striatus. However, this remains to be verified

  16. (68)Ga-Pentixafor-PET/CT for Imaging of Chemokine Receptor 4 Expression in Glioblastoma.

    Science.gov (United States)

    Lapa, Constantin; Lückerath, Katharina; Kleinlein, Irene; Monoranu, Camelia Maria; Linsenmann, Thomas; Kessler, Almuth F; Rudelius, Martina; Kropf, Saskia; Buck, Andreas K; Ernestus, Ralf-Ingo; Wester, Hans-Jürgen; Löhr, Mario; Herrmann, Ken

    2016-01-01

    Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand (68)Ga-Pentixafor. 15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent (68)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUVmax, SUVmean). Tumor-to-background ratios (TBR) were calculated for both PET probes. (68)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples. (68)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUVmean and SUVmax of 3.0±1.5 and 3.9±2.0 respectively. Respective values for (18)F-FET were 4.4±2.0 (SUVmean) and 5.3±2.3 (SUVmax). TBR for SUVmean and SUVmax were higher for (68)Ga-Pentixafor than for (18)F-FET (SUVmean 154.0±90.7 vs. 4.1±1.3; SUVmax 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high (68)Ga-Pentixafor uptake; regions of the same tumor without apparent (68)Ga-Pentixafor uptake showed no or low receptor expression. In this pilot study, (68)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, (68)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy. PMID:26909116

  17. Role of chemokine receptor CXCR2 expression in mammary tumor growth, angiogenesis and metastasis

    Directory of Open Access Journals (Sweden)

    Kalyan C Nannuru

    2011-01-01

    Full Text Available Background: Chemokines and their receptors have long been known to regulate metastasis in various cancers. Previous studies have shown that CXCR2 expression is upregulated in malignant breast cancer tissues but not in benign ductal epithelial samples. The functional role of CXCR2 in the metastatic phenotype of breast cancer still remains unclear. We hypothesize that the chemokine receptor, CXCR2, mediates tumor cell invasion and migration and promotes metastasis in breast cancer. The objective of this study is to investigate the potential role of CXCR2 in the metastatic phenotype of mouse mammary tumor cells. Materials and Methods: We evaluated the functional role of CXCR2 in breast cancer by stably downregulating the expression of CXCR2 in metastatic mammary tumor cell lines Cl66 and 4T1, using short hairpin RNA (shRNA. The effects of CXCR2 downregulation on tumor growth, invasion and metastatic potential were analyzed in vitro and in vivo. Results: We demonstrated knock down of CXCR2 in Cl66 and 4T1 cells (Cl66-shCXCR2 and 4T1-shCXCR2 cells by reverse transcriptase polymerase chain reaction (RT-PCR at the transcriptional level and by immunohistochemistry at the protein level. We did not observe a significant difference in in vitro cell proliferation between vector control and CXCR2 knock-down Cl66 or 4T1 cells. Next, we examined the invasive potential of Cl66-shCXCR2 cells by in vitro Matrigel invasion assay. We observed a significantly lower number (52 ± 5 of Cl66-shCXCR2 cells invading through Matrigel compared to control cells (Cl66-control (182 ± 3 (P < 0.05. We analyzed the in vivo metastatic potential of Cl66-shCXCR2 using a spontaneous metastasis model by orthotopically implanting cells into the mammary fat pad of female BALB/c mice. Animals were sacrificed 12 weeks post tumor implantation and tissue samples were analyzed for metastatic nodules. CXCR2 downregulation significantly inhibited tumor cell metastasis. All the mice (n = 10

  18. Nanofibrous scaffolds incorporating PDGF-BB microspheres induce chemokine expression and tissue neogenesis in vivo.

    Directory of Open Access Journals (Sweden)

    Qiming Jin

    Full Text Available Platelet-derived growth factor (PDGF exerts multiple cellular effects that stimulate wound repair in multiple tissues. However, a major obstacle for its successful clinical application is the delivery system, which ultimately controls the in vivo release rate of PDGF. Polylactic-co-glycolic acid (PLGA microspheres (MS in nanofibrous scaffolds (NFS have been shown to control the release of rhPDGF-BB in vitro. In order to investigate the effects of rhPDGF-BB release from MS in NFS on gene expression and enhancement of soft tissue engineering, rhPDGF-BB was incorporated into differing molecular weight (MW polymeric MS. By controlling the MW of the MS over a range of 6.5 KDa-64 KDa, release rates of PDGF can be regulated over periods of weeks to months in vitro. The NFS-MS scaffolds were divided into multiple groups based on MS release characteristics and PDGF concentration ranging from 2.5-25.0 microg and evaluated in vivo in a soft tissue wound repair model in the dorsa of rats. At 3, 7, 14 and 21 days post-implantation, the scaffold implants were harvested followed by assessments of cell penetration, vasculogenesis and tissue neogenesis. Gene expression profiles using cDNA microarrays were performed on the PDGF-releasing NFS. The percentage of tissue invasion into MS-containing NFS at 7 days was higher in the PDGF groups when compared to controls. Blood vessel number in the HMW groups containing either 2.5 or 25 microg PDGF was increased above those of other groups at 7d (p<0.01. Results from cDNA array showed that PDGF strongly enhanced in vivo gene expression of the CXC chemokine family members such as CXCL1, CXCL2 and CXCL5. Thus, sustained release of rhPDGF-BB, controlled by slow-releasing MS associated with the NFS delivery system, enhanced cell migration and angiogenesis in vivo, and may be related to an induced expression of chemokine-related genes. This approach offers a technology to accurately control growth factor release to promote

  19. Rubratoxin-B-induced secretion of chemokine ligands of cysteine-cysteine motif chemokine receptor 5 (CCR5) and its dependence on heat shock protein 90 in HL60 cells.

    Science.gov (United States)

    Nagashima, Hitoshi

    2015-11-01

    To elucidate the mechanism underlying rubratoxin B toxicity, the effects of rubratoxin B on the secretion of CCR5 chemokines, CCL3, CCL4, and CCL5, in a human promyelocytic leukemia cell line, HL60, were investigated. In addition, to examine whether the molecular chaperone 90-kDa heat shock protein (Hsp90) contributes to rubratoxin B toxicity, the effects of Hsp90-specific inhibitors, radicicol and geldanamycin, were investigated. Exposure to rubratoxin B for 24h induced secretion of each CCR5 chemokine, although the effect on CCL5 secretion was modest, and it enhanced secretion of proinflammatory cytokines tumor necrosis factor-α, CXCL8, and CCL2. Concomitant treatment with radicicol abolished the rubratoxin-induced secretion of all cytokines investigated. Geldanamycin antagonized the rubratoxin B-induced effects on CCL3 and CCL5, but not CCL4; the effects of geldanamycin were less than that of radicicol. Taken together, the results suggest that rubratoxin B, with the contribution of Hsp90, induces secretion of CCR5 chemokines.

  20. Neuroendocrine-immune interaction: regulation of inflammation via G-protein coupled receptors

    NARCIS (Netherlands)

    Verburg-van Kemenade, B.M.L.; Aa, van der L.M.; Chadzinska, M.K.

    2013-01-01

    Neuroendocrine- and immune systems interact in a bi-directional fashion to communicate the status of pathogen recognition to the brain and the immune response is influenced by physiological changes. The network of ligands and their receptors involved includes cytokines and chemokines, corticosteroid

  1. The cell wall component lipoteichoic acid of Staphylococcus aureus induces chemokine gene expression in bovine mammary epithelial cells

    Science.gov (United States)

    KIKU, Yoshio; NAGASAWA, Yuya; TANABE, Fuyuko; SUGAWARA, Kazue; WATANABE, Atsushi; HATA, Eiji; OZAWA, Tomomi; NAKAJIMA, Kei-ichi; ARAI, Toshiro; HAYASHI, Tomohito

    2016-01-01

    Staphylococcus aureus (SA) is a major cause of bovine mastitis, but its pathogenic mechanism remains poorly understood. To evaluate the role of lipoteichoic acid (LTA) in the immune or inflammatory response of SA mastitis, we investigated the gene expression profile in bovine mammary epithelial cells stimulated with LTA alone or with formalin-killed SA (FKSA) using cap analysis of gene expression. Seven common differentially expressed genes related to immune or inflammatory mediators were up-regulated under both LTA and FKSA stimulations. Three of these genes encode chemokines (IL-8, CXCL6 and CCL2) functioning as chemoattractant molecules for neutrophils and macrophages. These results suggest that the initial inflammatory response of SA infection in mammary gland may be related with LTA induced chemokine genes. PMID:27211287

  2. Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.

    Science.gov (United States)

    Chen, Huanhuan Joyce; Sun, Jian; Huang, Zhiliang; Hou, Harry; Arcilla, Myra; Rakhilin, Nikolai; Joe, Daniel J; Choi, Jiahn; Gadamsetty, Poornima; Milsom, Jeff; Nandakumar, Govind; Longman, Randy; Zhou, Xi Kathy; Edwards, Robert; Chen, Jonlin; Chen, Kai Yuan; Bu, Pengcheng; Wang, Lihua; Xu, Yitian; Munroe, Robert; Abratte, Christian; Miller, Andrew D; Gümüş, Zeynep H; Shuler, Michael; Nishimura, Nozomi; Edelmann, Winfried; Shen, Xiling; Lipkin, Steven M

    2015-06-01

    Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening.

  3. Pathological Role of Fractalkine/CX3CL1 in Rheumatic Diseases: A unique chemokine with multiple functions

    Directory of Open Access Journals (Sweden)

    Brian A. Jones

    2012-01-01

    Full Text Available Understanding rheumatic diseases from the perspective of chemokine biology has shaped and will continue to shape our approach for targeted drug design. Among different kinds of chemokines, fractalkine/CX3CL1 has been found to play an important role in inflammation, portraying unique functional and structural characteristics. This review summarizes the emerging role of fractalkine/CX3CL1 from a functional and clinical perspective and provides evidence to validate it as a potential therapeutic target in rheumatic diseases such as rheumatoid arthritis (RA, Sjögren's syndrome, systemic lupus erythematosus, scleroderma, as well as diseases related to vascular inflammation. From this, recent studies investigating potential therapeutic agents against fractalkine/CX3CL1’s role in pathology have shown promise.

  4. Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

    DEFF Research Database (Denmark)

    Nijnik, Anastasia; Madera, Laurence; Ma, Shuhua;

    2010-01-01

    With the rapid rise in the incidence of multidrug resistant infections, there is substantial interest in host defense peptides as templates for production of new antimicrobial therapeutics. Natural peptides are multifunctional mediators of the innate immune response, with some direct antimicrobial...... activity and diverse immunomodulatory properties. We have previously developed an innate defense regulator (IDR) 1, with protective activity against bacterial infection mediated entirely through its effects on the immunity of the host, as a novel approach to anti-infective therapy. In this study......, an immunomodulatory peptide IDR-1002 was selected from a library of bactenecin derivatives based on its substantially more potent ability to induce chemokines in human PBMCs. The enhanced chemokine induction activity of the peptide in vitro correlated with stronger protective activity in vivo in the Staphylococcus...

  5. IL-1 beta-induced chemokine and Fas expression are inhibited by suppressor of cytokine signalling-3 in insulin-producing cells

    DEFF Research Database (Denmark)

    Jacobsen, M.L.B.; Ronn, S.G.; Bruun, C.;

    2009-01-01

    of genes encoding the Fas receptor and several chemokines. We have previously shown that suppressor of cytokine signalling (SOCS)-3 inhibits IL-1 beta- and IFN-gamma-induced nitric oxide production in a beta cell line. The aim of this study was to investigate whether SOCS-3 can influence cytokine......Chemokines recruit activated immune cells to sites of inflammation and are important mediators of insulitis. Activation of the pro-apoptotic receptor Fas leads to apoptosis-mediated death of the Fas-expressing cell. The pro-inflammatory cytokines IL-1 beta and IFN-gamma regulate the transcription......-induced Fas and chemokine expression in beta cells. Using a beta cell line with inducible Socs3 expression or primary neonatal rat islet cells transduced with a Socs3-encoding adenovirus, we employed real-time RT-PCR analysis to investigate whether SOCS-3 affects cytokine-induced chemokine and Fas m...

  6. IL-1beta-induced chemokine and Fas expression are inhibited by suppressor of cytokine signalling-3 in insulin-producing cells

    DEFF Research Database (Denmark)

    Jacobsen, M L B; Rønn, S G; Bruun, C;

    2008-01-01

    the transcription of genes encoding the Fas receptor and several chemokines. We have previously shown that suppressor of cytokine signalling (SOCS)-3 inhibits IL-1beta- and IFN-gamma-induced nitric oxide production in a beta cell line. The aim of this study was to investigate whether SOCS-3 can influence cytokine......AIMS/HYPOTHESIS: Chemokines recruit activated immune cells to sites of inflammation and are important mediators of insulitis. Activation of the pro-apoptotic receptor Fas leads to apoptosis-mediated death of the Fas-expressing cell. The pro-inflammatory cytokines IL-1beta and IFN-gamma regulate......-induced Fas and chemokine expression in beta cells. METHODS: Using a beta cell line with inducible Socs3 expression or primary neonatal rat islet cells transduced with a Socs3-encoding adenovirus, we employed real-time RT-PCR analysis to investigate whether SOCS-3 affects cytokine-induced chemokine and Fas m...

  7. Chemokines: proinflammatory and cell traffic regulator cytokines Las quimioquinas: citoquinas proinflamatorias y reguladoras del tráfico celular

    Directory of Open Access Journals (Sweden)

    Carlos Julio Montoya Guarín

    2001-01-01

    Full Text Available Chemokines are a large group of proinflammatory cytokines; currently, there are about 40 different chemokines produced by different cellular sources and with pleiotropic actions. Interest in chemokines’ research is growing due to their selectivity to activate and to direct the traffic of different leukocyte populations, in contrast with other chemotactic factors that attract neutrophils and monocytes similarly. Furthermore, it has been observed that chemokines are involved in hematopoiesis, angiogenesis, tissue remodeling, tumor growth and apoptosis. As chemokines direct the migration and function of leukocytes, it has been proposed that they have an important role in the pathophysiology of some diseases such as immune-complex glomerulonephritis, ischemia–reperfussion, HIV infection and other immune reactions. Las quimioquinas constituyen un grupo numeroso de citoquinas proinflamatorias; hasta el momento se han caracterizado alrededor de 40 quimioquinas diferentes que provienen de variadas fuentes celulares y tienen acciones muy pleiotrópicas. Su estudio ha despertado gran interés debido a la selectividad que tienen para activar y dirigir el tráfico de diferentes subpoblaciones de leucocitos, a diferencia de otros factores quimiotácticos que atraen por igual a los neutrófilos y monocitos. Adicionalmente, se ha observado que las quimioquinas están involucradas en la hematopoyesis, angiogénesis, morfogénesis tisular, crecimiento tumoral y apoptosis. Debido a que las quimioquinas orquestan la migración y función de los leucocitos, se ha propuesto que cumplen un papel muy importante en la fisiopatología de algunas enfermedades como la glomerulonefritis inducida por inmunocomplejos, la isquemia reperfusión, la ateroesclerosis, la infección por el VIH y algunas reacciones autoinmunes.

