Inhibition of cytokine production by methotrexate. Studies in healthy volunteers and patients with rheumatoid arthritis

NARCIS (Netherlands)

Gerards, A. H.; de Lathouder, S.; de Groot, E. R.; Dijkmans, B. A. C.; Aarden, L. A.

2003-01-01

Objectives. To analyse whether the beneficial effects of methotrexate in rheumatoid arthritis (RA) could be due to inhibition of inflammatory cytokine production. Methods. Cytokine production was studied using whole blood (WB) and mononuclear cells (MNC) of healthy volunteers and RA patients.

Mechanism of inhibition of growth hormone receptor signaling by suppressor of cytokine signaling proteins

DEFF Research Database (Denmark)

Hansen, J A; Lindberg, K; Hilton, D J

1999-01-01

In this study we have investigated the role of suppressor of cytokine signaling (SOCS) proteins in GH receptor-mediated signaling. GH-induced transcription was inhibited by SOCS-1 and SOCS-3, while SOCS-2 and cytokine inducible SH2-containing protein (CIS) had no effect By using chimeric SOCS pro...

Translational overview of cytokine inhibition in acute myocardial infarction and chronic heart failure.

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Hartman, Minke H T; Groot, Hilde E; Leach, Irene Mateo; Karper, Jacco C; van der Harst, Pim

2018-02-15

Many cytokines are currently under investigation as potential target to improve cardiac function and outcome in the setting of acute myocardial infarction (MI) or chronic heart failure (HF). Here we aim to provide a translational overview of cytokine inhibiting therapies tested in experimental models and clinical studies. In various experimental studies, inhibition of interleukin-1 (IL-1), -6 (IL-6), -8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), CC- and CXC chemokines, and tumor necrosis factor-α (TNF-α) had beneficial effects on cardiac function and outcome. On the other hand, neutral or even detrimental results have been reported for some (IL-1, IL-6, IL-8, and MCP-1). Ambivalence of cytokine function, differences in study designs, treatment regimens and chosen endpoints hamper the translation of experimental research into clinical practice. Human studies are currently limited to IL-1β inhibition, IL-1 receptor antagonists (IL-1RA), IL-6 receptor antagonists (IL-6RA) or TNF inhibition. Despite favorable effects on cardiovascular events observed in retrospective cohort studies of rheumatoid arthritis patients treated with TNF inhibition or IL-1RA, most prospective studies reported disappointing and inconsistent results. Smaller studies (n 100) evaluating IL-1β inhibition presented positive results on outcome. In conclusion, of the 10 anticytokine therapies tested in animals models beneficial effects have been reported in at least one setting. In larger clinical studies, findings were unsatisfactory in all but one. Many anticytokine therapies with promising animal experimental data continue to require further evaluation in humans. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Cytokine responses in acute and persistent human parvovirus B19 infection

DEFF Research Database (Denmark)

Isa, A; Lundqvist, A; Lindblom, A

2007-01-01

The aim of this study was to characterize the proinflammatory and T helper (Th)1/Th2 cytokine responses during acute parvovirus B19 (B19) infection and determine whether an imbalance of the Th1/Th2 cytokine pattern is related to persistent B19 infection. Cytokines were quantified by multiplex beads...... immunoassay in serum from B19-infected patients and controls. The cytokine responses were correlated with B19 serology, quantitative B19 DNA levels and clinical symptoms. In addition to a proinflammatory response, elevated levels of the Th1 type of cytokines interleukin (IL)-2, IL-12 and IL-15 were evident...... at time of the initial peak of B19 viral load in a few patients during acute infection. This pattern was seen in the absence of an interferon (IFN)-gamma response. During follow-up (20-130 weeks post-acute infection) some of these patients had a sustained Th1 cytokine response. The Th1 cytokine response...

Effects of Danggui Sini decoction on neuropathic pain: experimental studies and clinical pharmacological significance of inhibiting glial activation and proinflammatory cytokines in the spinal cord
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Liu, Ming; Qiang, Qiu Hong; Ling, Qian; Yu, Chang Xi; Li, Xuejun; Liu, Suhuan; Yang, Shuyu

2017-05-01

Neuropathic pain responds poorly to drug treatments. Partial relief is achieved in only about half of the patients. Danggui Sini decoction (DSD), an aqueous extract of Angelica sinensis, Ramulus Cinnamomi, and Radix Puerariae, has been used extensively in China to treat inflammatory and ischemic diseases. The current study examined the putative effects of DSD on neuropathic pain. We used two commonly-used animal models: chronic constriction injury (CCI) and diabetic neuropathy for the study. And we examined effects of DSD on pain response, activation of microglia and astroglia in spinal dorsal horn, and expression of proinflammatory cytokines in the spinal cord. Consecutive intragastric administration of DSD (25 - 100 mg/kg) for 10 days inhibited the mechanical and thermal nociceptive response induced by CCI and diabetes without interfering with the normal pain response. Meanwhile, in both models, DSD inhibited the over-expression of specific markers for microglia (Iba-1) and astroglia (GFAP) activation in the spinal dorsal horn. DSD also reduced the elevated nuclear NF-κB level and inhibited the up-regulation of proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in the spinal cord. DSD can alleviate CCI and diabetes-induced neuropathic pain, and its effectiveness might be due to the inhibition of neuroinflammation in the spinal dorsal horn. The anti-inflammation effect of DSD may be related to the suppression of spinal NF-κB activation and/or cytokines expression.
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Trichuris suis ova therapy for allergic rhinitis does not affect allergen-specific cytokine responses despite a parasite-specific cytokine response

DEFF Research Database (Denmark)

Bourke, C.D.; Mutapi, F.; Nausch, N.

2012-01-01

Parasitic helminths have been shown to reduce inflammation in most experimental models of allergic disease, and this effect is mediated via cytokine responses. However, in humans, the effects of controlled helminth infection on cytokine responses during allergy have not been studied....

Attenuation of massive cytokine response to the staphylococcal enterotoxin B superantigen by the innate immunomodulatory protein lactoferrin

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Hayworth, J L; Kasper, K J; Leon-Ponte, M; Herfst, C A; Yue, D; Brintnell, W C; Mazzuca, D M; Heinrichs, D E; Cairns, E; Madrenas, J; Hoskin, D W; McCormick, J K; Haeryfar, S M M

2009-01-01

Staphylococcal enterotoxin B (SEB) is a pyrogenic exotoxin and a potent superantigen which causes massive T cell activation and cytokine secretion, leading to profound immunosuppression and morbidity. The inhibition of SEB-induced responses is thus considered a goal in the management of certain types of staphylococcal infections. Lactoferrin (LF) is a multi-functional glycoprotein with both bacteriostatic and bactericidal activities. In addition, LF is known to have potent immunomodulatory properties. Given the anti-microbial and anti-inflammatory properties of this protein, we hypothesized that LF can modulate T cell responses to SEB. Here, we report that bovine LF (bLF) was indeed able to attenuate SEB-induced proliferation, interleukin-2 production and CD25 expression by human leucocyte antigen (HLA)-DR4 transgenic mouse T cells. This inhibition was not due to bLF's iron-binding capacity, and could be mimicked by the bLF-derived peptide lactoferricin. Cytokine secretion by an engineered SEB-responsive human Jurkat T cell line and by peripheral blood mononuclear cells from healthy donors was also inhibited by bLF. These findings reveal a previously unrecognized property of LF in modulation of SEB-triggered immune activation and suggest a therapeutic potential for this naturally occurring protein during toxic shock syndrome. PMID:19659771

Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells.

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Park, Hyo-Hyun; Lee, Soyoung; Son, Hee-Young; Park, Seung-Bin; Kim, Mi-Sun; Choi, Eun-Ju; Singh, Thoudam S K; Ha, Jeoung-Hee; Lee, Maan-Gee; Kim, Jung-Eun; Hyun, Myung Chul; Kwon, Taeg Kyu; Kim, Yeo Hyang; Kim, Sang-Hyun

2008-10-01

Mast cells participate in allergy and inflammation by secreting inflammatory mediators such as histamine and proinflammatory cytokines. Flavonoids are naturally occurring molecules with antioxidant, cytoprotective, and antiinflammatory actions. However, effect of flavonoids on the release of histamine and proinflammatory mediator, and their comparative mechanism of action in mast cells were not well defined. Here, we compared the effect of six flavonoids (astragalin, fisetin, kaempferol, myricetin, quercetin, and rutin) on the mast cell-mediated allergic inflammation. Fisetin, kaempferol, myricetin, quercetin, and rutin inhibited IgE or phorbol-12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-mediated histamine release in RBL-2H3 cells. These five flavonoids also inhibited elevation of intracellular calcium. Gene expressions and secretion of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-8 were assessed in PMACI-stimulated human mast cells (HMC-1). Fisetin, quercetin, and rutin decreased gene expression and production of all the proinflammatory cytokines after PMACI stimulation. Myricetin attenuated TNF-alpha and IL-6 but not IL-1beta and IL-8. Fisetin, myricetin, and rutin suppressed activation of NF-kappaB indicated by inhibition of nuclear translocation of NF-kappaB, NF-kappaB/DNA binding, and NF-kappaB-dependent gene reporter assay. The pharmacological actions of these flavonoids suggest their potential activity for treatment of allergic inflammatory diseases through the down-regulation of mast cell activation.

Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation.

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Radtke, Simone; Wüller, Stefan; Yang, Xiang-ping; Lippok, Barbara E; Mütze, Barbara; Mais, Christine; de Leur, Hildegard Schmitz-Van; Bode, Johannes G; Gaestel, Matthias; Heinrich, Peter C; Behrmann, Iris; Schaper, Fred; Hermanns, Heike M

2010-03-15

The inflammatory response involves a complex interplay of different cytokines which act in an auto- or paracrine manner to induce the so-called acute phase response. Cytokines are known to crosstalk on multiple levels, for instance by regulating the mRNA stability of targeted cytokines through activation of the p38-MAPK pathway. In our study we discovered a new mechanism that answers the long-standing question how pro-inflammatory cytokines and environmental stress restrict immediate signalling of interleukin (IL)-6-type cytokines. We show that p38, activated by IL-1beta, TNFalpha or environmental stress, impairs IL-6-induced JAK/STAT signalling through phosphorylation of the common cytokine receptor subunit gp130 and its subsequent internalisation and degradation. We identify MK2 as the kinase that phosphorylates serine 782 in the cytoplasmic part of gp130. Consequently, inhibition of p38 or MK2, deletion of MK2 or mutation of crucial amino acids within the MK2 target site or the di-leucine internalisation motif blocks receptor depletion and restores IL-6-dependent STAT activation as well as gene induction. Hence, a novel negative crosstalk mechanism for cytokine signalling is described, where cytokine receptor turnover is regulated in trans by pro-inflammatory cytokines and stress stimuli to coordinate the inflammatory response.

Inhibition of Pro-inflammatory Mediators and Cytokines by Chlorella Vulgaris Extracts.

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Sibi, G; Rabina, Santa

2016-01-01

The aim of this study was to determine the in vitro anti-inflammatory activities of solvent fractions from Chlorella vulgaris by inhibiting the production of pro-inflammatory mediators and cytokines. Methanolic extracts (80%) of C. vulgaris were prepared and partitioned with solvents of increasing polarity viz., n-hexane, chloroform, ethanol, and water. Various concentrations of the fractions were tested for cytotoxicity in RAW 264.7 cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and the concentrations inducing cell growth inhibition by about 50% (IC50) were chosen for further studies. Lipopolysaccharide (LPS) stimulated RAW 264.7 cells were treated with varying concentrations of C. vulgaris fractions and examined for its effects on nitric oxide (NO) production by Griess assay. The release of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) were quantified using enzyme-linked immunosorbent assay using Celecoxib and polymyxin B as positive controls. MTT assay revealed all the solvent fractions that inhibited cell growth in a dose-dependent manner. Of all the extracts, 80% methanolic extract exhibited the strongest anti-inflammatory activity by inhibiting NO production (P < 0.01), PGE2 (P < 0.05), TNF-α, and IL-6 (P < 0.001) release in LPS induced RAW 264.7 cells. Both hexane and chloroform fractions recorded a significant (P < 0.05) and dose-dependent inhibition of LPS induced inflammatory mediators and cytokines in vitro. The anti-inflammatory effect of ethanol and aqueous extracts was not significant in the study. The significant inhibition of inflammatory mediators and cytokines by fractions from C. vulgaris suggests that this microalga would be a potential source of developing anti-inflammatory agents and a good alternate for conventional steroidal and nonsteroidal anti-inflammatory drugs. C. vulgaris extracts have potential anti-inflammatory activitySolvent extraction using methanol

Fisetin Inhibits Hyperglycemia-Induced Proinflammatory Cytokine Production by Epigenetic Mechanisms

OpenAIRE

Hye Joo Kim; Seong Hwan Kim; Jung-Mi Yun

2012-01-01

Diabetes is characterized by a proinflammatory state, and several inflammatory processes have been associated with both type 1 and type 2 diabetes and the resulting complications. High glucose levels induce the release of proinflammatory cytokines. Fisetin, a flavonoid dietary ingredient found in the smoke tree (Cotinus coggygria), and is also widely distributed in fruits and vegetables. Fisetin is known to exert anti-inflammatory effects via inhibition of the NF-?B signaling pathway. In this...

Inhibition of early T cell cytokine production by arsenic trioxide occurs independently of Nrf2.