  8. The early activation marker CD69 regulates the expression of chemokines and CD4 T cell accumulation in intestine.

    Directory of Open Access Journals (Sweden)

    Katarina Radulovic

    Full Text Available Migration of naïve and activated lymphocytes is regulated by the expression of various molecules such as chemokine receptors and ligands. CD69, the early activation marker of C-type lectin domain family, is also shown to regulate the lymphocyte migration by affecting their egress from the thymus and secondary lymphoid organs. Here, we aimed to investigate the role of CD69 in accumulation of CD4 T cells in intestine using murine models of inflammatory bowel disease. We found that genetic deletion of CD69 in mice increases the expression of the chemokines CCL-1, CXCL-10 and CCL-19 in CD4(+ T cells and/or CD4(- cells. Efficient in vitro migration of CD69-deficient CD4 T cells toward the chemokine stimuli was the result of increased expression and/or affinity of chemokine receptors. In vivo CD69(-/- CD4 T cells accumulate in the intestine in higher numbers than B6 CD4 T cells as observed in competitive homing assay, dextran sodium sulphate (DSS-induced colitis and antigen-specific transfer colitis. In DSS colitis CD69(-/- CD4 T cell accumulation in colonic lamina propria (cLP was associated with increased expression of CCL-1, CXCL-10 and CCL-19 genes. Furthermore, treatment of DSS-administrated CD69(-/- mice with the mixture of CCL-1, CXCL-10 and CCL-19 neutralizing Abs significantly decreased the histopathological signs of colitis. Transfer of OT-II×CD69(-/- CD45RB(high CD4 T cells into RAG(-/- hosts induced CD4 T cell accumulation in cLP. This study showed CD69 as negative regulator of inflammatory responses in intestine as it decreases the expression of chemotactic receptors and ligands and reduces the accumulation of CD4 T cells in cLP during colitis.

  9. The effect of aging and caloric restriction on murine CD8+ T cell chemokine receptor gene expression

    Directory of Open Access Journals (Sweden)

    Mo RuRan

    2007-11-01

    Full Text Available Abstract Background The mechanism explaining the increased disease susceptibility in aging is not well understood. CD8+ T cells are crucial in anti-viral and anti-tumor responses. Although the chemokine system plays a critical role in CD8+ T cell function, very little is known about the relationship between aging and the T cell chemokine system. Results In this study we have examined the effect of aging on murine CD8+ T cell chemokine receptor gene expression. Freshly isolated splenic CD8+ T cells from old C57BL/6 mice were found to have higher CCR1, CCR2, CCR4, CCR5 and CXCR5, and lower CCR7 gene expression compared to their younger cohort. Anti-CD3/anti-CD28 stimulation elicited a similar robust chemokine receptor response from young and old CD8+ T cells. Western blot analyses confirmed elevated protein level of CCR4 and CCR5 in aged CD8+ T cells. Increases in T cell CCR1 and CCR5 expression also correlate to increased in vitro chemotaxis response to macrophage-inflammatory protein-1 α(MIP-1α. Finally, caloric restriction selectively prevents the loss of CD8+ T cell CCR7 gene expression in aging to the level that is seen in young CD8+ T cells. Conclusion These findings are consistent with the notion that aging exists in a state of low grade pro-inflammatory environment. In addition, our results provide a potential mechanism for the reported aging-associated impaired T cell lymphoid homing and allograft response, and reduced survival in sepsis.

  10. Overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating chemokine expression

    Science.gov (United States)

    Duckworth, C; Zhang, L; Carroll, S L; Ethier, S P; Cheung, H W

    2016-01-01

    We previously found that the scaffold adapter GRB2-associated binding protein 2 (GAB2) is amplified and overexpressed in a subset of primary high-grade serous ovarian cancers and cell lines. Ovarian cancer cells overexpressing GAB2 are dependent on GAB2 for activation of the phosphatidylinositol 3-kinase (PI3K) pathway and are sensitive to PI3K inhibition. In this study, we show an important role of GAB2 overexpression in promoting tumor angiogenesis by upregulating expression of multiple chemokines. Specifically, we found that suppression of GAB2 by inducible small hairpin RNA in ovarian cancer cells inhibited tumor cell proliferation, angiogenesis and peritoneal tumor growth in immunodeficient mice. Overexpression of GAB2 upregulated the secretion of several chemokines from ovarian cancer cells, including CXCL1, CXCL2 and CXCL8. The secreted chemokines not only signal through endothelial CXCR2 receptor in a paracrine manner to promote endothelial tube formation, but also act as autocrine growth factors for GAB2-induced transformation of fallopian tube secretory epithelial cells and clonogenic growth of ovarian cancer cells overexpressing GAB2. Pharmacological inhibition of inhibitor of nuclear factor kappa-B kinase subunit β (IKKβ), but not PI3K, mechanistic target of rapamycin (mTOR) or mitogen-activated protein kinase (MEK), could effectively suppress GAB2-induced chemokine expression. Inhibition of IKKβ augmented the efficacy of PI3K/mTOR inhibition in suppressing clonogenic growth of ovarian cancer cells with GAB2 overexpression. Taken together, these findings suggest that overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating expression of CXCL1, CXCL2 and CXCL8 that is IKKβ-dependent. Co-targeting IKKβ and PI3K pathways downstream of GAB2 might be a promising therapeutic strategy for ovarian cancer that overexpresses GAB2. PMID:26657155

  11. Reversed binding of a small molecule ligand in homologous chemokine receptors - differential role of extracellular loop 2

    DEFF Research Database (Denmark)

    Jensen, P C; Thiele, S; Steen, A;

    2012-01-01

    The majority of small molecule compounds targeting chemokine receptors share a similar pharmacophore with a centrally located aliphatic positive charge and flanking aromatic moieties. Here we describe a novel piperidine-based compound with structural similarity to previously described CCR8-specif...... agonists, but containing a unique phenyl-tetrazol moiety which, in addition to activity at CCR8 was also active at CCR1....

  12. Thiazolidinediones inhibit airway smooth muscle release of the chemokine CXCL10: in vitro comparison with current asthma therapies

    OpenAIRE

    Seidel Petra; Alkhouri Hatem; Lalor Daniel J; Burgess Janette K; Armour Carol L; Hughes J

    2012-01-01

    Abstract Background Activated mast cells are present within airway smooth muscle (ASM) bundles in eosinophilic asthma. ASM production of the chemokine CXCL10 plays a role in their recruitment. Thus the effects of glucocorticoids (fluticasone, budesonide), long-acting β2-agonists (salmeterol, formoterol) and thiazolidinediones (ciglitazone, rosiglitazone) on CXCL10 production by ASM cells (ASMC) from people with and without asthma were investigated in vitro. Methods Confluent serum-deprived ce...

  13. Universal expression and dual function of the atypical chemokine receptor D6 on innate-like B cells in mice

    OpenAIRE

    Hansell, Chris A H; Schiering, Chris; Kinstrie, Ross; Ford, Laura; Bordon, Yvonne; McInnes, Iain B; Goodyear, Carl S.; Nibbs, Robert J B

    2011-01-01

    Mouse innate-like B cells are a heterogeneous collection of multifunctional cells that control infection, play housekeeping roles, contribute to adaptive immunity, and suppress inflammation. We show that, amongst leukocytes, chemokine internalisation by the D6 receptor is a unique and universal feature of all known innate-like B cell populations and, to our knowledge, the most effective unifying marker of these cells. Moreover, we identify novel D6active B1 cell subsets, including those we te...

  14. A meta-analysis for C-X-C chemokine receptor type 4 as a prognostic marker and potential drug target in hepatocellular carcinoma

    OpenAIRE

    Hu, Fei

    2015-01-01

    Fei Hu, Lin Miao, Yu Zhao, Yuan-Yuan Xiao, Qing XuDepartment of Medical Oncology, Shanghai Tenth People’s Hospital, Tongji University, School of Medicine, Shanghai, People’s Republic of ChinaAbstract: Chemokines (CKs), small proinflammatory chemoattractant cytokines that bind to specific G-protein coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. C-X-C chemokine receptor type 4 (CXCR4) has gained tremendous attention over th...

  15. Genome-wide association replicates the association of Duffy antigen receptor for chemokines (DARC) polymorphisms with serum monocyte chemoattractant protein-1 (MCP-1) levels in Hispanic children

    OpenAIRE

    Voruganti, V. Saroja.; Laston, Sandra; Haack, Karin; Mehta, Nitesh R.; Smith, C. Wayne; Cole, Shelley A.; Butte, Nancy F.; Comuzzie, Anthony G.

    2012-01-01

    Obesity is associated with a chronic low inflammatory state characterized by elevated levels of chemokines. Monocyte chemoattractant protein-1 (MCP-1) is a member of the cysteine-cysteine (CC) chemokine family and is increased in obesity. The purpose of this study was to identify loci regulating serum MCP-1 in obese Hispanic children from the Viva La Familia Study. A genome-wide association (GWA) analysis was performed in 815 children, ages 4-19 years, using genotypes assayed with the Illumin...

  16. Human C-C chemokine receptor 3 monoclonal antibody inhibits pulmonary inflammation in allergic mice

    Institute of Scientific and Technical Information of China (English)

    Kai WANG; Hua-hao SHEN; Wen LI; Hua-qiong HUANG

    2007-01-01

    Aim:To evaluate the effect of C-C chemokine receptor 3 (CCR3) blockade on pulmonary inflammation and mucus production in allergic mice. Methods:We used the synthetic peptide of the CCR3 NH2-terminal as the immunizing antigen and generated murine monoclonal antibody against the human CCR3. In addition,the generated antibody was administered to mice sensitized and challenged with ovalbumin. The inflammatory cells in bronchoalveolar lavage,cytokine levels,pulmonary histopathology,and mucus secretion were examined. Results:The Western blotting analysis indicated that the generated antibody bound to CCR3 specifically. The allergic mice treated with the antihuman CCR3 antibody exhibited a significant reduction of pulmonary inflammation accompanied with the alteration of cytokine. Conclusion:The antibody we generated was specific to CCR3. The inhibition of airway inflammation and mucus overproduction by the antibody suggested that the blockade of CCR3 is an appealing therapeutical target for asthma. The present research may provide an experimental basis for the further study of this agent.

  17. Impaired excitability of renal afferent innervation after exposure to the inflammatory chemokine CXCL1.

    Science.gov (United States)

    Ditting, Tilmann; Freisinger, Wolfgang; Rodionova, Kristina; Schatz, Johannes; Lale, Nena; Heinlein, Sonja; Linz, Peter; Ott, Christian; Schmieder, Roland E; Scrogin, Karie E; Veelken, Roland

    2016-03-01

    Recently, we showed that renal afferent neurons exhibit a unique firing pattern, i.e., predominantly sustained firing, upon stimulation. Pathological conditions such as renal inflammation likely alter excitability of renal afferent neurons. Here, we tested whether the proinflammatory chemokine CXCL1 alters the firing pattern of renal afferent neurons. Rat dorsal root ganglion neurons (Th11-L2), retrogradely labeled with dicarbocyanine dye, were incubated with CXCL1 (20 h) or vehicle before patch-clamp recording. The firing pattern of neurons was characterized as tonic, i.e., sustained action potential (AP) firing, or phasic, i.e., renal afferents treated with vehicle, 58.9% exhibited a tonic firing pattern vs. 7.8%, in unlabeled, nonrenal neurons (P renal neurons; hence the occurrence of tonic neurons with sustained firing upon electrical stimulation decreased (35.6 vs. 58.9%, P renal afferents from a predominantly tonic to a more phasic firing pattern, suggesting that CXCL1 reduced the sensitivity of renal afferent units upon stimulation.

  18. Impaired spleen structure and chemokine expression in ME7 scrapie-infected mice.

    Science.gov (United States)

    Kim, Soochan; Han, Sinsuk; Lee, Hyung Soo; Kim, Yong-Sun; Choi, Eun-Kyoung; Kim, Mi-Yeon

    2016-08-01

    We have previously demonstrated that prion protein-deficient (Prnp(0/0)) Zürich I mice display impaired T zone structure resulting from decreased splenic expression of the T cell homing chemokines, CCL19 and CCL21. Prions are transported to, and colonise in, the secondary lymphoid tissues. Therefore, in order to investigate how scrapie infection affects the splenic white pulp structure, we infected C57BL/6 mice with the mouse-adapted scrapie strain ME7 and analysed end-stage prion disease. We found that the white pulp regions of ME7-infected spleens were smaller, and contained markedly diminished T zones, as compared to control spleens. Although lymphoid tissue inducer cells were not affected, the expression of both CCL19 and CCL21 was decreased. In addition, the networks of follicular dendritic cells, which are known to express high levels of the cellular prion protein (PrP(C)) and to accumulate PrP(Sc) following scrapie infection, were larger in ME7-infected spleens. Further, they were associated with increased numbers of B cells expressing high levels of IgM. These data indicate that ME7-infected spleens display phenotype characteristics different from those reported for Prnp(0/0) spleens mainly due to the gain of PrP(Sc) function and suggest that the PrP(C) is required, not only to form the splenic white pulp structure, but also to maintain the intact T zone structure. PMID:27021907

  19. Chemokine receptor Ccr1 drives neutrophil-mediated kidney immunopathology and mortality in invasive candidiasis.

    Directory of Open Access Journals (Sweden)

    Michail S Lionakis

    Full Text Available Invasive candidiasis is the 4(th leading cause of nosocomial bloodstream infection in the US with mortality that exceeds 40% despite administration of antifungal therapy; neutropenia is a major risk factor for poor outcome after invasive candidiasis. In a fatal mouse model of invasive candidiasis that mimics human bloodstream-derived invasive candidiasis, the most highly infected organ is the kidney and neutrophils are the major cellular mediators of host defense; however, factors regulating neutrophil recruitment have not been previously defined. Here we show that mice lacking chemokine receptor Ccr1, which is widely expressed on leukocytes, had selectively impaired accumulation of neutrophils in the kidney limited to the late phase of the time course of the model; surprisingly, this was associated with improved renal function and survival without affecting tissue fungal burden. Consistent with this, neutrophils from wild-type mice in blood and kidney switched from Ccr1(lo to Ccr1(high at late time-points post-infection, when Ccr1 ligands were produced at high levels in the kidney and were chemotactic for kidney neutrophils ex vivo. Further, when a 1∶1 mixture of Ccr1(+/+ and Ccr1(-/- donor neutrophils was adoptively transferred intravenously into Candida-infected Ccr1(+/+ recipient mice, neutrophil trafficking into the kidney was significantly skewed toward Ccr1(+/+ cells. Thus, neutrophil Ccr1 amplifies late renal immunopathology and increases mortality in invasive candidiasis by mediating excessive recruitment of neutrophils from the blood to the target organ.

  20. Chemokine (C-X-C Ligand 12 Facilitates Trafficking of Donor Spermatogonial Stem Cells

    Directory of Open Access Journals (Sweden)

    Zhiyv Niu

    2016-01-01

    Full Text Available The chemokine (C-X-C receptor type 4 (CXCR4 is an early marker of primordial germ cells (PGCs essential for their migration and colonization of the gonads. In spermatogonial stem cells (SSCs, the expression of CXCR4 is promoted by the self-renewal factor, glial cell line-derived neurotrophic factor (GDNF. Here, we demonstrate an important role of CXCR4 during donor mouse SSCs reoccupation of the endogenous niche in recipient testis. Silencing of CXCR4 expression in mouse SSCs dramatically reduced the number of donor stem cell-derived colonies, whereas colony morphology and spermatogenesis were comparable to controls. Inhibition of CXCR4 signaling using a small molecule inhibitor (AMD3100 during the critical window of homing also significantly lowered the efficiency of donor-derived SSCs to establish spermatogenic colonies in recipient mice; however, the self-renewal of SSCs was not affected by exposure to AMD3100. Rather, in vitro migration assays demonstrate the influence of CXCR4-CXCL12 signaling in promoting germ cell migration. Together, these studies suggest that CXCR4-CXCL12 signaling functions to promote homing of SSCs towards the stem cell niche and plays a critical role in reestablishing spermatogenesis.