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Kelly R VanDenBerg

Full Text Available Nuclear factor erythroid 2-related factor 2 (Nrf2 is a stress-activated transcription factor that induces a variety of cytoprotective genes. Nrf2 also mediates immunosuppressive effects in multiple inflammatory models. Upon activation, Nrf2 dissociates from its repressor protein, Keap1, and translocates to the nucleus where it induces Nrf2 target genes. The Nrf2-Keap1 interaction is disrupted by the environmental toxicant and chemotherapeutic agent arsenic trioxide (ATO. The purpose of the present study was to determine the effects of ATO on early events of T cell activation and the role of Nrf2 in those effects. The Nrf2 target genes Hmox-1, Nqo-1, and Gclc were all upregulated by ATO (1-2 μM in splenocytes derived from wild-type, but not Nrf2-null, mice, suggesting that Nrf2 is activated by ATO in splenocytes. ATO also inhibited IFNγ, IL-2, and GM-CSF mRNA and protein production in wild-type splenocytes activated with the T cell activator, anti-CD3/anti-CD28. However, ATO also decreased production of these cytokines in activated splenocytes from Nrf2-null mice, suggesting the inhibition is independent of Nrf2. Interestingly, ATO inhibited TNFα protein secretion, but not mRNA expression, in activated splenocytes suggesting the inhibition is due to post-transcriptional modification. In addition, c-Fos DNA binding was significantly diminished by ATO in wild-type and Nrf2-null splenocytes activated with anti-CD3/anti-CD28, consistent with the observed inhibition of cytokine production by ATO. Collectively, this study suggests that although ATO activates Nrf2 in splenocytes, inhibition of early T cell cytokine production by ATO occurs independently of Nrf2 and may instead be due to impaired AP-1 DNA binding.

IL-33-induced alterations in murine intestinal function and cytokine responses are MyD88, STAT6, and IL-13-dependent

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IL-33 is a recently identified cytokine member of the IL-1 family. The biological activities of IL-33 are associated with promotion of Th2 and inhibition of Th1/Th17 immune responses. Exogenous IL-33 induces a typical “type 2” immune response in the gastrointestinal tract, yet the underlying mechani...

Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells.

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Abimannan, Thiruvaimozhi; Peroumal, Doureradjou; Parida, Jyoti R; Barik, Prakash K; Padhan, Prasanta; Devadas, Satish

2016-10-01

Reactive oxygen species (ROS) signaling is critical in T helper (Th) cell differentiation; however its role in differentiated Th cell functions is unclear. In this study, we investigated the role of oxidative stress on the effector functions of in vitro differentiated mouse Th17 and Th1 cells or CD4 + T cells from patients with Rheumatoid Arthritis using pro-oxidants plumbagin (PB) and hydrogen peroxide. We found that in mouse Th cells, non-toxic concentration of pro-oxidants inhibited reactivation induced expression of IL-17A in Th17 and IFN-γ in Th1 cells by reducing the expression of their respective TFs, RORγt and T-bet. Interestingly, in both the subsets, PB increased the expression of IL-4 by enhancing reactivation induced ERK1/2 phosphorylation. We further investigated the cytokine modulatory effect of PB on CD4 + T cells isolated from PBMCs of patients with Rheumatoid Arthritis, a well-known Th17 and or Th1 mediated disease. In human CD4 + T cells from Rheumatoid Arthritis patients, PB reduced the frequencies of IL-17A + (Th17), IFN - γ + (Th1) and IL-17A + /IFN - γ + (Th17/1) cells and also inhibited the production of pro-inflammatory cytokines TNF-α and IL-6. N-Acetyl Cysteine (NAC) an antioxidant completely reversed PB mediated cytokine modulatory effects in both mouse and human cells indicating a direct role for ROS. Together our data suggest that oxidative microenvironment can alter cytokine response of terminally differentiated cells and thus altering intracellular ROS could be a potential way to target Th17 and Th1 cells in autoimmune disorders. Copyright © 2016. Published by Elsevier Inc.

Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress

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Yu, Xiao-Jing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Zhang, Dong-Mei [Department of Physiology, Dalian Medical University, Dalian 116044 (China); Jia, Lin-Lin; Qi, Jie; Song, Xin-Ai; Tan, Hong [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Cui, Wei [Department of Endocrinology and Metabolism, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Chen, Wensheng [Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China)

2015-05-01

We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocyte diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of NF-κB attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of NF-κB attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of NF-κB attenuates hypertension-induced imbalance of cytokines

Acrolein and thiol-reactive electrophiles suppress allergen-induced innate airway epithelial responses by inhibition of DUOX1 and EGFR.

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Danyal, Karamatullah; de Jong, Willem; O'Brien, Edmund; Bauer, Robert A; Heppner, David E; Little, Andrew C; Hristova, Milena; Habibovic, Aida; van der Vliet, Albert

2016-11-01

Acrolein is a major thiol-reactive component of cigarette smoke (CS) that is thought to contribute to increased asthma incidence associated with smoking. Here, we explored the effects of acute acrolein exposure on innate airway responses to two common airborne allergens, house dust mite and Alternaria alternata, and observed that acrolein exposure of C57BL/6 mice (5 ppm, 4 h) dramatically inhibited innate airway responses to subsequent allergen challenge, demonstrated by attenuated release of the epithelial-derived cytokines IL-33, IL-25, and IL-1α. Acrolein and other anti-inflammatory thiol-reactive electrophiles, cinnamaldehyde, curcumin, and sulforaphane, similarly inhibited allergen-induced production of these cytokines from human or murine airway epithelial cells in vitro. Based on our previous observations indicating the importance of Ca 2+ -dependent signaling, activation of the NADPH oxidase DUOX1, and Src/EGFR-dependent signaling in allergen-induced epithelial secretion of these cytokines, we explored the impact of acrolein on these pathways. Acrolein and other thiol-reactive electrophiles were found to dramatically prevent allergen-induced activation of DUOX1 as well as EGFR, and acrolein was capable of inhibiting EGFR tyrosine kinase activity via modification of C797. Biotin-labeling strategies indicated increased cysteine modification and carbonylation of Src, EGFR, as well as DUOX1, in response to acrolein exposure in vitro and in vivo, suggesting that direct alkylation of these proteins on accessible cysteine residues may be responsible for their inhibition. Collectively, our findings indicate a novel anti-inflammatory mechanism of CS-derived acrolein and other thiol-reactive electrophiles, by directly inhibiting DUOX1- and EGFR-mediated airway epithelial responses to airborne allergens. Copyright © 2016 the American Physiological Society.

Inhibition of cytokine production by methotrexate. Studies in healthy volunteers and patients with rheumatoid arthritis.

OpenAIRE

Gerards, A.H.; Lathouder, de, S; Groot, E.R.; Dijkmans, B.A.C.; Aarden, L.A.

2003-01-01

OBJECTIVES: To analyse whether the beneficial effects of methotrexate in rheumatoid arthritis (RA) could be due to inhibition of inflammatory cytokine production. METHODS: Cytokine production was studied using whole blood (WB) and mononuclear cells (MNC) of healthy volunteers and RA patients. Cultures were stimulated with either bacterial products such as lipo-oligosaccharide (LOS) or Staphylococcus aureus Cowan I (SAC) to activate monocytes or with monoclonal antibodies to CD3 and CD28 to in...

CD83 Antibody Inhibits Human B Cell Responses to Antigen as well as Dendritic Cell-Mediated CD4 T Cell Responses.

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Wong, Kuan Y; Baron, Rebecca; Seldon, Therese A; Jones, Martina L; Rice, Alison M; Munster, David J

2018-05-15

Anti-CD83 Ab capable of Ab-dependent cellular cytotoxicity can deplete activated CD83 + human dendritic cells, thereby inhibiting CD4 T cell-mediated acute graft-versus-host disease. As CD83 is also expressed on the surface of activated B lymphocytes, we hypothesized that anti-CD83 would also inhibit B cell responses to stimulation. We found that anti-CD83 inhibited total IgM and IgG production in vitro by allostimulated human PBMC. Also, Ag-specific Ab responses to immunization of SCID mice xenografted with human PBMC were inhibited by anti-CD83 treatment. This inhibition occurred without depletion of all human B cells because anti-CD83 lysed activated CD83 + B cells by Ab-dependent cellular cytotoxicity and spared resting (CD83 - ) B cells. In cultured human PBMC, anti-CD83 inhibited tetanus toxoid-stimulated B cell proliferation and concomitant dendritic cell-mediated CD4 T cell proliferation and expression of IFN-γ and IL-17A, with minimal losses of B cells (80% of B cells but had no effect on CD4 T cell proliferation and cytokine expression. By virtue of the ability of anti-CD83 to selectively deplete activated, but not resting, B cells and dendritic cells, with the latter reducing CD4 T cell responses, anti-CD83 may be clinically useful in autoimmunity and transplantation. Advantages might include inhibited expansion of autoantigen- or alloantigen-specific B cells and CD4 T cells, thus preventing further production of pathogenic Abs and inflammatory cytokines while preserving protective memory and regulatory cells. Copyright © 2018 by The American Association of Immunologists, Inc.

Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo

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Yoshida, Ryoko; Suzuki, Mayu; Sakaguchi, Ryota; Hasegawa, Eiichi; Kimura, Akihiro; Shichita, Takashi; Sekiya, Takashi [Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582 (Japan); Japan Science and Technology Agency, CREST, Chiyoda-ku 102-0075 (Japan); Shiraishi, Hiroshi [Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga (Japan); Shimoda, Kouji [Department of Laboratory Animal Center, Keio University School of Medicine, Tokyo (Japan); Yoshimura, Akihiko, E-mail: yoshimura@a6.keio.jp [Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjyuku-ku, Tokyo 160-8582 (Japan); Japan Science and Technology Agency, CREST, Chiyoda-ku 102-0075 (Japan)

2012-06-29

Highlights: Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos produced less inflammatory cytokines. Black-Right-Pointing-Pointer Dendritic cells expressing stabilized c-Fos activated T cells less efficiently. Black-Right-Pointing-Pointer Transgenic mice expressing stabilized c-Fos were resistant to EAE model. -- Abstract: Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production by monocytic cells. We have shown that the transcription factor c-Fos is responsible for cAMP-mediated suppression of inflammatory cytokine production, and that c-Fos protein is stabilized by IKK{beta}-mediated phosphorylation. We found that S308 is one of the major phosphorylation sites, and that the S308D mutation prolongs c-Fos halflife. To investigate the role of stabilized c-Fos protein in dendritic cells (DCs) in vivo, we generated CD11c-promoter-deriven c-FosS308D transgenic mice. As expected, bone marrow-derived DCs (BMDCs) from these Tg mice produced smaller amounts of inflammatory cytokines, including TNF-{alpha}, IL-12, and IL-23, but higher levels of IL-10, in response to LPS, than those from wild-type (Wt) mice. When T cells were co-cultured with BMDCs from Tg mice, production of Th1 and Th17 cytokines was reduced, although T cell proliferation was not affected. Tg mice demonstrated more resistance to experimental autoimmune encephalomyelitis (EAE) than did Wt mice. These data suggest that c-Fos in DCs plays a suppressive role in certain innate and adaptive immune responses.

Interactions between cytokines and nitric oxide.

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Liew, F Y

1995-01-01

There is now an impressive range of evidence supporting the important role of cytokines in sleep regulation (see Krueger et al., 1995; De Simoni et al., 1995). It has also been reported that inhibition of nitric oxide (NO) synthesis suppresses sleep in rabbits (Kapás et al., 1994). This is not surprising, since NO is closely involved in neurotransmission (Garthwaite, 1991; Schuman and Madison, 1994) and cytokines are the major inducers of NO synthesis (Hibbs et al., 1990). Further, it is now clear that NO plays an important role in modulating immune responses, possibly through the differential regulation of cytokine synthesis (Taylor-Robinson et al., 1994). In this article, I will provide evidence for the interactions between cytokines and nitric oxide, and discuss their implications in the regulation of immune responses. I shall illustrate these mainly with results from my coworkers and I, from our laboratory rather than attempting an exhaustive review of the subject.

Autophagy Inhibition Contributes to ROS-Producing NLRP3-Dependent Inflammasome Activation and Cytokine Secretion in High Glucose-Induced Macrophages.

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Dai, Jiezhi; Zhang, Xiaotian; Li, Li; Chen, Hua; Chai, Yimin

2017-01-01

Type 2 diabetes is a persistent inflammatory response that impairs the healing process. We hypothesized that stimulation with high glucose following a pro-inflammatory signal would lead to autophagy inhibition, reactive oxygen species (ROS) production and eventually to the activation of the Nod-like receptor protein (NLRP) -3. Macrophages were isolated from human diabetic wound. We measured the expression of NLRP3, caspase1 and interleukin-1 beta (IL-1β) by western blot and real-time PCR, and the surface markers on cells by flow cytometry. THP-1-derived macrophages exposed to high glucose were applied to study the link between autophagy, ROS and NLRP3 activation. LC3-II, P62, NLRP3 inflammation and IL-1β expression were measured by western blot and real-time PCR. ROS production was measured with a Cellular Reactive Oxygen Species Detection Assay Kit. Macrophages isolated from diabetic wounds exhibited a pro-inflammatory phenotype, including sustained NLRP3 inflammasome activity associated with IL-1β secretion. Our data showed that high glucose inhibited autophagy, induced ROS production, and activated NLRP3 inflammasome and cytokine secretion in THP-1-derived macrophages. To study high glucose-induced NLRP3 inflammasome signalling, we performed studies using an autophagy inducer, a ROS inhibitor and a NLRP3 inhibitor and found that all reduced the NLRP3 inflammasome activation and cytokine secretion. Sustained NLRP3 inflammasome activity in wound-derived macrophages contributes to the hyper-inflammation in human diabetic wounds. Autophagy inhibition and ROS generation play an essential role in high glucose-induced NLRP3 inflammasome activation and cytokine secretion in macrophages. © 2017 The Author(s). Published by S. Karger AG, Basel.

Analysis of SF and plasma cytokines provides insights into the mechanisms of inflammatory arthritis and may predict response to therapy.

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Wright, Helen L; Bucknall, Roger C; Moots, Robert J; Edwards, Steven W

2012-03-01

Biologic drugs have revolutionized the care of RA, but are expensive and not universally effective. To further understand the inflammatory mechanisms underlying RA and identify potential biomarkers predicting response to therapy, we measured multiple cytokine concentrations in SF of patients with inflammatory arthritides (IAs) and, in a subset of patients with RA, correlated this with response to TNF-α inhibition. SF from 42 RA patients and 19 non-RA IA patients were analysed for 12 cytokines using a multiplex cytokine assay. Cytokines were also measured in the plasma of 16 RA patients before and following treatment with anti-TNF-α. Data were analysed using Mann-Whitney U-test, Spearman's rank correlation and cluster analysis with the Kruskal-Wallis test with Dunn's post-test analysis. RA SF contained significantly elevated levels of IL-1β, IL-1ra, IL-2, IL-4, IL-8, IL-10, IL-17, IFN-γ, G-CSF, GM-CSF and TNF-α compared with other IA SF. RA patients who did not respond to anti-TNF therapy had elevated IL-6 in their SF pre-therapy (P < 0.05), whereas responders had elevated IL-2 and G-CSF (P < 0.05). Plasma cytokine concentrations were not significantly modulated by TNF inhibitors, with the exception of IL-6, which decreased after 12 weeks (P < 0.05). Cytokine profiles in RA SF vary with treatment and response to therapy. Cytokine concentrations are significantly lower in plasma than in SF and relatively unchanged by TNF inhibitor therapy. Concentrations of IL-6, IL-2 and G-CSF in SF may predict response to TNF inhibitors.

Cytokines in the management of rotavirus infection: A systematic review of in vivo studies.

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Gandhi, Gopalsamy Rajiv; Santos, Victor Santana; Denadai, Marina; da Silva Calisto, Valdete Kaliane; de Souza Siqueira Quintans, Jullyana; de Oliveira E Silva, Ana Mara; de Souza Araújo, Adriano Antunes; Narain, Narendra; Cuevas, Luis Eduardo; Júnior, Lucindo José Quintans; Gurgel, Ricardo Queiroz

2017-08-01

Rotavirus is a leading cause of childhood diarrhoea. Rotavirus vaccines are effective against severe rotavirus gastroenteritis, but have lower efficacy in low income countries in Africa. Anti-rotavirus treatment is not available. This study reviews the literature of animal studies evaluating whether cytokine mediated pathways of immune activation could improve rotavirus therapy. We performed a systematic review of articles in English published from 2010 to 2016 reporting agents with in vivo antirotavirus activity for the management of rotavirus infection. The search was carried in PubMed, EMBASE, Scopus and Web of Science. Animal experiments where cytokines were investigated to assess the outcome of rotavirus therapy were included. A total of 869 publications were identified. Of these, 19 pertained the objectives of the review, and 11 articles described the effect of probiotics/commensals on rotavirus infection and immune responses in animals. Eight further in vivo studies evaluated the immunomodulating effects of herbs, secondary metabolites and food-derived products on cytokine responses of rotavirus-infected animals. Studies extensively reported the regulatory roles for T-helper (Th)1 (interferon gamma (IFN-γ), interleukin (IL)-2, IL-12) and Th2 (IL-4, IL-6, IL-10) cytokines responses to rotavirus pathogenesis and immunity, inhibiting rotavirus infection through suppression of inflammation by viral inhibition. Th1 and Th2 cytokines stimulate the immune system, inhibiting rotavirus binding and/or replication in animal models. Th1/Th2 cytokine responses have optimal immunomodulating effects to reduce rotavirus diarrhoea and enhance immune responses in experimental rotavirus infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

Stratum corneum cytokines and skin irritation response to sodium lauryl sulfate

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de Jongh, Cindy M.; Verberk, Maarten M.; Withagen, Carien E. T.; Jacobs, John J. L.; Rustemeyer, Thomas; Kezic, Sanja

2006-01-01

Little is known about cytokines involved in chronic irritant contact dermatitis. Individual cytokine profiles might explain at least part of the differences in the individual response to irritation. Our objective was to investigate the relation between baseline stratum corneum (SC) cytokine levels

Methyl Protodioscin from the Roots of Asparagus cochinchinensis Attenuates Airway Inflammation by Inhibiting Cytokine Production

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Ju Hee Lee

2015-01-01

Full Text Available The present study was designed to find pharmacologically active compound against airway inflammation from the roots of Asparagus cochinchinensis. The 70% ethanol extract of the roots of A. cochinchinensis (ACE was found to inhibit IL-6 production from IL-1β-treated lung epithelial cells (A549 and the major constituent, methyl protodioscin (MP, also strongly inhibited the production of IL-6, IL-8, and tumor necrosis factor- (TNF- α from A549 cells at 10–100 μM. This downregulating effect of proinflammatory cytokine production was found to be mediated, at least in part, via inhibition of c-Jun N-terminal kinase (JNK and c-Jun activation pathway. When examined on an in vivo model of airway inflammation in mice, lipopolysaccharide- (LPS- induced acute lung injury, ACE, and MP significantly inhibited cell infiltration in the bronchoalveolar lavage fluid by the oral treatment at doses of 100–400 mg/kg and 30–60 mg/kg, respectively. MP also inhibited the production of proinflammatory cytokines such as IL-6, TNF-α, and IL-1β in lung tissue. All of these findings provide scientific evidence supporting the role of A. cochinchinensis as a herbal remedy in treating airway inflammation and also suggest a therapeutic value of MP on airway inflammatory disorders.

A synthetic peptide blocking TRPV1 activation inhibits UV-induced skin responses.

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Kang, So Min; Han, Sangbum; Oh, Jang-Hee; Lee, Young Mee; Park, Chi-Hyun; Shin, Chang-Yup; Lee, Dong Hun; Chung, Jin Ho

2017-10-01

Transient receptor potential type 1 (TRPV1) can be activated by ultraviolet (UV) irradiation, and mediates UV-induced matrix metalloproteinase (MMP)-1 and proinflammatory cytokines in keratinocytes. Various chemicals and compounds targeting TRPV1 activation have been developed, but are not in clinical use mostly due to their safety issues. We aimed to develop a novel TRPV1-targeting peptide to inhibit UV-induced responses in human skin. We designed and generated a novel TRPV1 inhibitory peptide (TIP) which mimics the specific site in TRPV1 (aa 701-709: Gln-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr, QRAITILDT), Thr 705 , and tested its efficacy of blocking UV-induced responses in HaCaT, mouse, and human skin. TIP effectively inhibited capsaicin-induced calcium influx and TRPV1 activation. Treatment of HaCaT with TIP prevented UV-induced increases of MMP-1 and pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-α. In mouse skin in vivo, TIP inhibited UV-induced skin thickening and prevented UV-induced expression of MMP-13 and MMP-9. Moreover, TIP attenuated UV-induced erythema and the expression of MMP-1, MMP-2, IL-6, and IL-8 in human skin in vivo. The novel synthetic peptide targeting TRPV1 can ameliorate UV-induced skin responses in vitro and in vivo, providing a promising therapeutic approach against UV-induced inflammation and photoaging. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Persistence of STAT-1 inhibition and induction of cytokine resistance in pancreatic β cells treated with St John's wort and its component hyperforin.

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Novelli, Michela; Beffy, Pascale; Gregorelli, Alex; Porozov, Svetlana; Mascia, Fabrizio; Vantaggiato, Chiara; Masiello, Pellegrino; Menegazzi, Marta

2017-10-09

St John's wort extract (SJW) and its component hyperforin (HPF) were shown to potently inhibit cytokine-induced STAT-1 and NF-κB activation in pancreatic β cells and protect them against injury. This study aimed at exploring the time course of STAT-1 inhibition afforded by these natural compounds in the β-cell line INS-1E. INS-1E cells were pre-incubated with SJW extract (2-5 μg/ml) or HPF (0.5-2 μm) and then exposed to a cytokine mixture. In some experiments, these compounds were added after or removed before cytokine exposure. STAT-1 activation was assessed by electrophoretic mobility shift assay, apoptosis by caspase-3 activity assay, mRNA gene expression by RT-qPCR. Pre-incubation with SJW/HPF for 1-2 h exerted a remarkable STAT-1 downregulation, which was maintained upon removal of the compounds before early or delayed cytokine addition. When the protective compounds were added after cell exposure to cytokines, between 15 and 90 min, STAT-1 inhibition also occurred at a progressively decreasing extent. Upon 24-h incubation, SJW and HPF counteracted cytokine-induced β-cell dysfunction, apoptosis and target gene expression. SJW and HPF confer to β cells a state of 'cytokine resistance', which can be elicited both before and after cytokine exposure and safeguards these cells from deleterious cytokine effects. © 2017 Royal Pharmaceutical Society.

Baicalein inhibits IL-1β- and TNF-α-induced inflammatory cytokine production from human mast cells via regulation of the NF-κB pathway

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Krishnaswamy Guha

2007-11-01

Full Text Available Abstract Background Human mast cells are multifunctional cells capable of a wide variety of inflammatory responses. Baicalein (BAI, isolated from the traditional Chinese herbal medicine Huangqin (Scutellaria baicalensis Georgi, has been shown to have anti-inflammatory effects. We examined its effects and mechanisms on the expression of inflammatory cytokines in an IL-1β- and TNF-α-activated human mast cell line, HMC-1. Methods HMC-1 cells were stimulated either with IL-1β (10 ng/ml or TNF-α (100 U/ml in the presence or absence of BAI. We assessed the expression of IL-6, IL-8, and MCP-1 by ELISA and RT-PCR, NF-κB activation by electrophoretic mobility shift assay (EMSA, and IκBα activation by Western blot. Results BAI (1.8 to 30 μM significantly inhibited production of IL-6, IL-8, and MCP-1 in a dose-dependent manner in IL-1β-activated HMC-1. BAI (30 μM also significantly inhibited production of IL-6, IL-8, and MCP-1 in TNF-α-activated HMC-1. Inhibitory effects appear to involve the NF-κB pathway. BAI inhibited NF-κB activation in IL-1β- and TNF-α-activated HMC-1. Furthermore, BAI increased cytoplasmic IκBα proteins in IL-1β- and TNF-α-activated HMC-1. Conclusion Our results showed that BAI inhibited the production of inflammatory cytokines through inhibition of NF-κB activation and IκBα phosphorylation and degradation in human mast cells. This inhibitory effect of BAI on the expression of inflammatory cytokines suggests its usefulness in the development of novel anti-inflammatory therapies.

A small-molecule/cytokine combination enhances hematopoietic stem cell proliferation via inhibition of cell differentiation.

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Wang, Lan; Guan, Xin; Wang, Huihui; Shen, Bin; Zhang, Yu; Ren, Zhihua; Ma, Yupo; Ding, Xinxin; Jiang, Yongping

2017-07-18

Accumulated evidence supports the potent stimulating effects of multiple small molecules on the expansion of hematopoietic stem cells (HSCs) which are important for the therapy of various hematological disorders. Here, we report a novel, optimized formula, named the SC cocktail, which contains a combination of three such small molecules and four cytokines. Small-molecule candidates were individually screened and then combined at their optimal concentration with the presence of cytokines to achieve maximum capacity for stimulating the human CD34 + cell expansion ex vivo. The extent of cell expansion and the immunophenotype of expanded cells were assessed through flow cytometry. The functional preservation of HSC stemness was confirmed by additional cell and molecular assays in vitro. Subsequently, the expanded cells were transplanted into sublethally irradiated NOD/SCID mice for the assessment of human cell viability and engraftment potential in vivo. Furthermore, the expression of several genes in the cell proliferation and differentiation pathways was analyzed through quantitative polymerase chain reaction (qPCR) during the process of CD34 + cell expansion. The SC cocktail supported the retention of the immunophenotype of hematopoietic stem/progenitor cells remarkably well, by yielding purities of 86.6 ± 11.2% for CD34 + cells and 76.2 ± 10.5% for CD34 + CD38 - cells, respectively, for a 7-day culture. On day 7, the enhancement of expansion of CD34 + cells and CD34 + CD38 - cells reached a maxima of 28.0 ± 5.5-fold and 27.9 ± 4.3-fold, respectively. The SC cocktail-expanded CD34 + cells preserved the characteristics of HSCs by effectively inhibiting their differentiation in vitro and retained the multilineage differentiation potential in primary and secondary in vivo murine xenotransplantation trials. Further gene expression analysis suggested that the small-molecule combination strengthened the ability of the cytokines to enhance the Notch

Beneficial effects of cytokine induced hyperlipidemia.

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Feingold, K R; Hardardóttir, I; Grunfeld, C

1998-01-01

Infection, inflammation and trauma induce marked changes in the plasma levels of a wide variety of proteins (acute phase response), and these changes are mediated by cytokines. The acute phase response is thought to be beneficial to the host. The host's response to injury also results in dramatic alterations in lipid metabolism and circulating lipoprotein levels which are mediated by cytokines. A large number of cytokines including TNF, the interleukins, and the interferons increase serum triglyceride levels. This rapid increase (1-2 h) is predominantly due to an increase in hepatic VLDL secretion while the late increase may be due to a variety of factors including increased hepatic production of VLDL or delayed clearance secondary to a decrease in lipoprotein lipase activity and/or apolipoprotein E levels on VLDL. In animals other than primates, cytokines also increase serum cholesterol levels, most likely by increasing hepatic cholesterol. Cytokines increase hepatic cholesterol synthesis by stimulating HMG CoA reductase gene expression and decrease hepatic cholesterol catabolism by inhibiting cholesterol 7 alpha-hydroxylase, the key enzyme in bile acid synthesis. Injury and/or cytokines also decrease HDL cholesterol levels and induce alterations in the composition of HDL. The content of SAA and apolipoprotein J increase, apolipoprotein A1 may decrease, and the cholesterol ester content decreases while free cholesterol increases. Additionally, key proteins involved in HDL metabolism are altered by cytokines; LCAT activity, hepatic lipase activity, and CETP levels decrease. These changes in lipid and lipoprotein metabolism may be beneficial in a number of ways including: lipoproteins competing with viruses for cellular receptors, apolipoproteins neutralizing viruses, lipoproteins binding and targeting parasites for destruction, apolipoproteins lysing parasites, redistribution of nutrients to cells involved in the immune response and/or tissue repair, and

Withaferin A Associated Differential Regulation of Inflammatory Cytokines

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Seema Dubey

2018-02-01

Full Text Available A role of inflammation-associated cytokines/chemokines has been implicated in a wide variety of human diseases. Here, we investigated the regulation of inflammatory cytokines released by monocyte-derived THP-1 cells following treatment with the dietary agent withaferin A (WFA. Membrane-based cytokine array profiling of the culture supernatant from adenosine triphosphate-stimulated WFA-treated THP-1 cells showed differential regulation of multiple cytokines/chemokines. A selected group of cytokines/chemokines [interleukin-1 beta (IL-1β, CCL2/MCP-1, granulocyte-macrophage colony stimulating factor, PDGF-AA, PTX3, cystatin-3, relaxin-2, TNFRSF8/CD30, and ACRP30] was validated at the transcription level using qPCR. In silico analysis for transcriptional binding factors revealed the presence of nuclear factor-kappa B (NF-κB in a group of downregulated cytokine gene promoters. WFA treatment of THP-1 cells blocks the nuclear translocation of NF-kB and corresponds with the reduced levels of cytokine secretion. To further understand the differential expression of cytokines/chemokines, we showed that WFA alters the nigericin-induced co-localization of NLRP3 and ASC proteins, thereby inhibiting caspase-1 activation, which is responsible for the cleavage and maturation of pro-inflammatory cytokines IL-1β and IL-18. These data suggest that dietary agent WFA concurrently targets NF-κB and the inflammasome complex, leading to inhibition of IL-1β and IL-18, respectively, in addition to differential expression of multiple cytokines/chemokines. Taken together, these results provide a rationale for using WFA to further explore the anti-inflammatory mechanism of cytokines/chemokines associated with inflammatory diseases.