  1. NKT cells mediate the recruitment of neutrophils by stimulating epithelial chemokine secretion during colitis.

    Science.gov (United States)

    Huang, Enyu; Liu, Ronghua; Lu, Zhou; Liu, Jiajing; Liu, Xiaoming; Zhang, Dan; Chu, Yiwei

    2016-05-27

    Ulcerative colitis (UC) is a kind of inflammatory bowel diseases characterized by chronic inflammation and ulcer in colon, and UC patients have increased risk of getting colorectal cancer. NKT cells are cells that express both NK cell markers and semi-invariant CD1d-restricted TCRs, can regulate immune responses via secreting a variety of cytokines upon activation. In our research, we found that the NKT cell-deficient CD1d(-/-) mice had relieved colitis in the DSS-induced colitis model. Further investigations revealed that the colon of CD1d(-/-) mice expressed less neutrophil-attracting chemokine CXCL 1, 2 and 3, and had decreased neutrophil infiltration. Infiltrated neutrophils also produced less reactive oxygen species (ROS) and TNF-α, indicating they may cause less epithelial damage. In addition, colitis-associated colorectal cancer was also relieved in CD1d(-/-) mice. During colitis, NKT cells strongly expressed TNF-α, which could stimulate CXCL 1, 2, 3 expressions by the epithelium. In conclusion, NKT cells can regulate colitis via the NKT cell-epithelium-neutrophil axis. Targeting this mechanism may help to improve the therapy of UC and prevent colitis-associated colorectal cancer. PMID:27063801

  2. Chemokine receptor Ccr1 drives neutrophil-mediated kidney immunopathology and mortality in invasive candidiasis.

    Science.gov (United States)

    Lionakis, Michail S; Fischer, Brett G; Lim, Jean K; Swamydas, Muthulekha; Wan, Wuzhou; Richard Lee, Chyi-Chia; Cohen, Jeffrey I; Scheinberg, Phillip; Gao, Ji-Liang; Murphy, Philip M

    2012-01-01

    Invasive candidiasis is the 4(th) leading cause of nosocomial bloodstream infection in the US with mortality that exceeds 40% despite administration of antifungal therapy; neutropenia is a major risk factor for poor outcome after invasive candidiasis. In a fatal mouse model of invasive candidiasis that mimics human bloodstream-derived invasive candidiasis, the most highly infected organ is the kidney and neutrophils are the major cellular mediators of host defense; however, factors regulating neutrophil recruitment have not been previously defined. Here we show that mice lacking chemokine receptor Ccr1, which is widely expressed on leukocytes, had selectively impaired accumulation of neutrophils in the kidney limited to the late phase of the time course of the model; surprisingly, this was associated with improved renal function and survival without affecting tissue fungal burden. Consistent with this, neutrophils from wild-type mice in blood and kidney switched from Ccr1(lo) to Ccr1(high) at late time-points post-infection, when Ccr1 ligands were produced at high levels in the kidney and were chemotactic for kidney neutrophils ex vivo. Further, when a 1∶1 mixture of Ccr1(+/+) and Ccr1(-/-) donor neutrophils was adoptively transferred intravenously into Candida-infected Ccr1(+/+) recipient mice, neutrophil trafficking into the kidney was significantly skewed toward Ccr1(+/+) cells. Thus, neutrophil Ccr1 amplifies late renal immunopathology and increases mortality in invasive candidiasis by mediating excessive recruitment of neutrophils from the blood to the target organ.

  3. Chemokine receptor CCR5 antagonist maraviroc: medicinal chemistry and clinical applications.

    Science.gov (United States)

    Xu, Guoyan G; Guo, Jia; Wu, Yuntao

    2014-01-01

    The human immunodeficiency virus (HIV) causes acquired immumodeficiency syndrome (AIDS), one of the worst global pandemic. The virus infects human CD4 T cells and macrophages, and causes CD4 depletion. HIV enters target cells through the binding of the viral envelope glycoprotein to CD4 and the chemokine coreceptor, CXCR4 or CCR5. In particular, the CCR5-utilizing viruses predominate in the blood during the disease course. CCR5 is expressed on the surface of various immune cells including macrophages, monocytes, microglia, dendric cells, and active memory CD4 T cells. In the human population, the CCR5 genomic mutation, CCR5Δ32, is associated with relative resistance to HIV. These findings paved the way for the discovery and development of CCR5 inhibitors to block HIV transmission and replication. Maraviroc, discovered as a CCR5 antagonist, is the only CCR5 inhibitor that has been approved by both US FDA and the European Medicines Agency (EMA) for treating HIV/AIDS patients. In this review, we summarize the medicinal chemistry and clinical studies of Maraviroc.

  4. The Mechanism of Chemokine Receptor 9 Internalization Triggered by Interleukin 2 and Interleukin 4

    Institute of Scientific and Technical Information of China (English)

    Xiaoling Tong; Lijun Zhang; Li Zhang; Meng Hu; Jun Leng; Beibei Yu; Beibei Zhou; Yi Hu; Qiuping Zhang

    2009-01-01

    In previous study, we found that the chemokine receptor 9 (CCR9) was highly expressed on CD4+ T cells from patients with T-cell lineage acute lymphocytic leukemia (T-ALL) and mediated leukemia cell infiltration and metastasis. Combined use of interleukin 2 (IL-2) and IL-4 promoted the internalization of CCR9 and therefore attenuated leukemia cell infiltration and metastasis. In this study, we preliminarily investigated the mechanism of internalization of CCR9 on MOLT4 cell model (a human leukemia T-cell line, naturally expresses CCR9) and found that IL-2 upregulated the cell surface expression of IL-4Rα (CD124) greatly, whereas IL-4 had no significant influence on α (CD25) and β subunits (CD122) of IL-2R. Moreover, specific inhibitors, such as staurosporine, H89 and heparin, inhibited internalization of CCR9, which indicated a role of protein kinase C (PKC) and G protein-coupled kinase 2 (GRK2), respectively. Furthermore, GRK2 was upregulated and translocated to cell membrane in IL-2 and IL-4 treated cells which indicated that PKC could be a prerequisite for GRK2 activity.Cellular & Molecular Immunology. 2009;6(3):181-189.

  5. Human Cytomegalovirus Encoded Homologs of Cytokines, Chemokines and their Receptors: Roles in Immunomodulation

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    Brian P. McSharry

    2012-10-01

    Full Text Available Human cytomegalovirus (HCMV, the largest human herpesvirus, infects a majority of the world’s population. Like all herpesviruses, following primary productive infection, HCMV establishes a life-long latent infection, from which it can reactivate years later to produce new, infectious virus. Despite the presence of a massive and sustained anti-HCMV immune response, productively infected individuals can shed virus for extended periods of time, and once latent infection is established, it is never cleared from the host. It has been proposed that HCMV must therefore encode functions which help to evade immune mediated clearance during productive virus replication and latency. Molecular mimicry is a strategy used by many viruses to subvert and regulate anti-viral immunity and HCMV has hijacked/developed a range of functions that imitate host encoded immunomodulatory proteins. This review will focus on the HCMV encoded homologs of cellular cytokines/chemokines and their receptors, with an emphasis on how these virus encoded homologs may facilitate viral evasion of immune clearance.

  6. Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs.

    Science.gov (United States)

    Pradelli, Emmanuelle; Karimdjee-Soilihi, Babou; Michiels, Jean-François; Ricci, Jean-Ehrland; Millet, Marie-Ange; Vandenbos, Fanny; Sullivan, Timothy J; Collins, Tassie L; Johnson, Michael G; Medina, Julio C; Kleinerman, Eugenie S; Schmid-Alliana, Annie; Schmid-Antomarchi, Heidy

    2009-12-01

    Metastasis continues to be the leading cause of mortality for patients with cancer. Several years ago, it became clear that chemokines and their receptors could control the tumor progress. CXCR3 has now been identified in many cancers including osteosarcoma and CXCR3 ligands were expressed by lungs that are the primary sites to which this tumor metastasize. This study tested the hypothesis that disruption of the CXCR3/CXCR3 ligands complexes could lead to a decrease in lungs metastasis. The experimental design involved the use of the CXCR3 antagonist, AMG487 and 2 murine models of osteosarcoma lung metastases. After tail vein injection of osteosarcoma cells, mice that were systematically treated with AMG487 according to preventive or curative protocols had a significant reduction in metastatic disease. Treatment of osteosarcoma cells in vitro with AMG487 led to decreased migration, decreased matrix metalloproteinase activity, decreased proliferation/survival and increased caspase-independent death. Taken together, our results support the hypothesis that CXCR3 and their ligands intervene in the initial dissemination of the osteosarcoma cells to the lungs and stimulate the growth and expansion of the metastatic foci in later stages. Moreover, these studies indicate that targeting CXCR3 may specifically inhibit tumor metastasis without adversely affecting antitumoral host response. PMID:19544560

  7. Cytokines and Chemokines as Biomarkers of Community-Acquired Bacterial Infection

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    Michal Holub

    2013-01-01

    Full Text Available Routinely used biomarkers of bacterial etiology of infection, such as C-reactive protein and procalcitonin, have limited usefulness for evaluation of infections since their expression is enhanced by a number of different conditions. Therefore, several inflammatory cytokines and chemokines were analyzed with sera from patients hospitalized for moderate bacterial and viral infectious diseases. In total, 57 subjects were enrolled: 21 patients with community-acquired bacterial infections, 26 patients with viral infections, and 10 healthy subjects (control cohorts. The laboratory analyses were performed using Luminex technology, and the following molecules were examined: IL-1Ra, IL-2, IL-4, IL-6, IL-8, TNF-α, INF-γ, MIP-1β, and MCP-1. Bacterial etiology of infection was associated with significantly (P<0.001 elevated serum concentrations of IL-1Ra, IL-2, IL-6, and TNF-α in comparison to levels observed in the sera of patients with viral infections. In the patients with bacterial infections, IL-1Ra and IL-8 demonstrated positive correlation with C-reactive protein, whereas, IL-1Ra, TNF-α, and MCP-1 correlated with procalcitonin. Furthermore, elevated levels of IL-1Ra, IL-6, and TNF-α decreased within 3 days of antibiotic therapy to levels observed in control subjects. The results show IL-1Ra as a potential useful biomarker of community-acquired bacterial infection.

  8. Chemokine-Releasing Nanoparticles for Manipulation of the Lymph Node Microenvironment

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    Taissia G. Popova

    2015-03-01

    Full Text Available Chemokines (CKs secreted by the host cells into surrounding tissue establish concentration gradients directing the migration of leukocytes. We propose an in vivo CK gradient remodeling approach based on sustained release of CKs by the crosslinked poly(N-isopropylacrylamide hydrogel open meshwork nano-particles (NPs containing internal crosslinked dye affinity baits for a reversible CK binding and release. The sustained release is based on a new principle of affinity off-rate tuning. The NPs with Cibacron Blue F3G-A and Reactive Blue-4 baits demonstrated a low-micromolar affinity binding to IL-8, MIP-2, and MCP-1 with a half-life of several hours at 37 °C. The capacity of NPs loaded with IL-8 and MIP-1α to increase neutrophil recruitment to lymph nodes (LNs was tested in mice after footpad injection. Fluorescently-labeled NPs used as tracers indicated the delivery into the sub-capsular compartment of draining LNs. The animals administered the CK-loaded NPs demonstrated a widening of the sub-capsular space and a strong LN influx of leukocytes, while mice injected with control NPs without CKs or bolus doses of soluble CKs alone showed only a marginal neutrophil response. This technology provides a new means to therapeutically direct or restore immune cell traffic, and can also be employed for simultaneous therapy delivery.

  9. Chemokine Receptors, CXCR1 and CXCR2, Differentially Regulate Exosome Release in Hepatocytes.

    Science.gov (United States)

    Nojima, Hiroyuki; Konishi, Takanori; Freeman, Christopher M; Schuster, Rebecca M; Japtok, Lukasz; Kleuser, Burkhard; Edwards, Michael J; Gulbins, Erich; Lentsch, Alex B

    2016-01-01

    Exosomes are small membrane vesicles released by different cell types, including hepatocytes, that play important roles in intercellular communication. We have previously demonstrated that hepatocyte-derived exosomes contain the synthetic machinery to form sphingosine-1-phosphate (S1P) in target hepatocytes resulting in proliferation and liver regeneration after ischemia/reperfusion (I/R) injury. We also demonstrated that the chemokine receptors, CXCR1 and CXCR2, regulate liver recovery and regeneration after I/R injury. In the current study, we sought to determine if the regulatory effects of CXCR1 and CXCR2 on liver recovery and regeneration might occur via altered release of hepatocyte exosomes. We found that hepatocyte release of exosomes was dependent upon CXCR1 and CXCR2. CXCR1-deficient hepatocytes produced fewer exosomes, whereas CXCR2-deficient hepatocytes produced more exosomes compared to their wild-type controls. In CXCR2-deficient hepatocytes, there was increased activity of neutral sphingomyelinase (Nsm) and intracellular ceramide. CXCR1-deficient hepatocytes had no alterations in Nsm activity or ceramide production. Interestingly, exosomes from CXCR1-deficient hepatocytes had no effect on hepatocyte proliferation, due to a lack of neutral ceramidase and sphingosine kinase. The data demonstrate that CXCR1 and CXCR2 regulate hepatocyte exosome release. The mechanism utilized by CXCR1 remains elusive, but CXCR2 appears to modulate Nsm activity and resultant production of ceramide to control exosome release. CXCR1 is required for packaging of enzymes into exosomes that mediate their hepatocyte proliferative effect. PMID:27551720

  10. The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution.

    Science.gov (United States)

    Wang, Gui-Zhen; Cheng, Xin; Zhou, Bo; Wen, Zhe-Sheng; Huang, Yun-Chao; Chen, Hao-Bin; Li, Gao-Feng; Huang, Zhi-Liang; Zhou, Yong-Chun; Feng, Lin; Wei, Ming-Ming; Qu, Li-Wei; Cao, Yi; Zhou, Guang-Biao

    2015-11-13

    More than 90% of lung cancers are caused by cigarette smoke and air pollution, with polycyclic aromatic hydrocarbons (PAHs) as key carcinogens. In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China, attributed to smoky coal combustion-generated PAH pollution. Here, we screened for abnormal inflammatory factors in non-small cell lung cancers (NSCLCs) from Xuanwei and control regions (CR) where smoky coal was not used, and found that a chemokine CXCL13 was overexpressed in 63/70 (90%) of Xuanwei NSCLCs and 44/71 (62%) of smoker and 27/60 (45%) of non-smoker CR patients. CXCL13 overexpression was associated with the region Xuanwei and cigarette smoke. The key carcinogen benzo(a)pyrene (BaP) induced CXCL13 production in lung epithelial cells and in mice prior to development of detectable lung cancer. Deficiency in Cxcl13 or its receptor, Cxcr5, significantly attenuated BaP-induced lung cancer in mice, demonstrating CXCL13's critical role in PAH-induced lung carcinogenesis.

  11. Indoleamine 2, 3-dioxygenase (IDO) is essential for dendritic cell activation and chemotactic responsiveness to chemokines

    Institute of Scientific and Technical Information of China (English)

    Shih Ling HWANG; Nancy Pei-Yee CHUNG; Jacqueline Kwai-Yi CHAN; Chen-Lung Steve LIN

    2005-01-01

    Indoleamine 2, 3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism. In human and murine cells, IDO inhibits antigen-specific T cell proliferation in vitro and suppresses T cell responses to fetal alloantigens during murine pregnancy. In mice, IDO expression is an inducible feature of specific subsets of dendritic cells (DCs),and is important for T cell regulatory properties. However, the effect of IDO and tryptophan deprivation on DC functions remains unknown. We report here that when tryptophan utilization was prevented by a pharmacological inhibitor of IDO, 1-methyl tryptophan (1MT), DC activation induced by pathogenic stimulus lipopolysaccharide (LPS) or inflammatory cytokine TNF-α was inhibited both phenotypically and functionally. Such an effect was less remarkable when DC was stimulated by a physiological stimulus, CD40 ligand. Tryptophan deprivation during DC activation also regulated the expression of CCR5 and CXCR4, as well as DC responsiveness to chemokines. These results suggest that tryptophan usage in the microenvironment is essential for DC maturation, and may also play a role in the regulation of DC migratory behaviors.