Antioxidants inhibit SAA formation and pro-inflammatory cytokine release in a human cell model of alkaptonuria.

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Spreafico, Adriano; Millucci, Lia; Ghezzi, Lorenzo; Geminiani, Michela; Braconi, Daniela; Amato, Loredana; Chellini, Federico; Frediani, Bruno; Moretti, Elena; Collodel, Giulia; Bernardini, Giulia; Santucci, Annalisa

2013-09-01

Alkaptonuria (AKU) is an ultra-rare autosomal recessive disease that currently lacks an appropriate therapy. Recently we provided experimental evidence that AKU is a secondary serum amyloid A (SAA)-based amyloidosis. The aim of the present work was to evaluate the use of antioxidants to inhibit SAA amyloid and pro-inflammatory cytokine release in AKU. We adopted a human chondrocytic cell AKU model to evaluate the anti-amyloid capacity of a set of antioxidants that had previously been shown to counteract ochronosis in a serum AKU model. Amyloid presence was evaluated by Congo red staining. Homogentisic acid-induced SAA production and pro-inflammatory cytokine release (overexpressed in AKU patients) were evaluated by ELISA and multiplex systems, respectively. Lipid peroxidation was evaluated by means of a fluorescence-based assay. Our AKU model allowed us to prove the efficacy of ascorbic acid combined with N-acetylcysteine, taurine, phytic acid and lipoic acid in significantly inhibiting SAA production, pro-inflammatory cytokine release and membrane lipid peroxidation. All the tested antioxidant compounds were able to reduce the production of amyloid and may be the basis for establishing new therapies for AKU amyloidosis.

Pattern recognition receptor-mediated cytokine response in infants across 4 continents.

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Smolen, Kinga K; Ruck, Candice E; Fortuno, Edgardo S; Ho, Kevin; Dimitriu, Pedro; Mohn, William W; Speert, David P; Cooper, Philip J; Esser, Monika; Goetghebuer, Tessa; Marchant, Arnaud; Kollmann, Tobias R

2014-03-01

Susceptibility to infection as well as response to vaccination varies among populations. To date, the underlying mechanisms responsible for these clinical observations have not been fully delineated. Because innate immunity instructs adaptive immunity, we hypothesized that differences between populations in innate immune responses may represent a mechanistic link to variation in susceptibility to infection or response to vaccination. Determine whether differences in innate immune responses exist among infants from different continents of the world. We determined the innate cytokine response following pattern recognition receptor (PRR) stimulation of whole blood from 2-year-old infants across 4 continents (Africa, North America, South America, and Europe). We found that despite the many possible genetic and environmental exposure differences in infants across 4 continents, innate cytokine responses were similar for infants from North America, South America, and Europe. However, cells from South African infants secreted significantly lower levels of cytokines than did cells from infants from the 3 other sites, and did so following stimulation of extracellular and endosomal but not cytosolic PRRs. Substantial differences in innate cytokine responses to PRR stimulation exist among different populations of infants that could not have been predicted. Delineating the underlying mechanism(s) for these differences will not only aid in improving vaccine-mediated protection but possibly also provide clues for the susceptibility to infection in different regions of the world. Copyright © 2013 The Authors. Published by Mosby, Inc. All rights reserved.

COL-3, a chemically modified tetracycline, inhibits lipopolysaccharide-induced microglia activation and cytokine expression in the brain.

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Rawan Abdulhameed Edan

Full Text Available Microglia activation results in release of proinflammatory molecules including cytokines, which contribute to neuronal damage in the central nervous system (CNS if not controlled. Tetracycline antibiotics such as minocycline inhibit microglial activation and cytokine expression during CNS inflammation. In the present study we found that administration of chemically modified tetracycline-3 (COL-3, inhibits lipopolysaccharide (LPS-induced microglial and p38 MAPK activation, as well as the increase in TNF-α, but not IL-1β expression, in the brains of BALB/c mice. COL-3 has been described to have no antibacterial activity. We observed that COL-3 had no activity against a Gram-negative bacteria, Escherichia coli; however surprisingly, COL-3 had antibacterial activity against a Gram-positive bacteria Staphylococcus aureus, with a minimum inhibitory concentration of 1 mg/ml. Our data show that COL-3 has some antibacterial activity against S. aureus, inhibits LPS-induced neuroinflammation, and displays potential as a therapeutic agent for treatment of conditions involving CNS inflammation.

Academic stress-induced changes in Th1- and Th2-cytokine response

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Areej M. Assaf

2017-12-01

Full Text Available Psychological stress stimulates physiological responses releasing catecholamines and corticoids, which act via corresponding receptors on immune cells, producing a shift in the cytokine balance. These responses are variable depending on the nature of stressors. The effect of the academic stress on the production of the Th1-cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-6 and IL-8 and Th2-cytokines (IL-1ra, IL-4, IL-5 and IL-10 on 35 medical/health sciences students after completing their questionnaires was investigated. Blood samples were taken at three stages; baseline stage at the beginning, midterm and final academic examination stages. Plasma cortisol and cytokines were measured during the three stages. The last two stages were compared with the baseline non-stress period. Results of the stress induced during the final examination stage were the highest with a significant increase in cortisol release, IL-4, IL-5 and IL-1ra release with a shift in Th1:Th2 cytokines balance towards Th2. Whereby, the midterm stage did not show significant reduction in Th1-cytokines except for TNF-α, with an increase in IFN-γ level that was reduced in the third stage. Th2 cytokine, IL-1ra, had positive correlations with Th1 cytokines; IL-2 and IFN-γ in the second stage and IL-6 cytokine in the third stage. Cortisol was positively correlated with IL-8 in the last stage and heart rates had negative correlation with IL-10 in the first and last stages. Findings of this study indicate that exam stress down-regulates Th1 with a selective up-regulation of Th2-cytokines. In conclusion, Cortisol might have a role in suppressing the release of Th1- mediated cellular immune response which could increase the vulnerability among the students to infectious diseases.

Academic stress-induced changes in Th1- and Th2-cytokine response.

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Assaf, Areej M; Al-Abbassi, Reem; Al-Binni, Maysaa

2017-12-01

Psychological stress stimulates physiological responses releasing catecholamines and corticoids, which act via corresponding receptors on immune cells, producing a shift in the cytokine balance. These responses are variable depending on the nature of stressors. The effect of the academic stress on the production of the Th1-cytokines (TNF-α, IFN-γ, IL-1β, IL-2, IL-6 and IL-8) and Th2-cytokines (IL-1ra, IL-4, IL-5 and IL-10) on 35 medical/health sciences students after completing their questionnaires was investigated. Blood samples were taken at three stages; baseline stage at the beginning, midterm and final academic examination stages. Plasma cortisol and cytokines were measured during the three stages. The last two stages were compared with the baseline non-stress period. Results of the stress induced during the final examination stage were the highest with a significant increase in cortisol release, IL-4, IL-5 and IL-1ra release with a shift in Th1:Th2 cytokines balance towards Th2. Whereby, the midterm stage did not show significant reduction in Th1-cytokines except for TNF-α, with an increase in IFN-γ level that was reduced in the third stage. Th2 cytokine, IL-1ra, had positive correlations with Th1 cytokines; IL-2 and IFN-γ in the second stage and IL-6 cytokine in the third stage. Cortisol was positively correlated with IL-8 in the last stage and heart rates had negative correlation with IL-10 in the first and last stages. Findings of this study indicate that exam stress down-regulates Th1 with a selective up-regulation of Th2-cytokines. In conclusion, Cortisol might have a role in suppressing the release of Th1- mediated cellular immune response which could increase the vulnerability among the students to infectious diseases.

Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies.

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Brattsand, R; Linden, M

1996-01-01

Glucocorticoids inhibit the expression and action of most cytokines. This is part of the in vivo feed-back system between inflammation-derived cytokines and CNS-adrenal produced corticosteroids with the probable physiological relevance to balance parts of the host defence and anti-inflammatory systems of the body. Glucocorticoids modulate cytokine expression by a combination of genomic mechanisms. The activated glucocorticoid-receptor complex can (i) bind to and inactivate key proinflammatory transcription factors (e.g. AP-1, NF kappa B). This takes place at the promotor responsive elements of these factors, but has also been reported without the presence of DNA; (ii) via glucocorticoid responsive elements (GRE), upregulate the expression of cytokine inhibitory proteins, e.g. I kappa B, which inactivates the transcription factor NF kappa B and thereby the secondary expression of a series of cytokines; (iii) reduce the half-life time and utility of cytokine mRNAs. In studies with triggered human blood mononuclear cells in culture, glucocorticoids strongly diminish the production of the 'initial phase' cytokines IL-1 beta and TNF-alpha and the 'immunomodulatory' cytokines IL-2, IL-3, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, as well as of IL-6, IL-8 and the growth factor GM-CSF. While steroid treatment broadly attenuates cytokine production, it cannot modulate it selectively, e.g. just the TH0, the TH1 or the TH2 pathways. The production of the 'anti-inflammatory' IL-10 is also inhibited. The exceptions of steroid down-regulatory activity on cytokine expression seem to affect 'repair phase' cytokines like TGF-beta and PDGF. These are even reported to be upregulated, which may explain the rather weak steroid dampening action on healing and fibrotic processes. Some growth factors, e.g. G-CSF and M-CSF, are only weakly affected. In addition to diminishing the production of a cytokine, steroids can also often inhibit its subsequent actions. Because cytokines work in

Agmatine Reverses Sub-chronic Stress induced Nod-like Receptor Protein 3 (NLRP3) Activation and Cytokine Response in Rats.

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Sahin, Ceren; Albayrak, Ozgur; Akdeniz, Tuğba F; Akbulut, Zeynep; Yanikkaya Demirel, Gulderen; Aricioglu, Feyza

2016-10-01

The activation of Nod-like receptor protein 3 (NLRP3) has lately been implicated in stress and depression as an initiator mechanism required for the production of interleukin (IL)-1β and IL-18. Agmatine, an endogenous polyamine widely distributed in mammalian brain, is a novel neurotransmitter/neuromodulator, with antistress, anxiolytic and antidepressant-like effects. In this study, we examined the effect of exogenously administered agmatine on NLRP3 inflammasome pathway/cytokine responses in rats exposed to restraint stress for 7 days. The rats were divided into three groups: stress, stress+agmatine (40 mg/kg; i.p.) and control groups. Agmatine significantly down-regulated the gene expressions of all stress-induced NLRP3 inflammasome components (NLRP3, NF-κB, PYCARD, caspase-1, IL-1β and IL-18) in the hippocampus and prefrontal cortex (PFC) and reduced pro-inflammatory cytokine levels not only in both brain regions, but also in serum. Stress-reduced levels of IL-4 and IL-10, two major anti-inflammatory cytokines, were restored back to normal by agmatine treatment in the PFC. The findings of the present study suggest that stress-activated NLRP3 inflammasome and cytokine responses are reversed by an acute administration of agmatine. Whether antidepressant-like effect of agmatine can somehow, at least partially, be mediated by the inhibition of NLRP3 inflammasome cascade and relevant inflammatory responses requires further studies in animal models of depression. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Ceftiofur impairs pro-inflammatory cytokine secretion through the inhibition of the activation of NF-κB and MAPK

International Nuclear Information System (INIS)

Ci Xinxin; Song Yu; Zeng Fanqin; Zhang Xuemei; Li Hongyu; Wang Xinrui; Cui Junqing; Deng Xuming

2008-01-01

Ceftiofur is a new broad-spectrum, third-generation cephalosporin antibiotic for veterinary use. Immunopharmacological studies can provide new information on the immunomodulatory activities of some drugs, including their effect on cytokine productions. For this reason, we investigated the effect of ceftiofur on cytokine productions in vitro. We found that ceftiofur can downregulate tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), but did not affect interleukin-10 (IL-10) production. We further investigated signal transduction mechanisms to determine how ceftiofur affects. RAW 264.7 cells were pretreated with 1, 5, or 10 mg/L of ceftiofur 1 h prior to treatment with 1 mg/L of LPS. Thirty minutes later, cells were harvested and mitogen activated protein kinases (MAPKs) activation was measured by Western blot. Alternatively, cells were fixed and nuclear factor-κB (NF-κB) activation was measured using immunocytochemical analysis. Signal transduction studies showed that ceftiofur significantly inhibited extracellular signal-regulated kinase (ERK), p38, and c-jun NH 2 -terminal kinase (JNK) phosphorylation protein expression. Ceftiofur also inhibited p65-NF-κB translocation into the nucleus. Therefore, ceftiofur may inhibit LPS-induced production of inflammatory cytokines by blocking NF-κB and MAPKs signaling in RAW264.7 cells

Oral warfarin intake affects skin inflammatory cytokine responses in rats.

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Aleksandrov, Aleksandra Popov; Mirkov, Ivana; Zolotarevski, Lidija; Ninkov, Marina; Mileusnic, Dina; Kataranovski, Dragan; Kataranovski, Milena

2017-09-01

Warfarin is an anticoagulant used in prevention/prophylaxis of thromboembolism. Besides the effects on coagulation, non-hemorrhagic reactions have also been documented. Although cutaneous reactions were reported in some patients, the impact on skin immunity was not explored. In the present paper, the effect of 30-day oral warfarin intake on skin cytokine responses in rats was analyzed. Increased release of inflammatory cytokines (TNF, IL-1β and IL-10) was noted by skin explants from rats which received warfarin, but without effect on IL-6. No impact on epidermal cell cytokine secretion was seen, except a tendency of an increase of IL-6 response to stimulation with microbial product lipopolysaccharide (LPS). Topical application of contact allergen dinitrochlorobenzene (DNCB) resulted in slight (numerical solely) increase of TNF release by skin explants of warfarin-treated animals, while epidermal cells responded by increased secretion of all four cytokines examined. The data presented provide new information on the potential of oral warfarin to modulate skin innate immune activity. Copyright © 2017 Elsevier B.V. All rights reserved.

Stratum corneum cytokines and skin irritation response to sodium lauryl sulfate.

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De Jongh, Cindy M; Verberk, Maarten M; Withagen, Carien E T; Jacobs, John J L; Rustemeyer, Thomas; Kezic, Sanja

2006-06-01

Little is known about cytokines involved in chronic irritant contact dermatitis. Individual cytokine profiles might explain at least part of the differences in the individual response to irritation. Our objective was to investigate the relation between baseline stratum corneum (SC) cytokine levels and the skin response to a single and a repeated irritation test. This study also aimed to determine changes in SC cytokine levels after repeated irritation. Transepidermal water loss (TEWL) and erythema were measured in 20 volunteers after single 24-hr exposure to 1% sodium lauryl sulfate (SLS), and during and after repeated exposure to 0.1% SLS over a 3-week period. SC cytokine levels were measured from an unexposed skin site and from the repeatedly exposed site. Interleukin (IL)-1alpha decreased by 30% after repeated exposure, while IL-1RA increased 10-fold and IL-8 increased fourfold. Baseline IL-1RA and IL-8 values were predictors of TEWL and erythema after single exposure (r = 0.55-0.61). 6 subjects showed barrier recovery during repeated exposure. Baseline IL-1RA and IL-8 levels are likely to be indicators of higher skin irritability after single exposure to SLS. Barrier repair in some of the subjects might explain the lack of agreement between the TEWL response after single and repeated irritation.

Perilipin 1 Mediates Lipid Metabolism Homeostasis and Inhibits Inflammatory Cytokine Synthesis in Bovine Adipocytes.

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Zhang, Shiqi; Liu, Guowen; Xu, Chuang; Liu, Lei; Zhang, Qiang; Xu, Qiushi; Jia, Hongdou; Li, Xiaobing; Li, Xinwei

2018-01-01

Dairy cows with ketosis displayed lipid metabolic disorder and high inflammatory levels. Adipose tissue is an active lipid metabolism and endocrine tissue and is closely related to lipid metabolism homeostasis and inflammation. Perilipin 1 (PLIN1), an adipocyte-specific lipid-coated protein, may be involved in the above physiological function. The aim of this study is to investigate the role of PLIN1 in lipid metabolism regulation and inflammatory factor synthesis in cow adipocytes. The results showed that PLIN1 overexpression upregulated the expression of fatty acid and triglyceride (TAG) synthesis molecule sterol regulator element-binding protein-1c (SREBP-1c) and its target genes, diacylglycerol acyltransferase (DGAT) 1, and DGAT2, but inhibited the expression of lipolysis enzymes hormone-sensitive lipase (HSL) and CGI-58 for adipose triglyceride lipase (ATGL), thus augmenting the fatty acids and TAG synthesis and inhibiting lipolysis. Importantly, PLIN1 overexpression inhibited the activation of the NF-κB inflammatory pathway and decreased the expression and content of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) induced by lipopolysaccharide. Conversely, PLIN1 silencing inhibited TAG synthesis, promoted lipolysis, and overinduced the activation of the NF-κB inflammatory pathway in cow adipocytes. In ketotic cows, the expression of PLIN1 was markedly decreased, whereas lipid mobilization, NF-κB pathway, and downstream inflammatory cytokines were overinduced in adipose tissue. Taken together, these results indicate that PLIN1 can maintain lipid metabolism homeostasis and inhibit the NF-κB inflammatory pathway in adipocytes. However, low levels of PLIN1 reduced the inhibitory effect on fat mobilization, NF-κB pathway, and inflammatory cytokine synthesis in ketotic cows.

Perilipin 1 Mediates Lipid Metabolism Homeostasis and Inhibits Inflammatory Cytokine Synthesis in Bovine Adipocytes

Directory of Open Access Journals (Sweden)

Shiqi Zhang

2018-03-01

Full Text Available Dairy cows with ketosis displayed lipid metabolic disorder and high inflammatory levels. Adipose tissue is an active lipid metabolism and endocrine tissue and is closely related to lipid metabolism homeostasis and inflammation. Perilipin 1 (PLIN1, an adipocyte-specific lipid-coated protein, may be involved in the above physiological function. The aim of this study is to investigate the role of PLIN1 in lipid metabolism regulation and inflammatory factor synthesis in cow adipocytes. The results showed that PLIN1 overexpression upregulated the expression of fatty acid and triglyceride (TAG synthesis molecule sterol regulator element-binding protein-1c (SREBP-1c and its target genes, diacylglycerol acyltransferase (DGAT 1, and DGAT2, but inhibited the expression of lipolysis enzymes hormone-sensitive lipase (HSL and CGI-58 for adipose triglyceride lipase (ATGL, thus augmenting the fatty acids and TAG synthesis and inhibiting lipolysis. Importantly, PLIN1 overexpression inhibited the activation of the NF-κB inflammatory pathway and decreased the expression and content of tumor necrosis factor alpha (TNF-α, interleukin 1 beta (IL-1β, and interleukin 6 (IL-6 induced by lipopolysaccharide. Conversely, PLIN1 silencing inhibited TAG synthesis, promoted lipolysis, and overinduced the activation of the NF-κB inflammatory pathway in cow adipocytes. In ketotic cows, the expression of PLIN1 was markedly decreased, whereas lipid mobilization, NF-κB pathway, and downstream inflammatory cytokines were overinduced in adipose tissue. Taken together, these results indicate that PLIN1 can maintain lipid metabolism homeostasis and inhibit the NF-κB inflammatory pathway in adipocytes. However, low levels of PLIN1 reduced the inhibitory effect on fat mobilization, NF-κB pathway, and inflammatory cytokine synthesis in ketotic cows.

Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines.

Science.gov (United States)

Zong, L; Yu, Q H; Du, Y X; Deng, X M

2014-02-01

Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

Energy Technology Data Exchange (ETDEWEB)

Zong, L. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China); No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Yu, Q. H. [Second Military Medical University, Changhai Hospital, Department of Gastroenterology, Shanghai, China, Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai (China); Du, Y. X. [No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Deng, X. M. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China)

2014-03-03

Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

International Nuclear Information System (INIS)

Zong, L.; Yu, Q.H.; Du, Y.X.; Deng, X.M.

2014-01-01

Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis

Melanocortin peptides inhibit production of proinflammatory cytokines and nitric oxide by activated microglia.

Science.gov (United States)

Delgado, R; Carlin, A; Airaghi, L; Demitri, M T; Meda, L; Galimberti, D; Baron, P; Lipton, J M; Catania, A

1998-06-01

Inflammatory processes contribute to neurodegenerative disease, stroke, encephalitis, and other central nervous system (CNS) disorders. Activated microglia are a source of cytokines and other inflammatory agents within the CNS and it is therefore important to control glial function in order to preserve neural cells. Melanocortin peptides are pro-opiomelanocortin-derived amino acid sequences that include alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH). These peptides have potent and broad anti-inflammatory effects. We tested effects of alpha-MSH (1-13), alpha-MSH (11-13), and ACTH (1-24) on production of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) in a cultured murine microglial cell line (N9) stimulated with lipopolysaccharide (LPS) plus interferon gamma (IFN-gamma). Melanocortin peptides inhibited production of these cytokines and NO in a concentration-related fashion, probably by increasing intracellular cAMP. When stimulated with LPS + IFN-gamma, microglia increased release of alpha-MSH. Production of TNF-alpha, IL-6, and NO was greater in activated microglia after innmunoneutralization of endogenous alpha-MSH. The results suggest that alpha-MSH is an autocrine factor in microglia. Because melanocortin peptides inhibit production of pro-inflammatory mediators by activated microglia they might be useful in treatment of inflammatory/degenerative brain disorders.

miR-20a inhibits TCR-mediated signaling and cytokine production in human naïve CD4+ T cells.

Directory of Open Access Journals (Sweden)

Amarendra V Reddycherla

Full Text Available Upon TCR stimulation by peptide-MHC complexes, CD4+ T cells undergo activation and proliferation. This process will ultimately culminate in T-cell differentiation and the acquisition of effector functions. The production of specific cytokines by differentiated CD4+ T cells is crucial for the generation of the appropriate immune response. Altered CD4+ T-cell activation and cytokine production result in chronic inflammatory conditions and autoimmune disorders. miRNAs have been shown to be important regulators of T-cell biology. In this study, we have focused our investigation on miR-20a, a member of the miR-17-92 cluster, whose expression is decreased in patients suffering from multiple sclerosis. We have found that miR-20a is rapidly induced upon TCR-triggering in primary human naïve CD4+ T cells and that its transcription is regulated in a Erk-, NF-κB-, and Ca++-dependent manner. We have further shown that overexpression of miR-20a inhibits TCR-mediated signaling but not the proliferation of primary human naïve CD4+ T cells. However, miR-20a overexpression strongly suppresses IL-10 secretion and moderately decreases IL-2, IL-6 and IL8 production, which are crucial regulators of inflammatory responses. Our study suggests that miR-20a is a new player in the regulation of TCR signaling strength and cytokine production.

Pre-treatment with Toll-like receptor 4 antagonist inhibits lipopolysaccharide-induced preterm uterine contractility, cytokines, and prostaglandins in rhesus monkeys

Science.gov (United States)

Adams Waldorf, Kristina M.; Persing, David; Novy, Miles J.; Sadowsky, Drew W.; Gravett, Michael G.

2009-01-01

Intra-uterine infection, which occurs in the majority of early preterm births, triggers an immune response culminating in preterm labor. We hypothesized that blockade of lipopolysaccharide (LPS)-induced immune responses by a Toll-like receptor 4 antagonist (TLR4A) would prevent elevations in amniotic fluid (AF) cytokines, prostaglandins, and uterine contractility. Chronically catheterized rhesus monkeys at 128-147 days gestation received intra-amniotic infusions of either: 1) saline (n=6), 2) LPS (0.15-10μg; n=4), or 3) TLR4A pre-treatment with LPS (10 μg) one hour later (n=4). AF cytokines, prostaglandins, and uterine contractility were compared using oneway ANOVA with Bonferroni-adjusted pairwise comparisons. Compared to saline controls, LPS induced significant elevations in AF IL-8, TNF-α, PGE2, PGF2α, and uterine contractility (p<0.05). In contrast, TLR4A pre-treatment inhibited LPS-induced uterine activity and was associated with significantly lower AF IL-8, TNF-α, PGE2, and PGF2α versus LPS alone (p<0.05). Toll-like receptor antagonists, together with antibiotics, may delay or prevent infection-associated preterm birth. PMID:18187405

Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis

DEFF Research Database (Denmark)

Bendtzen, K; Hansen, P R; Rieneck, K

2003-01-01

and interleukin 6 (70-90% inhibition). Release of these cytokines was also suppressed when testing whole blood from RA patients receiving 50 mg spironolactone twice daily, indicating that pharmaceutical use of the drug may suppress the release of inflammatory cytokines. Spironolactone therapy was generally well...

6-Shogaol, an active compound of ginger, alleviates allergic dermatitis-like skin lesions via cytokine inhibition by activating the Nrf2 pathway

Energy Technology Data Exchange (ETDEWEB)

Park, Gunhyuk, E-mail: uranos5@kiom.re.kr [The K-herb Research Center, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054 (Korea, Republic of); Oh, Dal-Seok [The K-herb Research Center, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054 (Korea, Republic of); Lee, Mi Gi; Lee, Chang Eon [Major in Cosmeceutical Science, Division of Bio-technology and Convergence, Daegu Haany University, Gyeongsan (Korea, Republic of); Kim, Yong-ung, E-mail: ykim@dhu.ac.kr [Department of Pharmaceutical Engineering, College of Biomedical Science, Daegu Haany University (Korea, Republic of)

2016-11-01

Allergic dermatitis (AD) clinically presents with skin erythematous plaques, eruption, and elevated serum IgE, and T helper cell type 2 and 1 (Th2 and Th1) cytokine levels. 6-Shogaol [1-(4-hydroxy-methoxyphenyl)-4-decen-one], a pungent compound isolated from ginger, has shown anti-inflammatory effects, but its inhibitory effects on AD are unknown. The aim of this study was to examine whether 6-shogaol inhibits AD-like skin lesions and their underlying mechanism in vivo and in vitro. An AD-like response was induced by tumor necrosis factor-α (TNF-α) + IFN-γ in human keratinocytes or by 2,4-dinitrochlorobenzene (DNCB) in mice. In vivo, 6-shogaol inhibited the development of DNCB-induced AD-like skin lesions and scratching behavior, and showed significant reduction in Th2/1-mediated inflammatory cytokines, IgE, TNF-α, IFN-γ, thymus and activation-regulated chemokine, IL-1, 4, 12, and 13, cyclooxygenase-2, and nitric oxide synthase levels. In vitro, 6-shogaol inhibited reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) signaling, and increased the levels of total glutathione, heme oxygenase-1, and quinone 1 via nuclear factor erythroid 2 related factor 2 (Nrf2) activation. 6-Shogaol can alleviate AD-like skin lesions by inhibiting immune mediators via regulating the ROS/MAPKs/Nrf2 signaling pathway, and may be an effective alternative therapy for AD. - Highlights: • 6-Shogaol inhibited Th2/1-mediated inflammatory mediators in vitro and in vivo. • 6-Shogaol regulated ROS/MAPKs/Nrf2 signaling pathway. • 6-Shogaol can protect against the development of AD-like skin lesions.