  12. Deficiency for the chemokine monocyte chemoattractant protein-1 aggravates tubular damage after renal ischemia/reperfusion injury.

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    Ingrid Stroo

    Full Text Available Temporal expression of chemokines is a crucial factor in the regulation of renal ischemia/reperfusion (I/R injury and repair. Beside their role in the migration and activation of inflammatory cells to sites of injury, chemokines are also involved in other processes such as angiogenesis, development and migration of stem cells. In the present study we investigated the role of the chemokine MCP-1 (monocyte chemoattractant protein-1 or CCL2, the main chemoattractant for monocytes, during renal I/R injury. MCP-1 expression peaks several days after inducing renal I/R injury coinciding with macrophage accumulation. However, MCP-1 deficient mice had a significant decreased survival and increased renal damage within the first two days, i.e. the acute inflammatory response, after renal I/R injury with no evidence of altered macrophage accumulation. Kidneys and primary tubular epithelial cells from MCP-1 deficient mice showed increased apoptosis after ischemia. Taken together, MCP-1 protects the kidney during the acute inflammatory response following renal I/R injury.

  13. CXCL9 contributes to antimicrobial protection of the gut during citrobacter rodentium infection independent of chemokine-receptor signaling.

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    Sarah A Reid-Yu

    2015-02-01

    Full Text Available Chemokines have been shown to be effective bactericidal molecules against a variety of bacteria and fungi in vitro. These direct antimicrobial effects are independent of their chemotactic activities involving immunological receptors. However, the direct biological role that these proteins may play in host defense, particularly against intestinal pathogens, is poorly understood. Here, we show that CXCL9, an ELR- chemokine, exhibits direct antimicrobial activity against Citrobacter rodentium, an attaching/effacing pathogen that infects the gut mucosa. Inhibition of this antimicrobial activity in vivo using anti-CXCL9 antibodies increases host susceptibility to C. rodentium infection with pronounced bacterial penetration into crypts, increased bacterial load, and worsened tissue pathology. Using Rag1(-/- mice and CXCR3(-/- mice, we demonstrate that the role for CXCL9 in protecting the gut mucosa is independent of an adaptive response or its immunological receptor, CXCR3. Finally, we provide evidence that phagocytes function in tandem with NK cells for robust CXCL9 responses to C. rodentium. These findings identify a novel role for the immune cell-derived CXCL9 chemokine in directing a protective antimicrobial response in the intestinal mucosa.

  14. CXCL9 contributes to antimicrobial protection of the gut during citrobacter rodentium infection independent of chemokine-receptor signaling.

    Science.gov (United States)

    Reid-Yu, Sarah A; Tuinema, Brian R; Small, Cherrie N; Xing, Lydia; Coombes, Brian K

    2015-02-01

    Chemokines have been shown to be effective bactericidal molecules against a variety of bacteria and fungi in vitro. These direct antimicrobial effects are independent of their chemotactic activities involving immunological receptors. However, the direct biological role that these proteins may play in host defense, particularly against intestinal pathogens, is poorly understood. Here, we show that CXCL9, an ELR- chemokine, exhibits direct antimicrobial activity against Citrobacter rodentium, an attaching/effacing pathogen that infects the gut mucosa. Inhibition of this antimicrobial activity in vivo using anti-CXCL9 antibodies increases host susceptibility to C. rodentium infection with pronounced bacterial penetration into crypts, increased bacterial load, and worsened tissue pathology. Using Rag1(-/-) mice and CXCR3(-/-) mice, we demonstrate that the role for CXCL9 in protecting the gut mucosa is independent of an adaptive response or its immunological receptor, CXCR3. Finally, we provide evidence that phagocytes function in tandem with NK cells for robust CXCL9 responses to C. rodentium. These findings identify a novel role for the immune cell-derived CXCL9 chemokine in directing a protective antimicrobial response in the intestinal mucosa.

  15. The chemokine (C-C motif) ligand protein synthesis inhibitor bindarit prevents cytoskeletal rearrangement and contraction of human mesangial cells.

    Science.gov (United States)

    Paccosi, Sara; Giachi, Matelda; Di Gennaro, Paola; Guglielmotti, Angelo; Parenti, Astrid

    2016-09-01

    Intraglomerular mesangial cells (MCs) maintain structural and functional integrity of renal glomerular microcirculation and homeostasis of mesangial matrix. Following different types of injury, MCs change their phenotype upregulating the expression of α-smooth muscle actin (α-SMA), changing contractile abilities and increasing the production of matrix proteins, chemokines and cytokines. CCL2 is a chemokine known to be involved in the pathogenesis of renal diseases. Its glomerular upregulation correlates with the extent of renal damage. Bindarit is an indazolic derivative endowed with anti-inflammatory activity when tested in experimental diseases. It selectively inhibits the synthesis of inflammatory C-C chemokines including CCL2, CCL7 and CCL8. This work aims to analyse bindarit effects on ET1-, AngII- and TGFβ-induced mesangial cell dysfunction. Bindarit significantly reduced AngII-, ET1- and TGFβ-induced α-SMA upregulation. In a collagen contraction assay, bindarit reduced AngII-, ET1- and TGFβ-induced HRMC contraction. Within 3-6h stimulation, vinculin organization and phosphorylation was significantly impaired by bindarit in AngII-, ET1- and TGFβ-stimulated cells without any effect on F-actin distribution. Conversely, p38 phosphorylation was not significantly inhibited by bindarit. Our data strengthen the importance of CCL2 on ET-1, AngII- and TGFβ-induced mesangial cell dysfunction, adding new insights into the cellular mechanisms responsible of bindarit protective effects in human MC dysfunction. PMID:27309675

  16. Generalized Lévy walks and the role of chemokines in migration of effector CD8+ T cells.

    Science.gov (United States)

    Harris, Tajie H; Banigan, Edward J; Christian, David A; Konradt, Christoph; Tait Wojno, Elia D; Norose, Kazumi; Wilson, Emma H; John, Beena; Weninger, Wolfgang; Luster, Andrew D; Liu, Andrea J; Hunter, Christopher A

    2012-06-28

    Chemokines have a central role in regulating processes essential to the immune function of T cells, such as their migration within lymphoid tissues and targeting of pathogens in sites of inflammation. Here we track T cells using multi-photon microscopy to demonstrate that the chemokine CXCL10 enhances the ability of CD8+ T cells to control the pathogen Toxoplasma gondii in the brains of chronically infected mice. This chemokine boosts T-cell function in two different ways: it maintains the effector T-cell population in the brain and speeds up the average migration speed without changing the nature of the walk statistics. Notably, these statistics are not Brownian; rather, CD8+ T-cell motility in the brain is well described by a generalized Lévy walk. According to our model, this unexpected feature enables T cells to find rare targets with more than an order of magnitude more efficiency than Brownian random walkers. Thus, CD8+ T-cell behaviour is similar to Lévy strategies reported in organisms ranging from mussels to marine predators and monkeys, and CXCL10 aids T cells in shortening the average time taken to find rare targets.

  17. Universal expression and dual function of the atypical chemokine receptor D6 on innate-like B cells in mice

    Science.gov (United States)

    Hansell, Chris A. H.; Schiering, Chris; Kinstrie, Ross; Ford, Laura; Bordon, Yvonne; McInnes, Iain B.; Goodyear, Carl S.; Nibbs, Robert J. B.

    2011-01-01

    Mouse innate-like B cells are a heterogeneous collection of multifunctional cells that control infection, play housekeeping roles, contribute to adaptive immunity, and suppress inflammation. We show that, amongst leukocytes, chemokine internalisation by the D6 receptor is a unique and universal feature of all known innate-like B cell populations and, to our knowledge, the most effective unifying marker of these cells. Moreover, we identify novel D6active B1 cell subsets, including those we term B1d, which lack CD5 and CD11b but exhibit typical B1 cell properties, including spontaneous ex vivo production of IgM, interleukin-10, and anti-phosphorylcholine antibody. The unprecedented opportunity to examine D6 on primary cells has allowed us to clarify its ligand specificity and show that, consistent with a scavenging role, D6 internalises chemokines but cannot induce Ca2+ fluxes or chemotaxis. Unexpectedly, however, D6 can also suppress the function of CXCR5, a critical chemokine receptor in innate-like B cell biology. This is associated with a reduction in B1 cells and circulating class-switched anti-phosphorylcholine antibody in D6-deficient mice. Thus, we identify a unifying marker of innate-like B cells; describe novel B1 cell subsets; reveal a dual role for D6; and provide the first evidence of defects in resting D6-deficient mice. PMID:21450903

  18. Triptolide suppresses IL-1β-induced chemokine and stromelysin-1 gene expression in human colonic subepithelial myofibroblasts

    Institute of Scientific and Technical Information of China (English)

    Qing-song TAO; Jian-an REN; Jie-shou LI

    2007-01-01

    Aim: To examine the inhibitive effects of triptolide on the expression of IL-8, monocyte chemotactic protein (MCP)-1, and matrix metalloproteinases (MMP)-3 in subepithelial myofibroblasts (SEMF) stimulated with IL-1β. Methods: SEMF cultures were established from normal colons in patients who underwent gut resection for colorectal carcinoma. Chemokine and MMP-3 expressions were determined by ELISA and RT-PCR. The cytosolic amount of phosphorylation of IκB-α (p-IκB-α) was determined by Western blotting. The DNA binding capacity of NF-κB was evaluated by electrophoretic mobility shift assays. Results: IL-1βstimulated protein and mRNA expression of IL-8, MCP-1, and MMP-3 in SEMF,Triptolide inhibited these effects of IL-1β in a dose-dependent manner. Mecha-nistic studies revealed that triptolide markedly decreased IL-1β-induced NF- κB DNA binding capacity and cytosolic amount of p-IκB-α. These results showed that triptolide inhibited IL-1β-induced chemokine and MMP-3 expression in SEMF through the NF-κB pathway. Conclusion: Triptolide inhibited IL-1β-induced chemokine and MMP-3 expression in SEMF by preventing the phosphorylation of IκB-α.

  19. Circulating cytokines and chemokines associated with plasma leakage and hepatic dysfunction in Brazilian children with dengue fever.

    Science.gov (United States)

    Ferreira, Ralph Antonio Xavier; de Oliveira, Solange Artimos; Gandini, Mariana; Ferreira, Laura da Cunha; Correa, Gladys; Abiraude, Fernanda Mattos; Reid, Mariana Mancebo; Cruz, Oswaldo Gonçalves; Kubelka, Claire Fernandes

    2015-09-01

    Dengue fever is usually a benign acute viral infection transmitted by arthropods but may evolve to severe clinical manifestations such as coagulation and/or hemodynamic disorders, caused mainly by an increase of vascular permeability. Deregulated circulating immunological factors have been associated with severity. In Brazil severe cases appeared in children only recently and we evaluated the profile of cytokine/chemokine kinetics in 134 hospitalized young patients during the epidemic in Rio de Janeiro in 2008. Inflammatory cytokines TNF and IFNγ were found elevated during the acute phase in children as well as the anti-inflammatory IL10 and chemokines MIF and CXCL10/IP10, all last three persisting longer during the recovery phase. Severe disease fitting the dengue hemorrhagic fever pattern (WHO, 1997) was associated with higher IL10 and CXCL10/IP10 circulating levels (peak levels at seven days with Phistory of prior infection (93%). This is the first study demonstrating cytokine and chemokine association with severity during dengue fever in Brazilian children. IL10 and CXCL10/IP10 play a role in the disease severity associated with induction of vascular leakage and a novel association with changes in liver dysfunction. PMID:25944351

  20. Chemokine binding protein M3 of murine gammaherpesvirus 68 modulates the host response to infection in a natural host.

    Directory of Open Access Journals (Sweden)

    David J Hughes

    2011-03-01

    Full Text Available Murine γ-herpesvirus 68 (MHV-68 infection of Mus musculus-derived strains of mice is an attractive model of γ-herpesvirus infection. Surprisingly, however, ablation of expression of MHV-68 M3, a secreted protein with broad chemokine-binding properties in vitro, has no discernable effect during experimental infection via the respiratory tract. Here we demonstrate that M3 indeed contributes significantly to MHV-68 infection, but only in the context of a natural host, the wood mouse (Apodemus sylvaticus. Specifically, M3 was essential for two features unique to the wood mouse: virus-dependent inducible bronchus-associated lymphoid tissue (iBALT in the lung and highly organized secondary follicles in the spleen, both predominant sites of latency in these organs. Consequently, lack of M3 resulted in substantially reduced latency in the spleen and lung. In the absence of M3, splenic germinal centers appeared as previously described for MHV-68-infected laboratory strains of mice, further evidence that M3 is not fully functional in the established model host. Finally, analyses of M3's influence on chemokine and cytokine levels within the lungs of infected wood mice were consistent with the known chemokine-binding profile of M3, and revealed additional influences that provide further insight into its role in MHV-68 biology.

  1. ELR chemokine signaling in host defense and disease in a viral model of central nervous system disease

    Directory of Open Access Journals (Sweden)

    Martin P Hosking

    2014-06-01

    Full Text Available Intracranial infection of the neurotropic JHM strain of mouse hepatitis virus (JHMV into the central nervous system (CNS of susceptible strains of mice results in an acute encephalomyelitis, accompanied by viral replication in glial cells and robust infiltration of virus-specific T cells that contribute to host defense through cytokine secretion and cytolytic activity. Mice that survive the acute stage of disease develop an immune-mediated demyelinating diseases characterized by viral persistence in white matter tracts and a chronic neuroinflammatory response dominated by T cells and macrophages. Early following JHMV infection, there is a dynamic expression of chemokines and chemokine receptors that contribute to neuroinflammation by regulating innate and adaptive immune responses as well influencing glial biology. In response to JHMV infection, we have shown that signaling through the chemokine receptor CXCR2 contributes to host defense through recruitment of polymorphonuclear cells (PMNs to the CNS that enhance permeability of the blood-brain-barrier (BBB and facilitating entry of virus-specific T cells into the parenchyma. Further, CXCR2 promotes the protection of oligodendroglia from cytokine-induced apoptosis and restricts the severity of demyelination. This review covers aspects related to the role of CXCR2 in host defense and disease in response to JHMV infection.

  2. Antitumor immunity by a dendritic cell vaccine encoding secondary lymphoid chemokine and tumor lysate on murine prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Jun Lu; Qi Zhang; Chun-Min Liang; Shu-Jie Xia; Cui-Ping Zhong; Da-Wei Wang

    2008-01-01

    Aim: To investigate the antitumor immunity by a dendritic cell (DC) vaccine encoding secondary lymphoid chemokine gene and tumor lysate on murine prostate cancer. Methods: DC from bone marrow of C57BL/6 were transfected with a plasmid vector expressing secondary lymphoid chemokine (SLC) cDNA by Lipofectamine2000 liposome and tumor lysate. Total RNA extracted from SLC+lysate-DC was used to verify the expression of SLC by reverse transcriptase-polymerase chain reaction (RT-PCR). The immunotherapeutic effect of DC vaccine on murine prostate cancer was assessed. Results: We found that in the prostate tumor model of C57BL/6 mice, the adminstration of SLC+lysate-DC inhibited tumor growth most significantly when compared with SLC-DC, lysate-DC, DC or phos-phate buffer solution (PBS) counterparts (P<0.01). Immunohistochemical fluorescent staining analysis showed the infiltration of more CD4+, CD8+ T cell and CD11c+ DC within established tumor treated by SLC+lysate-DC vaccine than other DC vaccines (P<0.01). Conclusion: DC vaccine encoding secondary lymphoid chemokine and tumor lysate can elicit significant antitumor immunity by infiltration of CD4+, CD8+ T cell and DC, which might provide a potential immunotherapy method for prostate cancer.