6-Shogaol, an active compound of ginger, alleviates allergic dermatitis-like skin lesions via cytokine inhibition by activating the Nrf2 pathway

International Nuclear Information System (INIS)

Park, Gunhyuk; Oh, Dal-Seok; Lee, Mi Gi; Lee, Chang Eon; Kim, Yong-ung

2016-01-01

Allergic dermatitis (AD) clinically presents with skin erythematous plaques, eruption, and elevated serum IgE, and T helper cell type 2 and 1 (Th2 and Th1) cytokine levels. 6-Shogaol [1-(4-hydroxy-methoxyphenyl)-4-decen-one], a pungent compound isolated from ginger, has shown anti-inflammatory effects, but its inhibitory effects on AD are unknown. The aim of this study was to examine whether 6-shogaol inhibits AD-like skin lesions and their underlying mechanism in vivo and in vitro. An AD-like response was induced by tumor necrosis factor-α (TNF-α) + IFN-γ in human keratinocytes or by 2,4-dinitrochlorobenzene (DNCB) in mice. In vivo, 6-shogaol inhibited the development of DNCB-induced AD-like skin lesions and scratching behavior, and showed significant reduction in Th2/1-mediated inflammatory cytokines, IgE, TNF-α, IFN-γ, thymus and activation-regulated chemokine, IL-1, 4, 12, and 13, cyclooxygenase-2, and nitric oxide synthase levels. In vitro, 6-shogaol inhibited reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) signaling, and increased the levels of total glutathione, heme oxygenase-1, and quinone 1 via nuclear factor erythroid 2 related factor 2 (Nrf2) activation. 6-Shogaol can alleviate AD-like skin lesions by inhibiting immune mediators via regulating the ROS/MAPKs/Nrf2 signaling pathway, and may be an effective alternative therapy for AD. - Highlights: • 6-Shogaol inhibited Th2/1-mediated inflammatory mediators in vitro and in vivo. • 6-Shogaol regulated ROS/MAPKs/Nrf2 signaling pathway. • 6-Shogaol can protect against the development of AD-like skin lesions.

Soluble β-(1,3)-glucans enhance LPS-induced response in the monocyte activation test, but inhibit LPS-mediated febrile response in rabbits: Implications for pyrogenicity tests.

Science.gov (United States)

Pardo-Ruiz, Zenia; Menéndez-Sardiñas, Dalia E; Pacios-Michelena, Anabel; Gabilondo-Ramírez, Tatiana; Montero-Alejo, Vivian; Perdomo-Morales, Rolando

2016-01-01

In the present study, we aimed to determine the influence of β-(1,3)-d-glucans on the LPS-induced pro-inflammatory cytokine response in the Monocyte Activation Test (MAT) for pyrogens, and on the LPS-induced febrile response in the Rabbit Pyrogen Test (RPT), thus evaluating the resulting effect in the outcome of each test. It was found that β-(1,3)-d-glucans elicited the production of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α, also known as endogenous pyrogens, but not enough to classify them as pyrogenic according to MAT. The same β-(1,3)-d-glucans samples were non-pyrogenic by RPT. However, β-(1,3)-d-glucans significantly enhanced the LPS-induced pro-inflammatory cytokines response in MAT, insomuch that samples containing non-pyrogenic concentrations of LPS become pyrogenic. On the other hand, β-(1,3)-d-glucans had no effect on sub-pyrogenic LPS doses in the RPT, but surprisingly, inhibited the LPS-induced febrile response of pyrogenic LPS concentrations. Thus, while β-(1,3)-d-glucans could mask the LPS pyrogenic activity in the RPT, they exerted an overstimulation of pro-inflammatory cytokines in the MAT. Hence, MAT provides higher safety since it evidences an unwanted biological response, which is not completely controlled and is overlooked by the RPT. Copyright © 2015 Elsevier B.V. All rights reserved.

Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

Directory of Open Access Journals (Sweden)

L. Zong

2014-03-01

Full Text Available Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN and lipopolysaccharide (LPS in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST and alanine aminotransferase (ALT. Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

Mycobacteria-specific cytokine responses as correlates of treatment response in active and latent tuberculosis.

Science.gov (United States)

Clifford, Vanessa; Tebruegge, Marc; Zufferey, Christel; Germano, Susie; Forbes, Ben; Cosentino, Lucy; McBryde, Emma; Eisen, Damon; Robins-Browne, Roy; Street, Alan; Denholm, Justin; Curtis, Nigel

2017-08-01

A biomarker indicating successful tuberculosis (TB) therapy would assist in determining appropriate length of treatment. This study aimed to determine changes in mycobacteria-specific antigen-induced cytokine biomarkers in patients receiving therapy for latent or active TB, to identify biomarkers potentially correlating with treatment success. A total of 33 adults with active TB and 36 with latent TB were followed longitudinally over therapy. Whole blood stimulation assays using mycobacteria-specific antigens (CFP-10, ESAT-6, PPD) were done on samples obtained at 0, 1, 3, 6 and 9 months. Cytokine responses (IFN-γ, IL-1ra, IL-2, IL-10, IL-13, IP-10, MIP-1β, and TNF-α) in supernatants were measured by Luminex xMAP immunoassay. In active TB cases, median IL-1ra (with CFP-10 and with PPD stimulation), IP-10 (CFP-10, ESAT-6), MIP-1β (ESAT-6, PPD), and TNF-α (ESAT-6) responses declined significantly over the course of therapy. In latent TB cases, median IL-1ra (CFP-10, ESAT-6, PPD), IL-2 (CFP-10, ESAT-6), and IP-10 (CFP-10, ESAT-6) responses declined significantly. Mycobacteria-specific cytokine responses change significantly over the course of therapy, and their kinetics in active TB differ from those observed in latent TB. In particular, mycobacteria-specific IL-1ra responses are potential correlates of successful therapy in both active and latent TB. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Cytokine-Modulating Strategies and Newer Cytokine Targets for Arthritis Therapy

Directory of Open Access Journals (Sweden)

Shivaprasad H. Venkatesha

2014-12-01

Full Text Available Cytokines are the key mediators of inflammation in the course of autoimmune arthritis and other immune-mediated diseases. Uncontrolled production of the pro-inflammatory cytokines such as interferon-γ (IFN-γ, tumor necrosis factor α (TNFα, interleukin-6 (IL-6, and IL-17 can promote autoimmune pathology, whereas anti-inflammatory cytokines including IL-4, IL-10, and IL-27 can help control inflammation and tissue damage. The pro-inflammatory cytokines are the prime targets of the strategies to control rheumatoid arthritis (RA. For example, the neutralization of TNFα, either by engineered anti-cytokine antibodies or by soluble cytokine receptors as decoys, has proven successful in the treatment of RA. The activity of pro-inflammatory cytokines can also be downregulated either by using specific siRNA to inhibit the expression of a particular cytokine or by using small molecule inhibitors of cytokine signaling. Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity. Unexpectedly, under certain conditions, TNFα, IFN-γ, and few other cytokines can display anti-inflammatory activities. Increasing awareness of this phenomenon might help develop appropriate regimens to harness or avoid this effect. Furthermore, the relatively newer cytokines such as IL-32, IL-34 and IL-35 are being investigated for their potential role in the pathogenesis and treatment of arthritis.

Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

International Nuclear Information System (INIS)

Su, Qing; Qin, Da-Nian; Wang, Fu-Xin; Ren, Jun; Li, Hong-Bao; Zhang, Meng; Yang, Qing; Miao, Yu-Wang; Yu, Xiao-Jing; Qi, Jie; Zhu, Zhiming; Zhu, Guo-Qing; Kang, Yu-Ming

2014-01-01

Aims: To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. Methods and results: Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91 phox (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91 phox , ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. Conclusion: These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension. - Highlights: • The effect of chronic inhibiting PVN superoxide on hypertension was investigated. • ANG II infusion induced increased proinflammatory cytokines and superoxide in PVN. • ANG II infusion resulted in oxidative stress, sympathoexcitation and hypertension. • Chronic inhibiting PVN superoxide attenuates RAS and cytokines in hypertension

Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

Energy Technology Data Exchange (ETDEWEB)

Su, Qing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China); Wang, Fu-Xin [Department of Neurology, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002 (China); Ren, Jun [Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071 (United States); Li, Hong-Bao; Zhang, Meng; Yang, Qing; Miao, Yu-Wang; Yu, Xiao-Jing; Qi, Jie [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhu, Zhiming [Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, The Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China)

2014-04-15

Aims: To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. Methods and results: Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91{sup phox} (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91{sup phox}, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. Conclusion: These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension. - Highlights: • The effect of chronic inhibiting PVN superoxide on hypertension was investigated. • ANG II infusion induced increased proinflammatory cytokines and superoxide in PVN. • ANG II infusion resulted in oxidative stress, sympathoexcitation and hypertension. • Chronic inhibiting PVN superoxide attenuates RAS and cytokines in hypertension.

Cytokine response to Escherichia coli in gnotobiotic pigs

Czech Academy of Sciences Publication Activity Database

Šplíchal, Igor; Šplíchalová, Alla; Trebichavský, Ilja

2008-01-01

Roč. 53, č. 2 (2008), s. 161-164 ISSN 0015-5632 R&D Projects: GA ČR GA523/05/0249 Institutional research plan: CEZ:AV0Z50200510 Keywords : germ-free pigs * escherichia coli * cytokine response Subject RIV: EE - Microbiology, Virology Impact factor: 1.172, year: 2008

Delineation of diverse macrophage activation programs in response to intracellular parasites and cytokines.

Directory of Open Access Journals (Sweden)

Shuyi Zhang

2010-03-01

Full Text Available The ability to reside and proliferate in macrophages is characteristic of several infectious agents that are of major importance to public health, including the intracellular parasites Trypanosoma cruzi (the etiological agent of Chagas disease and Leishmania species (etiological agents of Kala-Azar and cutaneous leishmaniasis. Although recent studies have elucidated some of the ways macrophages respond to these pathogens, the relationships between activation programs elicited by these pathogens and the macrophage activation programs elicited by bacterial pathogens and cytokines have not been delineated.To provide a global perspective on the relationships between macrophage activation programs and to understand how certain pathogens circumvent them, we used transcriptional profiling by genome-wide microarray analysis to compare the responses of mouse macrophages following exposure to the intracellular parasites T. cruzi and Leishmania mexicana, the bacterial product lipopolysaccharide (LPS, and the cytokines IFNG, TNF, IFNB, IL-4, IL-10, and IL-17. We found that LPS induced a classical activation state that resembled macrophage stimulation by the Th1 cytokines IFNG and TNF. However, infection by the protozoan pathogen L. mexicana produced so few transcriptional changes that the infected macrophages were almost indistinguishable from uninfected cells. T. cruzi activated macrophages produced a transcriptional signature characterized by the induction of interferon-stimulated genes by 24 h post-infection. Despite this delayed IFN response by T. cruzi, the transcriptional response of macrophages infected by the kinetoplastid pathogens more closely resembled the transcriptional response of macrophages stimulated by the cytokines IL-4, IL-10, and IL-17 than macrophages stimulated by Th1 cytokines.This study provides global gene expression data for a diverse set of biologically significant pathogens and cytokines and identifies the relationships between

Total glucosides of paeony inhibit the inflammatory responses of mice with allergic contact dermatitis by restoring the balanced secretion of pro-/anti-inflammatory cytokines.

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Wang, Chun; Yuan, Jun; Wu, Hua-Xun; Chang, Yan; Wang, Qing-Tong; Wu, Yu-Jing; Zhou, Peng; Yang, Xiao-Dan; Yu, Jun; Wei, Wei

2015-02-01

The present study aimed to investigate the regulation exerted by the total glucosides of paeony (TGP) on the production of interleukin-2 (IL-2), IL-4, IL-10 and IL-17 in the serum and lymphocytes of mice with allergic contact dermatitis (ACD). ACD in mice was induced by the repeated application of 2,4-dinitrochlorobenzene (DNCB) to their skins. The mice were orally administered TGP (35, 70, and 140mg/kg/d) and prednisone (Pre, 5mg/kg/d) from day 1 to day 7 after immunization. The inflammatory responses were evaluated by ear swelling and histological examination. Thymocyte proliferation was assayed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide assay. The cytokine production in the serum and lymphocytes supernatant was measured by enzyme-linked immunosorbent assay. The results indicated that the topical application of DNCB to the skin provoked obvious inflammatory responses. The oral administration of TGP (70 and 140mg/kg/d) and Pre (5mg/kg/d) significantly inhibited skin inflammation, decreased the thymus and spleen indices, and inhibited thymocyte proliferation in mice treated with DNCB. Further study indicated that TGP increased IL-4 and IL-10 production but decreased the production of IL-2 and IL-17 in the serum and lymphocyte supernatant. The correlation analysis suggested significantly positive correlations between IL-2 and IL-17 production and the severity of skin inflammation, whereas negative correlations were obtained for IL-4 and IL-10 production and skin inflammation. In summary, these results suggest that the therapeutic effects of TGP on ACD may result from its regulation of the imbalanced secretion of IL-2/IL-4 and IL-10/IL-17. Copyright © 2014 Elsevier B.V. All rights reserved.