  3. An anti-inflammatory oligopeptide produced by Entamoeba histolytica down-regulates the expression of pro-inflammatory chemokines.

    Science.gov (United States)

    Utrera-Barillas, Dolores; Velazquez, Juan R; Enciso, Antonio; Cruz, Samira Muñoz; Rico, Guadalupe; Curiel-Quesada, Everardo; Teran, Luis M; Kretschmer, Roberto R

    2003-10-01

    Axenically grown Entamoeba histolytica produces a pentapeptide (Met-Gln-Cys-Asn-Ser) with anti-inflammatory properties that, among others, inhibits the in vitro and in vivo locomotion of human monocytes, sparing polymorphonuclear leucocytes from this effect [hence the name originally given. Monocyte Locomotion Inhibitory Factor (MLIF)]. A synthetic construct of this peptide displays the same effects as the native material. We now added MLIF to resting and PMA-stimulated cells of a human monocyte cell line and measured the effect upon mRNA and protein expression of pro-inflammatory chemokines (RANTES, IP-10, MIP-1alpha, MIP-1beta, MCP-1, IL-8, I-309 and lymphotactin) and the shared CC receptor repertoire. The constitutive expression of these chemokines and the CC receptors was unaffected, whereas induced expression of MIP-1alpha, MIP-1beta, and I-309, and that of the CCR1 receptor--all involved in monocyte chemotaxis--was significantly inhibited by MLIF. This suggests that the inhibition of monocyte functions by MLIF may not only be exerted directly on these cells, but also--and perhaps foremost--through a conglomerate down-regulation of endogenous pro-inflammatory chemokines.

  4. Aspartate-Based CXCR4 Chemokine Receptor Binding of Cross-Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes.

    Science.gov (United States)

    Maples, Randall D; Cain, Amy N; Burke, Benjamin P; Silversides, Jon D; Mewis, Ryan E; D'huys, Thomas; Schols, Dominique; Linder, Douglas P; Archibald, Stephen J; Hubin, Timothy J

    2016-08-26

    The CXCR4 chemokine receptor is implicated in a number of diseases including HIV infection and cancer development and metastasis. Previous studies have demonstrated that configurationally restricted bis-tetraazamacrocyclic metal complexes are high-affinity CXCR4 antagonists. Here, we present the synthesis of Cu(2+) and Zn(2+) acetate complexes of six cross-bridged tetraazamacrocycles to mimic their coordination interaction with the aspartate side chains known to bind them to CXCR4. X-ray crystal structures for three new Cu(2+) acetate complexes and two new Zn(2+) acetate complexes demonstrate metal-ion-dependent differences in the mode of binding the acetate ligand concomitantly with the requisite cis-V-configured cross-bridged tetraazamacrocyle. Concurrent density functional theory molecular modelling studies produced an energetic rationale for the unexpected [Zn(OAc)(H2 O)](+) coordination motif present in all of the Zn(2+) cross-bridged tetraazamacrocycle crystal structures, which differs from the chelating acetate [Zn(OAc)](+) structures of known unbridged and side-bridged tetraazamacrocyclic Zn(2+) -containing CXCR4 antagonists. PMID:27458983

  5. The constitutive activation of the CEF-4/9E3 chemokine gene depends on C/EBPbeta in v-src transformed chicken embryo fibroblasts

    DEFF Research Database (Denmark)

    Gagliardi, M; Maynard, S; Bojovic, B;

    2001-01-01

    The CEF-4/9E3 chemokine gene is expressed constitutively in chicken embryo fibroblasts (CEF) transformed by the Rous sarcoma virus (RSV). This aberrant induction is controlled at the transcriptional and post-transcriptional levels. Transcriptional activation depends on multiple elements of the CEF......-4 promoter composing a Src-responsive-Unit or SRU. The SRU includes a TPA responsive element, a PRDII/kappaB domain and a CAAT box. In this report, we identify C/EBPbeta as a component of the trans-acting factor interacting with the CAAT box of the CEF-4 promoter. In addition, we show that C....../EBPbeta (designated Delta184-C/EBPbeta) in RSV-transformed CEF. Delta184-C/EBPbeta decreased the accumulation of the CEF-4 mRNA and activation of the CEF-4 promoter by pp60(v-src). The induction of the Cox-2 gene (CEF-147) was also reduced by Delta184-C/EBPbeta. The effect of the dominant negative mutant was observed...

  6. Tunable chemokine production by antigen presenting dendritic cells in response to changes in regulatory T cell frequency in mouse reactive lymph nodes.

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    Valentina Dal Secco

    Full Text Available BACKGROUND: Although evidence exists that regulatory T cells (Tregs can suppress the effector phase of immune responses, it is clear that their major role is in suppressing T cell priming in secondary lymphoid organs. Recent experiments using two photon laser microscopy indicate that dendritic cells (DCs are central to Treg cell function and that the in vivo mechanisms of T cell regulation are more complex than those described in vitro. PRINCIPAL FINDINGS: Here we have sought to determine whether and how modulation of Treg numbers modifies the lymph node (LN microenvironment. We found that pro-inflammatory chemokines -- CCL2 (MCP-1 and CCL3 (MIP-la -- are secreted in the LN early (24 h after T cell activation, that this secretion is dependent on antigen-specific DC-T cell interactions, and that it was inversely related to the frequency of Tregs specific for the same antigen. Furthermore, we demonstrate that Tregs modify the chemoattractant properties of antigen-presenting DCs, which, as the frequency of Tregs increases, fail to produce CCL2 and CCL3 and to attract antigen-specific T cells. CONCLUSIONS: These results substantiate a major role of Tregs in LN patterning during antigen-specific immune responses.

  7. The Viral G Protein-Coupled Receptor ORF74 Hijacks β-Arrestins for Endocytic Trafficking in Response to Human Chemokines.

    Science.gov (United States)

    de Munnik, Sabrina M; Kooistra, Albert J; van Offenbeek, Jody; Nijmeijer, Saskia; de Graaf, Chris; Smit, Martine J; Leurs, Rob; Vischer, Henry F

    2015-01-01

    Kaposi's sarcoma-associated herpesvirus-infected cells express the virally encoded G protein-coupled receptor ORF74. Although ORF74 is constitutively active, it binds human CXC chemokines that modulate this basal activity. ORF74-induced signaling has been demonstrated to underlie the development of the angioproliferative tumor Kaposi's sarcoma. Whereas G protein-dependent signaling of ORF74 has been the subject of several studies, the interaction of this viral GPCR with β-arrestins has hitherto not been investigated. Bioluminescence resonance energy transfer experiments demonstrate that ORF74 recruits β-arrestins and subsequently internalizes in response to human CXCL1 and CXCL8, but not CXCL10. Internalized ORF74 traffics via early endosomes to recycling and late endosomes. Site-directed mutagenesis and homology modeling identified four serine and threonine residues at the distal end of the intracellular carboxyl-terminal of ORF74 that are required for β-arrestin recruitment and subsequent endocytic trafficking. Hijacking of the human endocytic trafficking machinery is a previously unrecognized action of ORF74.

  8. HIV-1 Nef down-modulates C-C and C-X-C chemokine receptors via ubiquitin and ubiquitin-independent mechanism.

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    Prabha Chandrasekaran

    Full Text Available Human and Simian Immunodeficiency virus (HIV-1, HIV-2, and SIV encode an accessory protein, Nef, which is a pathogenesis and virulence factor. Nef is a multivalent adapter that dysregulates the trafficking of many immune cell receptors, including chemokine receptors (CKRs. Physiological endocytic itinerary of agonist occupied CXCR4 involves ubiquitinylation of the phosphorylated receptor at three critical lysine residues and dynamin-dependent trafficking through the ESCRT pathway into lysosomes for degradation. Likewise, Nef induced CXCR4 degradation was critically dependent on the three lysines in the C-terminal -SSLKILSKGK- motif. Nef directly recruits the HECT domain E3 ligases AIP4 or NEDD4 to CXCR4 in the resting state. This mechanism was confirmed by ternary interactions of Nef, CXCR4 and AIP4 or NEDD4; by reversal of Nef effect by expression of catalytically inactive AIP4-C830A mutant; and siRNA knockdown of AIP4, NEDD4 or some ESCRT-0 adapters. However, ubiquitinylation dependent lysosomal degradation was not the only mechanism by which Nef downregulated CKRs. Agonist and Nef mediated CXCR2 (and CXCR1 degradation was ubiquitinylation independent. Nef also profoundly downregulated the naturally truncated CXCR4 associated with WHIM syndrome and engineered variants of CXCR4 that resist CXCL12 induced internalization via an ubiquitinylation independent mechanism.

  9. The Role of Chemokines in Shaping the Balance Between CD4(+) T Cell Subsets and Its Therapeutic Implications in Autoimmune and Cancer Diseases.

    Science.gov (United States)

    Karin, Nathan; Wildbaum, Gizi

    2015-01-01

    Chemokines are the key activators of adhesion molecule and also drivers of leukocyte migration to inflammatory sites and are therefore mostly considered as proinflammatory mediators. Many studies, including ours, imply that targeting the function of several key chemokines, but not many others, could effectively suppress inflammatory responses and inflammatory autoimmunity. Along with this, a single chemokine named CXCL10 could be used to induce antitumor immunity, and thereby suppress myeloma. Our working hypothesis is that some chemokines differ from others as aside from being chemoattractants for leukocytes and effective activators of adhesion receptors that possess additional biological properties making them "driver chemokines." We came up with this notion when studying the interlay between CXCR4 and CXCL12 and between CXCR3 and its three ligands: CXCL9, CXCL10, and CXCL11. The current mini-review focuses on these ligands and their biological properties. First, we elaborate the role of cytokines in directing the polarization of effector and regulatory T cell subset and the plasticity of this process. Then, we extend this notion to chemokines while focusing on CXCL 12 and the CXCR3 ligands. Finally, we elaborate the potential clinical implications of these studies for therapy of autoimmunity, graft-versus-host disease, and cancer. PMID:26648938

  10. Cytokine & chemokine response in the lungs, pleural fluid and serum in thoracic surgery using one-lung ventilation

    Directory of Open Access Journals (Sweden)

    Breunig Andreas

    2011-11-01

    Full Text Available Abstract Background Thoracic surgery mandates usually a one-lung ventilation (OLV strategy with the collapse of the operated lung and ventilation of the non-operated lung. These procedures trigger a substantial inflammatory response. The aim of this study was to analyze the cytokine and chemokine reaction in both lungs, pleural space and blood in patients undergoing lung resection with OLV with special interest in the chemokine growth-regulated peptide alpha (GROα which is the human equivalent to the rat cytokine-induced neutrophil chemoattractant-1 (CINC-1. Methods Broncho-alveolar lavage (BAL fluid of both the collapsed, operated and the ventilated, non-operated lung, respectively, pleural space drainage fluid and blood was collected and the concentrations of interleukin (IL-6, IL-1RA and GROα were determined with enzyme-linked immunosorbent assays in 15 patients. Results Substantial inter-individual differences in the BAL fluid between patients in cytokine and chemokine levels occurred. In the pleural fluid and the blood these inter-individual differences were less pronounced. Both sides of the lung were affected and showed a significant increase in IL-6 and IL-1RA concentrations over time but not in GROα concentrations. Except for IL-6, which increased more in the collapsed, operated lung, no difference between the collapsed, operated and the ventilated, non-operated lung occurred. In the blood, IL-6 and IL-1RA increased early, already at the end of surgery. GROα was not detectable. In the pleural fluid, both cytokine and chemokine concentrations increased by day one. The increase was significantly higher in the pleural fluid compared to the blood. Conclusion The inflammatory response of cytokines affects both the collapsed, operated and the ventilated, non-operated lungs. The difference in extent of response underlines the complexity of the inflammatory processes during OLV. In contrast to the cytokines, the chemokine GRO

  11. Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1{alpha}, suppress amyloid {beta}-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Raman, Dayanidhi; Milatovic, Snjezana-Zaja [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Milatovic, Dejan [Department of Pediatrics/Pediatric Toxicology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Splittgerber, Ryan [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Fan, Guo-Huang [Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37221 (United States); Richmond, Ann, E-mail: ann.richmond@vanderbilt.edu [VA Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States)

    2011-11-15

    Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-{beta} (A{beta}). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1{alpha} (SDF-1{alpha}), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress A{beta}-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1{alpha} significantly protected neurons from A{beta}-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1{alpha}. Intra-cerebroventricular (ICV) injection of A{beta} led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The A{beta}-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1{alpha}. Additionally, MIP-2 or SDF-1{alpha} was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against A{beta} neurotoxicity in CXCR2-/- mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. -- Research highlights: Black-Right-Pointing-Pointer Neuroprotective ability of the chemokines MIP2 and CXCL12 against A{beta} toxicity. Black-Right-Pointing-Pointer MIP

  12. C-C chemokine receptor-7 mediated endocytosis of antibody cargoes into intact cells

    Directory of Open Access Journals (Sweden)

    Xavier eCharest-Morin

    2013-09-01

    Full Text Available The C-C chemokine receptor-7 (CCR7 is a G protein coupled receptor that has a role in leukocyte homing, but that is also expressed in aggressive tumor cells. Preclinical research supports that CCR7 is a valid target in oncology. In view of the increasing availability of therapeutic monoclonal antibodies that carry cytotoxic cargoes, we studied the feasibility of forcing intact cells to internalize known monoclonal antibodies by exploiting the cycle of endocytosis and recycling triggered by the CCR7 agonist CCL19. Firstly, an anti-CCR7 antibody (CD197; clone 150503 labeled surface recombinant CCR7 expressed in intact HEK 293a cells and the fluorescent antibody was internalized following CCL19 treatment. Secondly, a recombinant myc-tagged CCL19 construction was exploited along the anti-myc monoclonal antibody 4A6. The myc-tagged ligand was produced as a conditioned medium of transfected HEK 293a cells that contained the equivalent of 430 ng/ml of immunoreactive CCL19 (average value, ELISA determination. CCL19-myc, but not authentic CCL19, carried the fluorophore-labeled antibody 4A6 into other recipient cells that expressed recombinant CCR7 (microscopy, cytofluorometry. The immune complexes were apparent in endosomal structures, colocalized well with the small GTPase Rab5 and progressed toward Rab7-positive endosomes. A dominant negative form of Rab5 (GDP-locked inhibited this endocytosis. Further, endosomes in CCL19-myc- or CCL19-stimulated cells were positive for β-arrestin2, but rarely for β-arrestin1. Following treatment with CCL19-myc and the 4A6 antibody, the melanoma cell line A375 that expresses endogenous CCR7 was specifically stained using a secondary peroxidase-conjugated antibody. Agonist-stimulated CCR7 can transport antibody-based cargoes, with possible therapeutic applications in oncology.

  13. CXC CHEMOKINE RECEPTOR 3 MODULATES BLEOMYCIN-INDUCED PULMONARY INJURY VIA INVOLVING INFLAMMATORY PROCESS

    Institute of Scientific and Technical Information of China (English)

    Jin-ming Gao; Bao Lu; Zi-jian Guo

    2006-01-01

    Objective To investigate the role of CXC chemokine receptor 3(CXCR3 ) in bleomycin-induced lung injury by using CXCR3 gene deficient mice.Methods Sex-, age-, and weight-matched C57BL/6 CXCR3 gene knockout mice and C57BL/6 wide type mice were challenged by injection of bleomycin via trachea. Lung tissue was stained with HE method. Airway resistance was measured. Bronchoalveolar lavage (BAL) was performed using phosphate buffered saline twice, cell number and differentials were counted by Diff-Qnick staining. Interleukin(IL)-4, IL-5, IL-12p40, and interfon-γ in BAL fluid and lung homogenate were measured by enzyme-linked immunosorbent assay. Unpaired t test was explored to compare the difference between two groups.Results On day 7 after bleomycin injection via trachea, CXCR3 knockout mice were protected from bleomycininduced lung injury as evidenced by fewer accumulation of inflammatory cells in the airway and lung interstitium compared with their wild type littermates ( P<0.05 ). Airway resistance was also lower in CXCR3 knockout mice compared with wild type mice (P<0.01 ). Significantly lower level of inflammatory cytokines release, including the altered production of IL-4 and IL-5 both in BAL fluid and lung tissue was seen in CXCR3 knockout mice than in wild type mice (both P<0.05).Conclusion CXCR3 signaling promotes inflammatory cells recruiting and initiates inflammatory cytokines cascade following endotracheal bleomycin administration, indicating that CXCR3 might be a therapeutic target for pulmonary injury.

  14. Serum thymus and activation-regulated chemokine as disease activity and response biomarker in alopecia areata.

    Science.gov (United States)

    Inui, Shigeki; Noguchi, Fumihito; Nakajima, Takeshi; Itami, Satoshi

    2013-11-01

    Serum thymus and activation-regulated chemokine/CCL17 (sTARC) is known as a good indicator for atopic dermatitis severity. Herein, we investigate whether sTARC correlates with severity and therapeutic response for alopecia areata (AA) in our 121 patients. The sTARC mean of AA totalis and universalis was significantly higher than mild AA. Next, we compared sTARC of diffuse AA (n = 14) and severity-controlled patchy AA (n = 32) and found that sTARC in diffuse AA (564.2 ± 400.0 pg/mL) was significantly higher than that of the patchy type (344.0 ± 239.8 pg/mL), suggesting a potential role of TARC in active progression of diffuse AA. Ten patients with diffuse AA were treated with i.v. corticosteroid pulse therapy. Then, we tested whether sTARC can predict prognosis after the pulse therapy and found that baseline sTARC in the poor responders (1025.5 ± 484.8 pg/mL) was significantly higher than that in the good responders (complete remission at 24 months after the pulse therapy, 347.8 ± 135.7 pg/mL), indicating sTARC as a response biomarker in the corticosteroid pulse therapy for diffuse AA. Finally, to investigate TARC production in the affected hair follicles, we performed immunohistochemical double staining of TARC and CD68 using scalp skin specimens of diffuse AA with high titers of sTARC. The results showed their co-localization in the infiltrating cells around the AA hair follicles, suggesting that TARC is mainly produced from CD68(+) histiocytes. In conclusion, sTARC is a disease activity and response biomarker in AA, providing new insight beyond the T-helper 1/2 paradigm to solve the immunological pathogenesis of AA.

  15. Non-canonical NFκB activation promotes chemokine expression in podocytes

    Science.gov (United States)

    Valiño-Rivas, Lara; Gonzalez-Lafuente, Laura; Sanz, Ana B.; Ruiz-Ortega, Marta; Ortiz, Alberto; Sanchez-Niño, Maria D.

    2016-01-01

    TNF-like weak inducer of apoptosis (TWEAK) receptor Fn14 is expressed by podocytes and Fn14 deficiency protects from experimental proteinuric kidney disease. However, the downstream effectors of TWEAK/Fn14 in podocytes are poorly characterized. We have explored TWEAK activation of non-canonical NFκB signaling in cultured podocytes. In cultured podocytes, TWEAK increased the expression of the chemokines CCL21, CCL19 and RANTES in a time-dependent manner. The inhibitor of canonical NFκB activation parthenolide inhibited the CCL19 and the early RANTES responses, but not the CCL21 or late RANTES responses. In this regard, TWEAK induced non-canonical NFκB activation in podocytes, characterized by NFκB2/p100 processing to NFκB2/p52 and nuclear migration of RelB/p52. Silencing by a specific siRNA of NIK, the upstream kinase of the non-canonical NFκB pathway, prevented CCL21 upregulation but did not modulate CCL19 or RANTES expression in response to TWEAK, thus establishing CCL21 as a non-canonical NFκB target in podocytes. Increased kidney Fn14 and CCL21 expression was also observed in rat proteinuric kidney disease induced by puromycin, and was localized to podocytes. In conclusion, TWEAK activates the non-canonical NFκB pathway in podocytes, leading to upregulation of CCL21 expression. The non-canonical NFκB pathway should be explored as a potential therapeutic target in proteinuric kidney disease. PMID:27353019

  16. Elevated expression of CC Chemokine ligand 23 in eosinophilic chronic rhinosinusitis with nasal polyps

    Science.gov (United States)

    Poposki, Julie A.; Uzzaman, Ashraf; Nagarkar, Deepti R.; Chustz, Regina T.; Peters, Anju T.; Suh, Lydia A.; Carter, Roderick; Norton, James; Harris, Kathleen E.; Grammer, Leslie C.; Tan, Bruce K.; Chandra, Rakesh K.; Conley, David B.; Kern, Robert C.; Schleimer, Robert P.; Kato, Atsushi

    2011-01-01

    Background Chronic rhinosinusitis (CRS) is a heterogeneous chronic disease characterized by local inflammation of the sinonasal tissues. The pathogenesis of CRS remains controversial but it has been associated with the accumulation of various immune and inflammatory cells in sinus tissue. Objectives The objective of this study was to investigate the expression of chemokine CCL23, known to bind to CCR1 and recruit monocytes, macrophages, and dendritic cells, in patients with CRS. Methods We collected nasal tissue from patients with CRS and control subjects. We assayed mRNA for CCL23 by using real-time PCR and measured CCL23 protein by ELISA, immunohistochemistry and immunofluorescence. Results CCL23 mRNA was significantly elevated in nasal polyps from patients with polypoid CRS (CRSwNP) (p<0.05) compared to inferior turbinate and uncinate tissue from patients with CRS or control subjects. CCL23 protein was also elevated in nasal polyps, although these levels were not statistically significant. Immunohistochemical analysis revealed CCL23 expression in mucosal epithelial cells and inflammatory cells, but accumulation of CCL23 positive inflammatory cells occurred only in nasal polyps. Immunofluorescence data showed CCL23 co-localization with ECP positive eosinophils. The concentration of CCL23 in nasal polyps positively correlated with the concentration of ECP, suggesting that eosinophils are major CCL23 producing cells in nasal polyps. Finally, we found that CCL23 protein was significantly elevated in nasal polyps from patients with CRSwNP with aspirin sensitivity. Conclusion Overproduction of CCL23 in nasal polyps may contribute to the pathogenesis of eosinophilic CRSwNP via the recruitment of CCR1 positive inflammatory cells including monocytes and macrophages, and the amplification of local inflammation. PMID:21497884

  17. Bridged cyclams as imaging agents for chemokine receptor 4 (CXCR4)

    International Nuclear Information System (INIS)

    Over-expression of chemokine receptor 4 (CXCR4) is present in a majority of cancers, has been linked to an aggressive phenotype, and may indicate the metastatic potential of primary tumor. Several CXCR4 targeted therapeutics are in clinical trials and the development of the corresponding imaging agents is an area of active interest. Previously, 64Cu-labeled imaging agents for CXCR4 have provided clear images of CXCR4-bearing tissues in relevant experimental models but demonstrated fast washout from tissues harboring receptor. Addition of stabilizing bridges is known to provide more robust chelator-Cu(II) complexes. In addition, bridged cyclam-based CXCR4 binding agents demonstrated increased receptor residence times relative to existing agents. Based on that knowledge we synthesized several bridged cyclam analogs of AMD3465, a monocyclam-based CXCR4 imaging agent, to increase the retention time of the tracer bound to the receptor to allow for protracted imaging and improved target-to-non-target ratios. Specific accumulation of two radiolabeled, cross-bridged analogs ([64Cu] RAD1-24 and [64Cu]RAD1-52) was observed in U87-stb-CXCR4 tumors in both PET/CT imaging and biodistribution studies. At 90 min post-injection of radiotracer, tumor-to-muscle and tumor-to-blood ratios reached 106.05 ± 17.19 and 28.08 ± 4.78, respectively, for cross-bridged pyrimidine analog [64Cu]RAD1-52. Receptor blockade performed in vivo denoted target binding specificity. The biodistribution and PET/CT imaging studies with the radiolabeled bridged cyclams demonstrated longer tumor retention and comparable uptake to [64Cu]AMD3465, though [64Cu]AMD3465 demonstrated superior overall pharmacokinetics

  18. Effects of cefodizime on chemokines of liver tissues in mice with immunological hepatic injury

    Institute of Scientific and Technical Information of China (English)

    WANG Peng; KAN Quan-cheng; YU Zu-jiang; LI Ling; PAN Xue

    2011-01-01

    Background Chronic hepatic inflammation is characterized by the accumulation of lymphocytes as a consequence of increased recruitment from the blood and retention within the tissue at sites of infection. CXC chemokine ligand 16 (CXCL16) mRNA has been detected in both inflamed and normal liver tissues and is strongly upregulated in the injured liver tissues in a murine model. The aim of this study was to investigate the effect of cefodizime on CXCL16 mRNA of liver tissues in mice with immunological hepatic injury.Methods The murine model of immunological hepatic injury was induced by Bacillus Calmette Guerin and Lipoposaccharide. The mice with immunological hepatic injury were randomly assigned to the model group, the cefodizime group and the ceftriaxone group. The three groups were continuously given agents for seven days and CXCL16 mRNA of liver tissue was determined and contrasted with the control group treated by normal saline. Reverse transcription-polymerase chain reaction was used to assay CXCL16 mRNA levels in liver tissues.Results The expressions of CXCL16 mRNA were significantly higher in the model group and the ceftriaxone group than in the control group and the cefodizime group (P <0.05), indicating the mice in the model group and the ceftriaxone group were immunodeficient. There was no statistical difference in the expressions of CXCL16 mRNA between the control group and the cefodizime group. Similarly, no statistical difference in the expressions of CXCL16 mRNA between the model group and the ceftriaxone group was detected (P >0.05).Conclusion Cefodizime effectively reduces the infiltration of lymphocytes into liver tissues and alleviates the liver damage by decreasing CXCL16 mRNA in liver tissues in mice with immunological hepatic injury.

  19. The chemokine receptor CXCR4 strongly promotes neuroblastoma primary tumour and metastatic growth, but not invasion.

    Directory of Open Access Journals (Sweden)

    Roland Meier

    Full Text Available Neuroblastoma (NB is a heterogeneous, and particularly malignant childhood neoplasm in its higher stages, with a propensity to form metastasis in selected organs, in particular liver and bone marrow, and for which there is still no efficient treatment available beyond surgery. Recent evidence indicates that the CXCR4/CXCL12 chemokine/receptor axis may be involved in promoting NB invasion and metastasis. In this study, we explored the potential role of CXCR4 in the malignant behaviour of NB, using a combination of in vitro functional analyses and in vivo growth and metastasis assessment in an orthotopic NB mouse model. We show here that CXCR4 overexpression in non-metastatic CXCR4-negative NB cells IGR-NB8 and in moderately metastatic, CXCR4 expressing NB cells IGR-N91, strongly increased tumour growth of primary tumours and liver metastases, without altering the frequency or the pattern of metastasis. Moreover shRNA-mediated knock-down experiments confirmed our observations by showing that silencing CXCR4 in NB cells impairs in vitro and almost abrogates in vivo growth. High levels of CXCL12 were detected in the mouse adrenal gland (the primary tumour site, and in the liver suggesting a paracrine effect of host-derived CXCL12 on NB growth. In conclusion, this study reveals a yet unreported NB-specific predominant growth and survival-promoting role of CXCR4, which warrants a critical reconsideration of the role of CXCR4 in the malignant behaviour of NB and other cancers.

  20. CHEMOKINE RECEPTORS AT DISTINCT DIFFERENTIATION STAGES OF T-HELPERS FROM PERIPHERAL BLOOD

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    I. V. Kudryavtsev

    2016-01-01

    Full Text Available Expression of chemokine receptors (CCR4, CCR6, CXCR3 and CXCR5 on T-helper (Th cells at various levels of differentiation in a group of healthy volunteers (n = 52 was assessed on the basis of CD45RA and CD62L expression, using the eight-color flow cytometry. It was found that the “naive” T helper cells (N with CD45RA+CD62L+ phenotype express CXCR3 (4.94±0.39%, and CXCR5 (3.63±0.25%. About 50% of central memory T helpers (CD45RA–CD62L+, CM were CXCR3 positive, and 43.72±1.27% of CM cells expressed CCR6, whereas CXCR5 and CCR4 levels were about 30%. Furthermore, CXCR3 was expressed by 76.76±0.75% of the CD3+CD4+CD45RA–CD62L– (EM population, and similar values were obtained for CCR6, while the relative abundance of CXCR5+ cells decreased to 13.68±0.50%, and CCR4 levels did not change and accounted for 33.26±1.13% positive cells. Likewise, co-expression of the chemokine receptors was studied for the abovementioned subpopulations of T helper cells. Among the CXCR5– Th, Th1 cells were identified as CXCR3+CCR6–CCR4– (this subset also contained Th9, and CXCR3+CCR6+CCR4– subsets, referred to as Th1/Th17. Th2 were detected on the basis of CCR4 expression in absence of all other chemokine receptors. In addition to the mentioned Th1/Th17 populations, Th 17 cells were found in the subsets of Th17 CXCR3–CCR6+CCR4– and CXCR3–CR6+CCR4+. The latter also contained a Th22 population. Follicular Th cell populations (CXCR5+ consisted of, at least, six different subsets: CXCR3–CCR6–CCR4– (Tfh/Tfh2, CXCR3–CCR6–CCR4+ (Tfh2, CXCR3-CCR6+CCR4–(Tfh17, CXCR3–CCR6+CCR4+ (Tfh17, CXCR3+CCR6–CCR4– (Tfh1 and CXCR3+CCR6+CCR4–(Tfh1/Tfh17. The cells with Th1/Th9 and Th1/Th17 phenotypes dominated among CM (about 13%, whereas their relative abundance within EM increased to 22.37±1.69% and 31.69±1.52%, respectively. The amounts of Th2 were 8.15±0.46% within CM, and only 1.72±0.15% for EM population. For the cells

  1. Combination of basic fibroblast growth factor and epidermal growth factor enhances proliferation and neuronal/glial differential of postnatal human enteric neurosphere cells in vitro.

    Science.gov (United States)

    Pan, Wei-Kang; Yu, Hui; Wu, A-Li; Gao, Ya; Zheng, Bai-Jun; Li, Peng; Yang, Wei-Li; Huang, Qiang; Wang, Huai-Jie; Ge, Xin

    2016-08-01

    Human enteric neural stem cells (hENSCs) proliferate and differentiate into neurons and glial cells in response to a complex network of neurotrophic factors to form the enteric nervous system. The primary aim of this study was to determine the effect of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) on in-vitro expansion and differentiation of postnatal hENSCs-containing enteric neurosphere cells. Enteric neurosphere cells were isolated from rectal polyp specimens of 75 children (age, 1-13 years) and conditioned with bFGF, EGF, bFGF+EGF, or plain culture media. Proliferation of enteric neurosphere cells was examined using the methyl thiazolyl tetrazolium colorimetric assay over 7 days of culture. Fetal bovine serum (10%) was added to induce the differentiation of parental enteric neurosphere cells, and differentiated offspring cells were immunophenotyped against p75 neutrophin receptor (neural stem cells), peripherin (neuronal cells), and glial fibrillary acidic protein (glial cells). Combining bFGF and EGF significantly improved the proliferation of enteric neurosphere cells compared with bFGF or EGF alone (both P<0.01) throughout 7 days of culture. The addition of bFGF drove a significantly greater proportion of enteric neurosphere cells to differentiate into neuronal cells than that of EGF (P<0.01), whereas addition of EGF resulted in significantly more glial differentiation compared with addition of bFGF (P<0.01). Combining bFGF and EGF drove enteric neurosphere cells to differentiate into neuronal cells in a proportion similar to glial cells. Our results showed that the combination of bFGF and EGF significantly enhanced the proliferation and differentiation of postnatal hENSCs-containing enteric neurosphere cells in vitro. PMID:27306591

  2. Differences in sensitivity to mTHPC-mediated photodynamic therapy of neurons, glial cells and MCF7 cells in a 3-dimensional cell culture model

    OpenAIRE

    Wright, K E; MacRobert, A J; Phillips, J. B.