Zinc and Regulation of Inflammatory Cytokines: Implications for Cardiometabolic Disease

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Foster, Meika; Samman, Samir

2012-01-01

In atherosclerosis and diabetes mellitus, the concomitant presence of low-grade systemic inflammation and mild zinc deficiency highlights a role for zinc nutrition in the management of chronic disease. This review aims to evaluate the literature that reports on the interactions of zinc and cytokines. In humans, inflammatory cytokines have been shown both to up- and down-regulate the expression of specific cellular zinc transporters in response to an increased demand for zinc in inflammatory conditions. The acute phase response includes a rapid decline in the plasma zinc concentration as a result of the redistribution of zinc into cellular compartments. Zinc deficiency influences the generation of cytokines, including IL-1β, IL-2, IL-6, and TNF-α, and in response to zinc supplementation plasma cytokines exhibit a dose-dependent response. The mechanism of action may reflect the ability of zinc to either induce or inhibit the activation of NF-κB. Confounders in understanding the zinc-cytokine relationship on the basis of in vitro experimentation include methodological issues such as the cell type and the means of activating cells in culture. Impaired zinc homeostasis and chronic inflammation feature prominently in a number of cardiometabolic diseases. Given the high prevalence of zinc deficiency and chronic disease globally, the interplay of zinc and inflammation warrants further examination. PMID:22852057

Ureaplasma Species Differentially Modulate Pro- and Anti-Inflammatory Cytokine Responses in Newborn and Adult Human Monocytes Pushing the State Toward Pro-Inflammation

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Glaser, Kirsten; Silwedel, Christine; Fehrholz, Markus; Waaga-Gasser, Ana M.; Henrich, Birgit; Claus, Heike; Speer, Christian P.

2017-01-01

Background: Ureaplasma species have been associated with chorioamnionitis and preterm birth and have been implicated in the pathogenesis of neonatal short and long-term morbidity. However, being mostly commensal bacteria, controversy remains on the pro-inflammatory capacity of Ureaplasma. Discussions are ongoing on the incidence and impact of prenatal, perinatal, and postnatal infection. The present study addressed the impact of Ureaplasma isolates on monocyte-driven inflammation. Methods: Cord blood monocytes of term neonates and adult monocytes, either native or LPS-primed, were cultured with Ureaplasma urealyticum (U. urealyticum) serovar 8 (Uu8) and Ureaplasma parvum serovar 3 (Up3). Using qRT-PCR, cytokine flow cytometry, and multi-analyte immunoassay, we assessed mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-12p40, IL-10, and IL-1 receptor antagonist (IL-1ra) as well as Toll-like receptor (TLR) 2 and TLR4. Results: Uu8 and Up3 induced mRNA expression and protein release of TNF-α, IL-1β and IL-8 in term neonatal and adult monocytes (p Ureaplasma-stimulated cells paralleled those results. Ureaplasma-induced cytokine levels did not significantly differ from LPS-mediated levels except for lower intracellular IL-1β in adult monocytes (Uu8: p ureaplasmas did not induce IL-12p40 response and promoted lower amounts of anti-inflammatory IL-10 and IL-1ra than LPS, provoking a cytokine imbalance more in favor of pro-inflammation (IL-1β/IL-10, IL-8/IL-10 and IL-8/IL-1ra: p Ureaplasma isolates in human monocytes. Stimulating pro-inflammatory cytokine responses while hardly inducing immunomodulatory and anti-inflammatory cytokines, ureaplasmas might push monocyte immune responses toward pro-inflammation. Inhibition of LPS-induced cytokines in adult monocytes in contrast to sustained inflammation in term neonatal monocytes indicates a differential modulation of host immune responses to a second stimulus. Modification of

MW151 Inhibited IL-1β Levels after Traumatic Brain Injury with No Effect on Microglia Physiological Responses.

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Adam D Bachstetter

Full Text Available A prevailing neuroinflammation hypothesis is that increased production of proinflammatory cytokines contributes to progressive neuropathology, secondary to the primary damage caused by a traumatic brain injury (TBI. In support of the hypothesis, post-injury interventions that inhibit the proinflammatory cytokine surge can attenuate the progressive pathology. However, other post-injury neuroinflammatory responses are key to endogenous recovery responses. Therefore, it is critical that pharmacological attenuation of detrimental or dysregulated neuroinflammatory processes avoid pan-suppression of inflammation. MW151 is a CNS-penetrant, small molecule experimental therapeutic that restores injury- or disease-induced overproduction of proinflammatory cytokines towards homeostasis without immunosuppression. Post-injury administration of MW151 in a closed head injury model of mild TBI suppressed acute cytokine up-regulation and downstream cognitive impairment. Here, we report results from a diffuse brain injury model in mice using midline fluid percussion. Low dose (0.5-5.0 mg/kg administration of MW151 suppresses interleukin-1 beta (IL-1β levels in the cortex while sparing reactive microglia and astrocyte responses. To probe molecular mechanisms, we used live cell imaging of the BV-2 microglia cell line to demonstrate that MW151 does not affect proliferation, migration, or phagocytosis of the cells. Our results provide insight into the roles of glial responses to brain injury and indicate the feasibility of using appropriate dosing for selective therapeutic modulation of injurious IL-1β increases while sparing other glial responses to injury.

Cerebellar cytokine expression in a rat model for fetal asphyctic preconditioning and perinatal asphyxia

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Vlassaks, Evi; Brudek, Tomasz; Pakkenberg, Bente

2014-01-01

the effects of perinatal asphyxia and fetal asphyctic preconditioning on the inflammatory cytokine response in the cerebellum. Fetal asphyxia was induced at embryonic day 17 by clamping the uterine vasculature for 30 min. At term birth, global perinatal asphyxia was induced by placing the uterine horns...... was decreased 96 h postfetal asphyxia. When applied as preconditioning stimulus, fetal asphyxia attenuates the cerebellar cytokine response. These results indicate that sublethal fetal asphyxia may protect the cerebellum from perinatal asphyxia-induced damage via inhibition of inflammation.......Asphyctic brain injury is a major cause of neuronal inflammation in the perinatal period. Fetal asphyctic preconditioning has been shown to modulate the cerebral inflammatory cytokine response, hereby protecting the brain against asphyctic injury at birth. This study was designated to examine...

Regulation of Cytokine Production by the Unfolded Protein Response; Implications for Infection and Autoimmunity

OpenAIRE

Judith A. Smith; Judith A. Smith

2018-01-01

Protein folding in the endoplasmic reticulum (ER) is an essential cell function. To safeguard this process in the face of environmental threats and internal stressors, cells mount an evolutionarily conserved response known as the unfolded protein response (UPR). Invading pathogens induce cellular stress that impacts protein folding, thus the UPR is well situated to sense danger and contribute to immune responses. Cytokines (inflammatory cytokines and interferons) critically mediate host defen...

Idiosyncratic Drug-Induced Liver Injury: Is Drug-Cytokine Interaction the Linchpin?

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Roth, Robert A; Maiuri, Ashley R; Ganey, Patricia E

2017-02-01

Idiosyncratic drug-induced liver injury continues to be a human health problem in part because drugs that cause these reactions are not identified in current preclinical testing and because progress in prevention is hampered by incomplete knowledge of mechanisms that underlie these adverse responses. Several hypotheses involving adaptive immune responses, inflammatory stress, inability to adapt to stress, and multiple, concurrent factors have been proposed. Yet much remains unknown about how drugs interact with the liver to effect death of hepatocytes. Evidence supporting hypotheses implicating adaptive or innate immune responses in afflicted patients has begun to emerge and is bolstered by results obtained in experimental animal models and in vitro systems. A commonality in adaptive and innate immunity is the production of cytokines, including interferon-γ (IFNγ). IFNγ initiates cell signaling pathways that culminate in cell death or inhibition of proliferative repair. Tumor necrosis factor-α, another cytokine prominent in immune responses, can also promote cell death. Furthermore, tumor necrosis factor-α interacts with IFNγ, leading to enhanced cellular responses to each cytokine. In this short review, we propose that the interaction of drugs with these cytokines contributes to idiosyncratic drug-induced liver injury, and mechanisms by which this could occur are discussed. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS).

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Haverkamp, M H; van de Vosse, E; Goldbach-Mansky, R; Holland, S M

2014-09-01

Cryopyrin-associated periodic syndrome (CAPS) is characterized by dysregulated inflammation with excessive interleukin (IL)-1β activation and secretion. Neonatal-onset multi-system inflammatory disease (NOMID) is the most severe form. We explored cytokine responses in 32 CAPS patients before and after IL-1β blocking therapy. We measured cytokines produced by activated peripheral blood monuclear cells (PBMCs) from treated and untreated CAPS patients after stimulation for 48 h with phytohaemagglutinin (PHA), PHA plus IL-12, lipopolysaccharide (LPS) or LPS plus interferon (IFN)-γ. We measured IL-1β, IL-6, IL-10, tumour necrosis factor (TNF), IL-12p70 and IFN-γ in the supernatants. PBMCs from three untreated CAPS patients were cultured in the presence of the IL-1β blocker Anakinra. Fifty healthy individuals served as controls. CAPS patients had high spontaneous production of IL-1β, IL-6, TNF and IFN-γ by unstimulated cells. However, stimulation indexes (SIs, ratio of stimulated to unstimulated production) of these cytokines to PHA and LPS were low in NOMID patients compared to controls. Unstimulated IL-10 and IL-12p70 production was normal, but up-regulation after PHA and LPS was also low. LPS plus IFN-γ inadequately up-regulated the production of IL-1β, IL-6, TNF and IL-10 in CAPS patients. In-vitro but not in-vivo treatment with Anakinra improved SIs by lowering spontaneous cytokine production. However, in-vitro treatment did not improve the low stimulated cytokine levels. Activating mutations in NLRP3 in CAPS are correlated with poor SIs to PHA, LPS and IFN-γ. The impairment in stimulated cytokine responses in spite of IL-1β blocking therapy suggests a broader intrinsic defect in CAPS patients, which is not corrected by targeting IL-1β. © 2014 British Society for Immunology.

The role of stress mediators in modulation of cytokine production by ethanol

International Nuclear Information System (INIS)

Glover, Mitzi; Cheng Bing; Fan Ruping; Pruett, Stephen

2009-01-01

Acute ethanol exposure in humans and in animal models activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS); the resultant increases in concentration of neuroendocrine mediators contribute to some of the immunosuppressive effects of ethanol. However, the role of these mediators in the ethanol-induced inhibition of inflammatory responses is not clear. This is complicated by the fact that most inflammatory stimuli also activate the HPA axis and SNS, and it has not been determined if ethanol plus an inflammatory stimulus increases these stress responses. Addressing this issue is the major focus of the study described herein. Complementary approaches were used, including quantitative assessment of the stress response in mice treated with polyinosinic-polycytidylic acid (poly I:C, as an inflammatory stimulus) and inhibition of the production or action of key HPA axis and SNS mediators. Treatment of mice with ethanol shortly before treatment with poly I:C yielded a significant increase in the corticosterone response as compared to the response to poly I:C alone, but the increase was small and not likely sufficient to account for the anti-inflammatory effects of ethanol. Inhibition of catecholamine and glucocorticoid production by adrenalectomy, and inhibition of catecholamine action with a sustained release antagonist (nadalol) supported this conclusion and revealed that 'excess' stress responses associated with ethanol treatment is not the mechanism of suppression of pro-inflammatory cytokine production, but stress-induced corticosterone does regulate production of several of these cytokines, which has not previously been reported.

The role of stress mediators in modulation of cytokine production by ethanol

Energy Technology Data Exchange (ETDEWEB)

Glover, Mitzi; Bing, Cheng; Ruping, Fan [LSU Health Sciences Center, Department of Cellular Biology and Anatomy, Shreveport, LA 71130 (United States); Pruett, Stephen [LSU Health Sciences Center, Department of Cellular Biology and Anatomy, Shreveport, LA 71130 (United States); Mississippi State University College of Veterinary Medicine, Department of Basic Sciences, P.O. Box 6100, Mississippi State, MS 39762-6100 (United States)], E-mail: pruett@cvm.msstate.edu

2009-08-15

Acute ethanol exposure in humans and in animal models activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS); the resultant increases in concentration of neuroendocrine mediators contribute to some of the immunosuppressive effects of ethanol. However, the role of these mediators in the ethanol-induced inhibition of inflammatory responses is not clear. This is complicated by the fact that most inflammatory stimuli also activate the HPA axis and SNS, and it has not been determined if ethanol plus an inflammatory stimulus increases these stress responses. Addressing this issue is the major focus of the study described herein. Complementary approaches were used, including quantitative assessment of the stress response in mice treated with polyinosinic-polycytidylic acid (poly I:C, as an inflammatory stimulus) and inhibition of the production or action of key HPA axis and SNS mediators. Treatment of mice with ethanol shortly before treatment with poly I:C yielded a significant increase in the corticosterone response as compared to the response to poly I:C alone, but the increase was small and not likely sufficient to account for the anti-inflammatory effects of ethanol. Inhibition of catecholamine and glucocorticoid production by adrenalectomy, and inhibition of catecholamine action with a sustained release antagonist (nadalol) supported this conclusion and revealed that 'excess' stress responses associated with ethanol treatment is not the mechanism of suppression of pro-inflammatory cytokine production, but stress-induced corticosterone does regulate production of several of these cytokines, which has not previously been reported.

Cytokines and Liver Diseases

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Herbert Tilg

2001-01-01

Full Text Available Cytokines are pleiotropic peptides produced by virtually every nucleated cell in the body. In most tissues, including the liver, constitutive production of cytokines is absent or minimal. There is increasing evidence that several cytokines mediate hepatic inflammation, apoptosis and necrosis of liver cells, cholestasis and fibrosis. Interestingly, the same mediators also mediate the regeneration of liver tissue after injury. Among the various cytokines, the proinflammatory cytokine tumour necrosis factor-alpha (TNF-a has emerged as a key factor in various aspects of liver disease, such as cachexia and/or cholestasis. Thus, antagonism of TNF-a and other injury-related cytokines in liver diseases merits evaluation as a treatment of these diseases. However, because the same cytokines are also necessary for the regeneration of the tissue after the liver has been injured, inhibition of these mediators might impair hepatic recovery. The near future will bring the exiting clinical challenge of testing new anticytokine strategies in various liver diseases.