    2008-01-01

    The effect of photodynamic therapy (PDT) on the cells of the nervous system is an important consideration in the treatment of tumours that are located within or adjacent to the brain, spinal cord and peripheral nerves. Previous studies have reported the sparing of nerves during PDT using meta-tetrahydroxyphenylchlorin (mTHPC, Foscan®) in patients and in animal models. The aim of this study was to investigate the effects of mTHPC on key nervous system cells using a 3-dimensional cell culture s...

  3. 弥漫增生型狼疮肾炎患者趋化因子及其受体的表达%The study of chemokines and chemokine receptors expression in patients with proliferative lupus nephritis

    Institute of Scientific and Technical Information of China (English)

    郭桂梅; 陈顺乐; 沈南; 戴岷; 倪旭鸣; 郑林

    2008-01-01

    目的 了解弥漫增生型狼疮肾炎(LN)患者趋化因子MCP-1、CCL19、CXCL9、CXCL10和趋化因子受体CCR2、CCR7、CXCR3的表达,探讨趋化因子及其受体在LN发病中的作用.方法 ①同步收集12例弥漫增生型LN患者肾组织和外周血,抽提总RNA并反转录为cDNA,以实时荧光定量聚合酶链反应(PCR)方法 检测趋化因子基因MCP-1、CCL19、CXCL9、CXCL10和趋化因子受体基因CCR2、CCR7、CXCR3的表达水平.②应用免疫荧光抗体标记、激光扫描共聚焦显微镜技术观察患者肾组织趋化因子MCP-1、CCL19、CXCL9和CXCL10的表达.结果 弥漫增生型LN患者趋化因子基因MCP-1、CCL19、CXCL9和CXCL10 mRNA在肾脏组织和外周血的表达呈同步增高趋势,4种趋化因子蛋白在肾小球的表达显著增高.趋化因子受体CCR2和CXCR3在LN患者外周血高表达.结论 趋化因子MCP-1、CCL19、CXCL9和CXCL10外周血表达水平可能做为评估狼疮患者肾脏病变的生物学标记.阻断趋化因子与其相应受体的结合将可能减轻患者的临床症状、改善预后.%Objective To explore the role of chemokines and ehemokine receptors in the etiopathog-enesis of diffuse proliferative lupus nephritis (LN). Methods ① Total RNA from the kidney tissues and peripheral blood cells of 12 patients with diffuse proliferative LN and 10 normal controls were prepared simultaneously and reverse transcribed into complementary DNA. Sybr green dye based real-time quantitative PCR method was used to compare the expression levels (indicated as-AACt value) of MCP-1, CCL19,CXCLg, CXCL10 and CCR2, CCR7, CXCR3. ② Immunofluoresceee labeling and immunohistochemical staining technique were used to observe the distribution of chemokines MCP-1, CCL19, CXCL9 and CXCL10 in normal and patients kidney tissues. Results The 4 chemokines genes (MCP-1, CCL19, CXCL9 and CXCL10) were consistently highly expressed in kidney tissues and peripheral blood ceils of diffuse proliferative LN

  4. Serum concentrations of the interferon-gamma-inducible chemokine IP-10/CXCL10 are augmented in both newly diagnosed Type I diabetes mellitus patients and subjects at risk of developing the disease

    DEFF Research Database (Denmark)

    Nicoletti, F; Conget, I; Di Mauro, M;

    2002-01-01

    Chemokines are chemotactic cytokines controlling the recruitment of leukocytes from the blood by regulating integrin adhesiveness. It has been shown that the migration of CD4+Th1 and CD4+Th2 cells is governed by specific chemokines. Increasing evidence suggests that the CD4+Th1 cheomoattractant c...... chemokine CXCL10, also termed Interferon (IFN)-gamma -inducible protein (IP)-10 is pathogenetically involved in several immunoinflammatory and autoimmune diseases....

  5. Circulating thymus and activation-regulated chemokine/CC chemokine ligand 17 is a strong candidate diagnostic marker for interstitial lung disease in patients with malignant tumors: a result from a pilot study

    Directory of Open Access Journals (Sweden)

    Yamane H

    2015-06-01

    Full Text Available Hiromichi Yamane, Nobuaki Ochi, Tomoko Yamagishi, Yoshihiro Honda, Masami Takeyama, Nagio TakigawaDepartment of General Internal Medicine 4, Kawasaki Medical School, Kita-ku, Okayama, JapanIntroduction: Serum Krebs von den Lungen-6 (KL-6 level is an established diagnostic marker of interstitial lung disease (ILD. However, it is also elevated in patients with non-small cell lung cancer (NSCLC. The significance of circulating thymus and activation-regulated chemokine (TARC/CC chemokine ligand 17 (CCL17 in malignant diseases remains unknown.Methods: We measured circulating TARC/CCL17 and KL-6 using enzyme-linked immunosorbent assay and electrochemiluminescence immunoassay, respectively, in 26 patients with malignant disease and six patients with benign lung disease (BLD. The cutoff levels were 500 U/mL for KL-6 and 450 pg/mL for TARC/CCL17. The significance of the markers was evaluated in relationship to the presence of ILD (n=10. The statistical significance was set at P<0.05.Results: The KL-6 positive ratio was significantly higher in the patients with NSCLC (n=17 than in those with BLD. There was a significant difference in the KL-6 positive ratio between the patients with NSCLC without ILD and those with BLD without ILD. However, there were no significant differences in the TARC/CCL17 positive ratio between the patients with NSCLC and BLD or between those with NSCLC without ILD and those with BLD without ILD. The TARC/CCL17 positive ratio was significantly higher in the patients with malignancy and ILD than in those without ILD. There was also a significant difference in the TARC/CCL17 positive ratio between the patients with NSCLC without ILD and those with ILD.Conclusion: TARC/CCL17 may be useful for the diagnosis of ILD in patients with malignancies. Confirmation of the results is warranted through a large-scale study.Keywords: thymus and activation-regulated chemokine/CC chemokine ligand 17, Krebs von den Lungen-6, interstitial lung

  6. Activation and Recruitment of Regulatory T Cells via Chemokine Receptor Activation in Trichinella spiralis-Infected Mice.

    Science.gov (United States)

    Ahn, Jeong-Bin; Kang, Shin Ae; Kim, Dong-Hee; Yu, Hak Sun

    2016-04-01

    As most infections by the helminth parasite elicit the recruitment of CD4(+)CD25(+)Foxp3(+) T (Treg) cells, many scientists have suggested that these cells could be used for the treatment of immune-mediated inflammation and associated diseases. In order to investigate the distribution and alteration of activated Treg cells, we compared the expression levels of Treg cell activation markers in the ileum and gastrocnemius tissues 1, 2, and 4 weeks after infection. The number of Treg cells was monitored using GFP-coded Foxp3 transgenic mice. In mice at 1 week after Trichinella spiralis infection, the number of activated Treg cells was higher than in the control group. In mice at 2 weeks after infection, there was a significant increase in the number of cells expressing Foxp3 and CTLA-4 when compared to the control group and mice at 1 week after infection. At 4 weeks after infection, T. spiralis was easily identifiable in nurse cells in mouse muscles. In the intestine, the expression of Gzmb and Klrg1 decreased over time and that of Capg remained unchanged for the first and second week, then decreased in the 4th week. However, in the muscles, the expression of most chemokine genes was increased due to T. spiralis infection, in particular the expression levels of Gzmb, OX40, and CTLA-4 increased until week 4. In addition, increased gene expression of all chemokine receptors in muscle, CXCR3, CCR4, CCR5, CCR9, and CCR10, was observed up until the 4th week. In conclusion, various chemokine receptors showed increased expressions combined with recruitment of Treg cells in the muscle tissue. PMID:27180574

  7. Circulating cytokines and chemokines associated with plasma leakage and hepatic dysfunction in Brazilian children with dengue fever.

    Science.gov (United States)

    Ferreira, Ralph Antonio Xavier; de Oliveira, Solange Artimos; Gandini, Mariana; Ferreira, Laura da Cunha; Correa, Gladys; Abiraude, Fernanda Mattos; Reid, Mariana Mancebo; Cruz, Oswaldo Gonçalves; Kubelka, Claire Fernandes

    2015-09-01

    Dengue fever is usually a benign acute viral infection transmitted by arthropods but may evolve to severe clinical manifestations such as coagulation and/or hemodynamic disorders, caused mainly by an increase of vascular permeability. Deregulated circulating immunological factors have been associated with severity. In Brazil severe cases appeared in children only recently and we evaluated the profile of cytokine/chemokine kinetics in 134 hospitalized young patients during the epidemic in Rio de Janeiro in 2008. Inflammatory cytokines TNF and IFNγ were found elevated during the acute phase in children as well as the anti-inflammatory IL10 and chemokines MIF and CXCL10/IP10, all last three persisting longer during the recovery phase. Severe disease fitting the dengue hemorrhagic fever pattern (WHO, 1997) was associated with higher IL10 and CXCL10/IP10 circulating levels (peak levels at seven days with P<0.01 and P<0.001 respectively as compared to DF). These factors were higher in patients pulmonary effusion or ascites (P<0.05 for IL10 and P<0.01 for CXCL10/IP10). Both factors were also associated with liver changes such as AST increase correlated with CXCL10/IP10 (r=0.4300 with P<0.0001) and patients presenting painful hepatomegaly showed higher circulating levels of IL10 (P<0.01, at 7-9 days) and of CXCL10/IP10 (P<0.05, 4-6 days and P<0.001, 7-9 days) when compared to patients without apparent liver alterations. Most cases presented a history of prior infection (93%). This is the first study demonstrating cytokine and chemokine association with severity during dengue fever in Brazilian children. IL10 and CXCL10/IP10 play a role in the disease severity associated with induction of vascular leakage and a novel association with changes in liver dysfunction.

  8. Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-like receptor 9 agonists in prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Mukherjee S

    2014-06-01

    Full Text Available Sushovita Mukherjee, Mohammad Adnan Siddiqui, Shubham Dayal, Yasmine Zakaria Ayoub, Krishnamurthy Malathi Department of Biological Sciences, University of Toledo, Toledo, OH, USA Abstract: Chronic inflammation of the prostate contributes to the increased risk of prostate cancer. Microbial pathogens in the prostate cause inflammation that leads to prostatitis and proliferative inflammatory atrophy frequently associated with the development of prostate cancer. Bacterial lipopolysaccharides and DNA mediate immune responses by engaging Toll-like receptor (TLR 4 and 9, respectively. Synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODN mimic bacterial DNA and signal through TLR9 to initiate innate immune responses. Here, we show that stimulation of DU145, PC3, or LnCap prostate cancer cells by the TLR9 agonists, CpG-ODN, induces mRNA expression of IL-6, IL-8, CXCL1, IP-10, CCL5, and TGFβ. In addition, activity of matrix metalloproteinase (MMP-9 and -2 and cell migration increased on CpG-ODN treatment. Induction of cytokines and chemokines was mediated by NF-ΚB activation and translocation to the nucleus. Treatment with epigallocatechin-3-gallate (EGCG, the major constituent of green tea, prior to CpG-ODN stimulation, inhibits cytokine and chemokine gene induction, activity of MMP-9 and -2, and cell migration. EGCG treatment sequesters the p65 subunit of transcription factor NF-ΚB in the cytoplasm and inhibits transcriptional activity of the NF-ΚB-driven promoter in response to CpG-ODN. Our results suggest that the ability of the TLR9 agonists, CpG-ODN, to induce cytokines, chemokines, and MMP activity, as well as suppression by EGCG are independent of the androgen receptor and p53 status of the cells. EGCG may provide protective effects against inflammation in the prostate and benefit prostate cancer treatment. Keywords: CpG-ODN, EGCG, inflammation, NF-ΚB

  9. Autocrine production of beta-chemokines protects CMV-Specific CD4 T cells from HIV infection.

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    Joseph P Casazza

    2009-10-01

    Full Text Available Induction of a functional subset of HIV-specific CD4+ T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease progression. CMV-specific CD4+ T cells, which are less frequently infected than HIV-specific CD4+ T cells, are a model for such an effect. To determine the mechanism of this protection, we compared the functional response of HIV gag-specific and CMV pp65-specific CD4+ T cells in individuals co-infected with CMV and HIV. We found that CMV-specific CD4+ T cells rapidly up-regulated production of MIP-1alpha and MIP-1beta mRNA, resulting in a rapid increase in production of MIP-1alpha and MIP-1beta after cognate antigen stimulation. Production of beta-chemokines was associated with maturational phenotype and was rarely seen in HIV-specific CD4+ T cells. To test whether production of beta-chemokines by CD4+ T cells lowers their susceptibility to HIV infection, we measured cell-associated Gag DNA to assess the in vivo infection history of CMV-specific CD4+ T cells. We found that CMV-specific CD4+ T cells which produced MIP-1beta contained 10 times less Gag DNA than did those which failed to produce MIP-1beta. These data suggest that CD4+ T cells which produce MIP-1alpha and MIP-1beta bind these chemokines in an autocrine fashion which decreases the risk of in vivo HIV infection.

  10. In vitro characterization and inhibition of the CXCR4/CXCL12 chemokine axis in human uveal melanoma cell lines

    Directory of Open Access Journals (Sweden)

    Antecka Emilia

    2007-11-01

    Full Text Available Abstract Purpose The CXCR4/CXCL12 chemokine axis may play a critical role in guiding CXCR4+ circulating malignant cells to organ specific locations that actively secrete its ligand CXCL12 (SDF-1 such as bone, brain, liver, and lungs. We sought to characterize the presence of the CXCR4/CXCL12 axis in five uveal melanoma (UM cell lines in vitro. The ability of TN14003, a synthetic peptide inhibitor that targets the CXCR4 receptor complex, to inhibit this axis was also assessed. Methods Immunocytochemistry was performed against CXCR4 to confirm expression of this chemokine receptor in all five UM cell lines. Flow cytometry was preformed to evaluate CXCR4 cell surface expression on all five UM cell lines. A proliferation assay was also used to test effects TN14003 would have on cellular proliferation. Inhibition of cellular migration by specifically inhibiting the CXCR4/CXCL12 axis with TN14003 was also investigated. The binding efficacy of TN14003 to the CXCR4 receptor was assessed through flow cytometric methods. Results The CXCR4 receptor was present on all five UM cell lines. All five cell lines expressed different relative levels of surface CXCR4. TN14003 did not affect the proliferation of the five cell lines (p > 0.05. All cell lines migrated towards the chemokine CXCL12 at a level greater than the negative control (p Conclusion Interfering with the CXCR4/CXCL12 axis, using TN14003 was shown to effectively down regulate UM cell migration in vitro. Knowing that UM expresses the CXCR4 receptor, these CXCR4+ cells may be less likely to colonize distant organs that secrete the CXCL12 ligand, if treated with an inhibitor that binds CXCR4. Further studies should be pursued in order to test TN14003 efficacy in vivo.

  11. The CXC chemokine cCAF stimulates precocious deposition of ECM molecules by wound fibroblasts, accelerating development of granulation tissue

    Directory of Open Access Journals (Sweden)

    Li Qi-Jing

    2002-06-01

    Full Text Available Abstract Background During wound repair, fibroblasts orchestrate replacement of the provisional matrix formed during clotting with tenascin, cellular fibronectin and collagen III. These, in turn, are critical for migration of endothelial cells, keratinocytes and additional fibroblasts into the wound site. Fibroblasts are also important in the deposition of collagen I during scar formation. The CXC chemokine chicken Chemotactic and Angiogenic Factor (cCAF, is highly expressed by fibroblasts after wounding and during development of the granulation tissue, especially in areas where extracellular matrix (ECM is abundant. We hypothesized that cCAF stimulates fibroblasts to produce these matrix molecules. Results Here we show that this chemokine can stimulate precocious deposition of tenascin, fibronectin and collagen I, but not collagen III. Studies in culture and in vivo show that tenascin stimulation can also be achieved by the N-terminal 15 aas of the protein and occurs at the level of gene expression. In contrast, stimulation of fibronectin and collagen I both require the entire molecule and do not involve changes in gene expression. Fibronectin accumulation appears to be linked to tenascin production, and collagen I to decreased MMP-1 levels. In addition, cCAF is chemotactic for fibroblasts and accelerates their migration. Conclusions These previously unknown functions for chemokines suggest that cCAF, the chicken orthologue of human IL-8, enhances healing by rapidly chemoattracting fibroblasts into the wound site and stimulating them to produce ECM molecules, leading to precocious development of granulation tissue. This acceleration of the repair process may have important application to healing of impaired wounds.

  12. Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia.

    Science.gov (United States)

    Lockwood, Charles J; Huang, S Joseph; Chen, Chie-Pein; Huang, Yingqun; Xu, Jie; Faramarzi, Saeed; Kayisli, Ozlem; Kayisli, Umit; Koopman, Louise; Smedts, Dineke; Buchwalder, Lynn F; Schatz, Frederick

    2013-09-01

    First trimester human decidua is composed of decidual cells, CD56(bright)CD16(-) decidual natural killer (dNK) cells, and macrophages. Decidual cells incubated with NK cell-derived IFN-γ and either macrophage-derived TNF-α or IL-1β synergistically enhanced mRNA and protein expression of IP-10 and I-TAC. Both chemokines recruit CXCR3-expressing NK cells. This synergy required IFN-γ receptor 1 and 2 mediation via JAK/STAT and NFκB signaling pathways. However, synergy was not observed on neutrophil, monocyte, and NK cell-recruiting chemokines. Immunostaining of first trimester decidua localized IP-10, I-TAC, IFN-γR1, and -R2 to vimentin-positive decidual cells versus cytokeratin-positive interstitial trophoblasts. Flow cytometry identified high CXCR3 levels on dNK cells and minority peripheral CD56(bright)CD16(-) pNK cells and intermediate CXCR3 levels on the majority of CD56(dim)CD16(+) pNK cells. Incubation of pNK cells with either IP-10 or I-TAC elicited concentration-dependent enhanced CXCR3 levels and migration of both pNK cell subsets that peaked at 10 ng/mL, whereas each chemokine at a concentration of 50 ng/mL inhibited CXCR3 expression and pNK cell migration. Deciduae from women with preeclampsia, a leading cause of maternal and fetal morbidity and mortality, displayed significantly lower dNK cell numbers and higher IP-10 and I-TAC levels versus gestational age-matched controls. Significantly elevated IP-10 levels in first trimester sera from women eventually developing preeclampsia compared with controls, identifying IP-10 as a novel, robust early predictor of preeclampsia. PMID:23973270

  13. CXC chemokine subfamily and its biological relationship with tumor%趋化因子CXC亚家族及其与肿瘤的生物学关系

    Institute of Scientific and Technical Information of China (English)

    朱庆超; 汪昱

    2010-01-01

    Chemokines are a class of functional chemotactic peptide. CXC chemokine class is a large family of chemokines in a sub- tribe. In the occurrence and development of tumor cells, there often accompanied by a series of molecular and biology change. CXC chemokine subfamily is closely related to the body' s immune response to tumor and biological behaviors of tumor. In this paper, CXC chemokine sub-Several members of the tribe and their receptor and tumor biological relationship are reviewed.%趋化因子是一类具有化学趋化功能的多肽,CXC类趋化因子是趋化因子大家族中的一个亚族;在肿瘤细胞的发生、发展中常伴随着一系列的分子生物学改变,趋化因子CXC亚家族与机体对肿瘤的免疫应答及其与生物学之间有着密切的关系.本文就趋化因子CXC亚族中的几个成员及其受体与肿瘤的生物学关系进行综述.

  14. Altered thymocyte migration during experimental acute Trypanosoma cruzi infection: combined role of fibronectin and the chemokines CXCL12 and CCL4.

    Science.gov (United States)

    Mendes-da-Cruz, Daniella Arêas; Silva, João Santana; Cotta-de-Almeida, Vinícius; Savino, Wilson

    2006-06-01

    We previously showed migration disturbances in the thymus during experimental infection with Trypanosoma cruzi, the causative agent of Chagas disease. These changes were related to the enhanced expression of extracellular matrix ligands and receptors, leading to the escape of immature cells to the periphery. Here, we analyzed the expression and role of selected chemokines (CXCL12 and CCL4) and their receptors (CXCR4 and CCR5) in regulating thymocyte migration in conjunction with extracellular matrix during acute T. cruzi infection. We found increased chemokine deposition in the thymus of infected mice when compared to controls, accompanied by enhanced co-localization with fibronectin as well as up-regulated surface expression of CXCR4 and CCR5 in thymocytes. We also noticed altered thymocyte migration towards the chemokines analyzed. Such an enhancement was even more prominent when fibronectin was added as a haptotatic stimulus in combination with a given chemokine. Our findings suggest that thymocyte migration results from a combined action of chemokines and extracellular matrix (ECM), which can be altered during pathological conditions such as T. cruzi infection, and may be at the origin of the changes in the T cell repertoire seen in this pathological process.

  15. Higher circulating levels of chemokines CXCL10, CCL20 and CCL22 in patients with ischemic heart disease.

    Science.gov (United States)

    Safa, A; Rashidinejad, H R; Khalili, M; Dabiri, S; Nemati, M; Mohammadi, M M; Jafarzadeh, A

    2016-07-01

    Recruitment of leukocytes is one of the earliest events in the pathogenesis of ischemic heart disease (IHD) and chemokines play an important role in the migration of these cells into the inflammation sites. The aim of this study was to evaluate the CXCL10, CCL20 and CCL22 levels and the single nucleotide polymorphisms (SNPs) rs4508917, rs6749704 and rs4359426 in chemokine genes in patients with IHD to clarify any association. A total of 300 patients with IHD as having acute myocardial infarction (AMI; n=100), stable angina (SA; n=100) or unstable angina (UA; n=100) and 100 healthy subjects as a control group were enrolled to study. Serum samples from all participants were tested for the CXCL10, CCL20 and CCL22 levels by using ELISA. The SNPs were determined by polymerase chain reaction-restriction length polymorphism (PCR-RFLP) method. The mean serum concentrations of CXCL10, CCL20 and CCL22 in AMI patients (395.97±21.20Pg/mL, 108.38±10.31Pg/mL and 1852.58±205.77Pg/mL), SA patients (405.48±27.36Pg/mL, 90.20±7.69Pg/mL and 2322.04±231.23Pg/mL) and UA patients (396.69±22.79Pg/mL, 141.87±18.10Pg/mL and 2754.89±211.70Pg/mL) were significantly higher than in the healthy group (179.38±8.85Pg/mL, 51.92±4.62Pg/mL and 451.82±23.76Pg/mL, respectively; PACE) inhibitors and patients without mentioned treatment regarding the levels of chemokines. The frequency of the GG genotype at SNP rs4508917 in CXCL10 gene was higher, whereas the frequency of the AA genotype at SNP rs4359426 in CCL22 gene was lower in total patients with IHD as compared with healthy subjects (P<0.04 and P<0.002, respectively). These results showed that the higher levels of CXCL10, CCL20 and CCL22 were associated with IHD. The serum levels of chemokines may influence by the certain traditional risk factors of IHD and some studied SNPs, but did not influence by treatment and gender of patients. PMID:27152707

  16. The human herpes virus 8-encoded chemokine receptor is required for angioproliferation in a murine model of Kaposi's sarcoma

    DEFF Research Database (Denmark)

    Jensen, Kristian K; Manfra, Denise J; Grisotto, Marcos G;

    2005-01-01

    Kaposi's sarcoma (KS)-associated herpesvirus or human herpes virus 8 is considered the etiological agent of KS, a highly vascularized neoplasm that is the most common tumor affecting HIV/AIDS patients. The KS-associated herpesvirus/human herpes virus 8 open reading frame 74 encodes a constitutively...... active G protein-coupled receptor known as vGPCR that binds CXC chemokines with high affinity. In this study, we show that conditional transgenic expression of vGPCR by cells of endothelial origin triggers an angiogenic program in vivo, leading to development of an angioproliferative disease...

  17. Lysophosphatidic acid alters the expression profiles of angiogenic factors, cytokines, and chemokines in mouse liver sinusoidal endothelial cells.

    Directory of Open Access Journals (Sweden)

    Chia-Hung Chou

    Full Text Available Lysophosphatidic acid (LPA is a multi-function glycerophospholipid. LPA affects the proliferation of hepatocytes and stellate cells in vitro, and in a partial hepatectomy induced liver regeneration model, the circulating LPA levels and LPA receptor (LPAR expression levels in liver tissue are significantly changed. Liver sinusoidal endothelial cells (Lsecs play an important role during liver regeneration. However, the effects of LPA on Lsecs are not well known. Thus, we investigated the effects of LPA on the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs.Mouse Lsecs were isolated using CD31-coated magnetic beads. The mRNA expression levels of LPAR's and other target genes were determined by quantitative RT-PCR. The protein levels of angiogenesis factors, cytokines, and chemokines were determined using protein arrays and enzyme immunoassay (EIA. Critical LPAR related signal transduction was verified by using an appropriate chemical inhibitor.LPAR1 and LPAR3 mRNA's were expressed in mouse LPA-treated Lsecs. Treating Lsecs with a physiological level of LPA significantly enhanced the protein levels of angiogenesis related proteins (cyr61 and TIMP-1, cytokines (C5/C5a, M-CSF, and SDF-1, and chemokines (MCP-5, gp130, CCL28, and CXCL16. The LPAR1 and LPAR3 antagonist ki16425 significantly inhibited the LPA-enhanced expression of cyr61, TIMP-1, SDF-1, MCP-5, gp130, CCL28, and CXCL16, but not that of C5/C5a or M-CSF. LPA-induced C5/C5a and M-CSF expression may have been through an indirect regulation mechanism.LPA regulated the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs that was mediated via LPAR1 and LPAR3 signaling. Most of the factors that were enhanced by LPA have been found to play critical roles during liver regeneration. Thus, these results may prove useful for manipulating LPA effects on liver regeneration.

  18. Lysophosphatidic Acid Alters the Expression Profiles of Angiogenic Factors, Cytokines, and Chemokines in Mouse Liver Sinusoidal Endothelial Cells

    Science.gov (United States)

    Chou, Chia-Hung; Lai, Shou-Lun; Ho, Cheng-Maw; Lin, Wen-Hsi; Chen, Chiung-Nien; Lee, Po-Huang; Peng, Fu-Chuo; Kuo, Sung-Hsin; Wu, Szu-Yuan; Lai, Hong-Shiee

    2015-01-01

    Background and Aims Lysophosphatidic acid (LPA) is a multi-function glycerophospholipid. LPA affects the proliferation of hepatocytes and stellate cells in vitro, and in a partial hepatectomy induced liver regeneration model, the circulating LPA levels and LPA receptor (LPAR) expression levels in liver tissue are significantly changed. Liver sinusoidal endothelial cells (Lsecs) play an important role during liver regeneration. However, the effects of LPA on Lsecs are not well known. Thus, we investigated the effects of LPA on the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs. Methods Mouse Lsecs were isolated using CD31-coated magnetic beads. The mRNA expression levels of LPAR’s and other target genes were determined by quantitative RT-PCR. The protein levels of angiogenesis factors, cytokines, and chemokines were determined using protein arrays and enzyme immunoassay (EIA). Critical LPAR related signal transduction was verified by using an appropriate chemical inhibitor. Results LPAR1 and LPAR3 mRNA’s were expressed in mouse LPA-treated Lsecs. Treating Lsecs with a physiological level of LPA significantly enhanced the protein levels of angiogenesis related proteins (cyr61 and TIMP-1), cytokines (C5/C5a, M-CSF, and SDF-1), and chemokines (MCP-5, gp130, CCL28, and CXCL16). The LPAR1 and LPAR3 antagonist ki16425 significantly inhibited the LPA-enhanced expression of cyr61, TIMP-1, SDF-1, MCP-5, gp130, CCL28, and CXCL16, but not that of C5/C5a or M-CSF. LPA-induced C5/C5a and M-CSF expression may have been through an indirect regulation mechanism. Conclusion LPA regulated the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs that was mediated via LPAR1 and LPAR3 signaling. Most of the factors that were enhanced by LPA have been found to play critical roles during liver regeneration. Thus, these results may prove useful for manipulating LPA effects on liver regeneration. PMID:25822713

  19. Brain microvascular pericytes are immunoactive in culture: cytokine, chemokine, nitric oxide, and LRP-1 expression in response to lipopolysaccharide

    Directory of Open Access Journals (Sweden)

    Erickson Michelle A

    2011-10-01

    Full Text Available Abstract Background Brain microvascular pericytes are important constituents of the neurovascular unit. These cells are physically the closest cells to the microvascular endothelial cells in brain capillaries. They significantly contribute to the induction and maintenance of the barrier functions of the blood-brain barrier. However, very little is known about their immune activities or their roles in neuroinflammation. Here, we focused on the immunological profile of brain pericytes in culture in the quiescent and immune-challenged state by studying their production of immune mediators such as nitric oxide (NO, cytokines, and chemokines. We also examined the effects of immune challenge on pericyte expression of low density lipoprotein receptor-related protein-1 (LRP-1, a protein involved in the processing of amyloid precursor protein and the brain-to-blood efflux of amyloid-β peptide. Methods Supernatants were collected from primary cultures of mouse brain pericytes. Release of nitric oxide (NO was measured by the Griess reaction and the level of S-nitrosylation of pericyte proteins measured with a modified "biotin-switch" method. Specific mitogen-activated protein kinase (MAPK pathway inhibitors were used to determine involvement of these pathways on NO production. Cytokines and chemokines were analyzed by multianalyte technology. The expression of both subunits of LRP-1 was analyzed by western blot. Results Lipopolysaccharide (LPS induced release of NO by pericytes in a dose-dependent manner that was mediated through MAPK pathways. Nitrative stress resulted in S-nitrosylation of cellular proteins. Eighteen of twenty-three cytokines measured were released constitutively by pericytes or with stimulation by LPS, including interleukin (IL-12, IL-13, IL-9, IL-10, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, eotaxin, chemokine (C-C motif ligand (CCL-3, and CCL-4. Pericyte expressions of both subunits of

  20. Profiles of cytokine and chemokine gene expression in human pulmonary epithelial cells induced by human and avian influenza viruses

    OpenAIRE

    Chan Paul KS; Chu Ida MT; Yeung Apple CM; Lam WY

    2010-01-01

    Abstract Influenza pandemic remains a serious threat to human health. In this study, the repertoire of host cellular cytokine and chemokine responses to infections with highly pathogenic avian influenza H5N1, low pathogenicity avian influenza H9N2 and seasonal human influenza H1N1 were compared using an in vitro system based on human pulmonary epithelial cells. The results showed that H5N1 was more potent than H9N2 and H1N1 in inducing CXCL-10/IP-10, TNF-alpha and CCL-5/RANTES. The cytokine/c...