Metformin inhibits inflammatory response via AMPK–PTEN pathway in vascular smooth muscle cells

International Nuclear Information System (INIS)

Kim, Sun Ae; Choi, Hyoung Chul

2012-01-01

Highlights: ► PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. ► Metformin suppressed TNF-α-induced COX-2 and iNOS mRNA expression. ► Compound C and bpv (pic) increased iNOS and COX-2 protein expression. ► NF-κB activation was restored by inhibiting AMPK and PTEN. ► AMPK and PTEN regulated TNF-α-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK–PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 μM) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-α) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-κB. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-κB activation decreased in response to metformin and was restored by inhibiting AMPK and PTEN. Inhibiting AMPK and PTEN restored ROS levels stimulated with TNF-α. Taken together, PTEN could be a possible downstream regulator of AMPK, and the

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

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...... 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......-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...

Bee Venom Inhibits Porphyromonas gingivalis Lipopolysaccharides-Induced Pro-Inflammatory Cytokines through Suppression of NF-κB and AP-1 Signaling Pathways.

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Kim, Woon-Hae; An, Hyun-Jin; Kim, Jung-Yeon; Gwon, Mi-Gyeong; Gu, Hyemin; Park, Jae-Bok; Sung, Woo Jung; Kwon, Yong-Chul; Park, Kyung-Duck; Han, Sang Mi; Park, Kwan-Kyu

2016-11-10

Periodontitis is a chronic inflammatory disease that leads to destruction of tooth supporting tissues. Porphyromonas gingivalis ( P. gingivalis ), especially its lipopolysaccharides (LPS), is one of major pathogens that cause periodontitis. Bee venom (BV) has been widely used as a traditional medicine for various diseases. Previous studies have demonstrated the anti-inflammatory, anti-bacterial effects of BV. However, a direct role and cellular mechanism of BV on periodontitis-like human keratinocytes have not been explored. Therefore, we investigated the anti-inflammatory mechanism of BV against P. gingivalis LPS (PgLPS)-induced HaCaT human keratinocyte cell line. The anti-inflammatory effect of BV was demonstrated by various molecular biological methods. The results showed that PgLPS increased the expression of Toll-like receptor (TLR)-4 and pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, and interferon (IFN)-γ. In addition, PgLPS induced activation of the signaling pathways of inflammatory cytokines-related transcription factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1). BV effectively inhibited those pro-inflammatory cytokines through suppression of NF-κB and AP-1 signaling pathways. These results suggest that administration of BV attenuates PgLPS-induced inflammatory responses. Furthermore, BV may be a useful treatment to anti-inflammatory therapy for periodontitis.

Adjuvant effect of Asparagus racemosus Willd. derived saponins in antibody production, allergic response and pro-inflammatory cytokine modulation.

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Tiwari, Nimisha; Gupta, Vivek Kumar; Pandey, Pallavi; Patel, Dinesh Kumar; Banerjee, Suchitra; Darokar, Mahendra Pandurang; Pal, Anirban

2017-02-01

The study manifests the immunoadjuvant potential of saponin rich fraction from Asparagus racemosus in terms of cellular and humoral immune response that can be exploited against microbial infections. Asparagus racemosus (AR) has been attributed as an adaptogen and rasayana in traditional medication systems for enhancing the host defence mechanism. Spectrophotometric and HPTLC analysis ensured the presence of saponins. The saponin rich fractions were tested for immunoadjuvant property in ovalbumin immunised mice for the humoral response, quantified in terms of prolonged antibody production upto a duration of 56days. Proinflammatory cytokines (IL-6 and TNF) were estimated for the cellular immune response in LPS stimulated primary murine macrophages. The safety evaluation in terms of cytotoxicity and allergic response has also been evaluated through in-vitro (MTT) and in-vivo (IgE) respectively. ARS significantly inhibited the pro-inflammatory cytokines, in LPS stimulated murine macrophages with no intrinsic cytotoxicity. The significant increase in IgG production infers the utility of ARS for prolonged humoral response. Further, the antigen specific response of IL-12 at early stage and IgE titres also suggests the generation of cellular immune response and low allergic reaction respectively, as compared to conventional adjuvants. IL-6 and TNF fluctuations in LPS stimulated and non-stimulated macrophages along with IgG and IL-12 also confirmed the Th1/Th2 modulating effect of ARS. The study indicates potential effect of ARS as an adjuvant for the stimulation of cellular immune response in addition to generating a sustained adaptive response without any adverse effects paving way for further validation with pathogenic organisms. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Effect of praziquantel treatment during pregnancy on cytokine responses to schistosome antigens

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Tweyongyere, Robert; Mawa, Patrice A.; Ngom-Wegi, Sophy

2008-01-01

. Cytokine responses to S. mansoni worm and egg antigens were measured in whole blood culture before and 6 weeks after each treatment. RESULTS: Schistosome-specific cytokine responses were suppressed during pregnancy. Praziquantel treatment during pregnancy caused significant boosts in interferon-gamma (IFN......Praziquantel treatment of schistosomiasis boosts antischistosome responses, with type 2 helper T cell bias that may contribute to immunologically mediated killing and to protection against reinfection. Praziquantel treatment during pregnancy was recommended in 2002, but the immunological effects...... of the treatment had not been investigated. METHODS: A cohort of 387 Schistosoma mansoni-infected women were recruited from a larger trial of deworming during pregnancy. Women were randomized to receive either praziquantel or placebo during pregnancy. Six weeks after delivery, all women received praziquantel...

Administration of PDE4 Inhibitors Suppressed the Pannus-Like Inflammation by Inhibition of Cytokine Production by Macrophages and Synovial Fibroblast Proliferation

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Katsuya Kobayashi

2007-01-01

Full Text Available A marked proliferation of synovial fibroblasts in joints leads to pannus formation in rheumatoid arthritis (RA. Various kinds of cytokines are produced in the pannus. The purpose of this study is to elucidate the effects of phosphodiesterase 4 (PDE4 inhibitors in a new animal model for the evaluation of pannus formation and cytokine production in the pannus. Mice sensitized with methylated bovine serum albumin (mBSA were challenged by subcutaneous implantation of a membrane filter soaked in mBSA solution in the back of the mice. Drugs were orally administered for 10 days. The granuloma formed around the filter was collected on day 11. It was chopped into pieces and cultured in vitro for 24 hr. The cytokines were measured in the supernatants. The type of cytokines produced in the granuloma was quite similar to those produced in pannus in RA. Both PDE4 inhibitors, KF66490 and SB207499, suppressed the production of IL-1β, TNF-α, and IL-12, and the increase in myeloperoxidase activity, a marker enzyme for neutrophils and hydroxyproline content. Compared to leflunomide, PDE4 inhibitors more strongly suppressed IL-12 production and the increase in myeloperoxidase activity. PDE4 inhibitors also inhibited lipopolysaccharide-induced TNF-α and IL-12 production from thioglycolate-induced murine peritoneal macrophages and the proliferation of rat synovial fibroblasts. These results indicate this model makes it easy to evaluate the effect of drugs on various cytokine productions in a granuloma without any purification step and may be a relevant model for evaluating novel antirheumatic drugs on pannus formation in RA. PDE4 inhibitors could have therapeutic effects on pannus formation in RA by inhibition of cytokine production by macrophages and synovial fibroblast proliferation.

Administration of PDE4 inhibitors suppressed the pannus-like inflammation by inhibition of cytokine production by macrophages and synovial fibroblast proliferation.

Science.gov (United States)

Kobayashi, Katsuya; Suda, Toshio; Manabe, Haruhiko; Miki, Ichiro

2007-01-01

A marked proliferation of synovial fibroblasts in joints leads to pannus formation in rheumatoid arthritis (RA). Various kinds of cytokines are produced in the pannus. The purpose of this study is to elucidate the effects of phosphodiesterase 4 (PDE4) inhibitors in a new animal model for the evaluation of pannus formation and cytokine production in the pannus. Mice sensitized with methylated bovine serum albumin (mBSA) were challenged by subcutaneous implantation of a membrane filter soaked in mBSA solution in the back of the mice. Drugs were orally administered for 10 days. The granuloma formed around the filter was collected on day 11. It was chopped into pieces and cultured in vitro for 24 hr. The cytokines were measured in the supernatants. The type of cytokines produced in the granuloma was quite similar to those produced in pannus in RA. Both PDE4 inhibitors, KF66490 and SB207499, suppressed the production of IL-1beta, TNF-alpha, and IL-12, and the increase in myeloperoxidase activity, a marker enzyme for neutrophils and hydroxyproline content. Compared to leflunomide, PDE4 inhibitors more strongly suppressed IL-12 production and the increase in myeloperoxidase activity. PDE4 inhibitors also inhibited lipopolysaccharide-induced TNF-alpha and IL-12 production from thioglycolate-induced murine peritoneal macrophages and the proliferation of rat synovial fibroblasts. These results indicate this model makes it easy to evaluate the effect of drugs on various cytokine productions in a granuloma without any purification step and may be a relevant model for evaluating novel antirheumatic drugs on pannus formation in RA. PDE4 inhibitors could have therapeutic effects on pannus formation in RA by inhibition of cytokine production by macrophages and synovial fibroblast proliferation.

Inflammation in the CNS and Th17 Responses Are Inhibited by IFN-{gamma}-Induced IL-18 Binding Protein

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Millward, Jason M; Pedersen, Morten Løbner; Wheeler, Rachel D

2010-01-01

Inflammatory responses are essential for immune protection but may also cause pathology and must be regulated. Both Th1 and Th17 cells are implicated in the pathogenesis of autoimmune inflammatory diseases, such as multiple sclerosis. We show in this study that IL-18-binding protein (IL-18bp......), the endogenous inhibitor of the Th1-promoting cytokine IL-18, is upregulated by IFN-gamma in resident microglial cells in the CNS during multiple sclerosis-like disease in mice. Test of function by overexpression of IL-18bp in the CNS using a viral vector led to marked reduction in Th17 responses and robust...... inhibition of incidence, severity, and histopathology of disease, independently of IFN-gamma. The disease-limiting action of IL-18bp included suppression of APC-derived Th17-polarizing cytokines. IL-18bp thus acts as a sensor for IFN-gamma and can regulate both Th1 and Th17 responses in the CNS....

Nasal Lipopolysaccharide Challenge and Cytokine Measurement Reflects Innate Mucosal Immune Responsiveness.

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Jaideep Dhariwal

Full Text Available Practical methods of monitoring innate immune mucosal responsiveness are lacking. Lipopolysaccharide (LPS is a component of the cell wall of Gram negative bacteria and a potent activator of Toll-like receptor (TLR-4. To measure LPS responsiveness of the nasal mucosa, we administered LPS as a nasal spray and quantified chemokine and cytokine levels in mucosal lining fluid (MLF.We performed a 5-way cross-over, single blind, placebo-controlled study in 15 healthy non-atopic subjects (n = 14 per protocol. Doses of ultrapure LPS (1, 10, 30 or 100μg/100μl or placebo were administered by a single nasal spray to each nostril. Using the recently developed method of nasosorption with synthetic adsorptive matrices (SAM, a series of samples were taken. A panel of seven cytokines/chemokines were measured by multiplex immunoassay in MLF. mRNA for intercellular cell adhesion molecule-1 (ICAM-1 was quantified from nasal epithelial curettage samples taken before and after challenge.Topical nasal LPS was well tolerated, causing no symptoms and no visible changes to the nasal mucosa. LPS induced dose-related increases in MLF levels of IL-1β, IL-6, CXCL8 (IL-8 and CCL3 (MIP-1α (AUC at 0.5 to 10h, compared to placebo, p<0.05 at 30 and 100μg LPS. At 100μg LPS, IL-10, IFN-α and TNF-α were also increased (p<0.05. Dose-related changes in mucosal ICAM-1 mRNA were also seen after challenge, and neutrophils appeared to peak in MLF at 8h. However, 2 subjects with high baseline cytokine levels showed prominent cytokine and chemokine responses to relatively low LPS doses (10μg and 30μg LPS.Topical nasal LPS causes dose-dependent increases in cytokines, chemokines, mRNA and cells. However, responsiveness can show unpredictable variations, possibly because baseline innate tone is affected by environmental factors. We believe that this new technique will have wide application in the study of the innate immune responses of the respiratory mucosa.Ultrapure LPS was used

Differential response to dexamethasone on the TXB2 release in guinea-pig alveolar macrophages induced by zymosan and cytokines

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M. E. Salgueiro

1997-01-01

Full Text Available Glucocorticosteroids reduce the production of inflammatory mediators but this effect may depend on the stimulus. We have compared the time course of the effect of dexamethasone on the thromboxane B2 (TXB2 release induced by cytokine stimulation and zymosan in guinea-pig alveolar macrophages. Interleukin-1β (IL-1β, tumour necrosis factor-α (TNF-α and opsonized zymosan (OZ, all stimulate TXB2 release. High concentrations of dexamethasone (1–10 μM inhibit the TXB2 production induced by both cytokines and OZ, but the time course of this response is different. Four hours of incubation with dexamethasone reduce the basal TXB2 release and that induced by IL-1β and TNF-α, but do not modify the TXB2 release induced by OZ. However, this stimulus was reduced after 24 h incubation. Our results suggest that the antiinflammatory activity of glucocorticosteroids shows some dependence on stimulus and, therefore, may have more than one mechanism involved.

Cytokine responses to two common respiratory pathogens in children are dependent on interleukin-1β

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Alice C-H. Chen

2017-10-01

Full Text Available Protracted bacterial bronchitis (PBB in young children is a common cause of prolonged wet cough and may be a precursor to bronchiectasis in some children. Although PBB and bronchiectasis are both characterised by neutrophilic airway inflammation and a prominent interleukin (IL-1β signature, the contribution of the IL-1β pathway to host defence is not clear. This study aimed to compare systemic immune responses against common pathogens in children with PBB, bronchiectasis and control children and to determine the importance of the IL-1β pathway. Non-typeable Haemophilus influenzae (NTHi stimulation of peripheral blood mononuclear cells (PBMCs from control subjects (n=20, those with recurrent PBB (n=20 and bronchiectasis (n=20 induced high concentrations of IL-1β, IL-6, interferon (IFN-γ and IL-10. Blocking with an IL-1 receptor antagonist (IL-1Ra modified the cellular response to pathogens, inhibiting cytokine synthesis by NTHi-stimulated PBMCs and rhinovirus-stimulated PBMCs (in a separate PBB cohort. Inhibition of IFN-γ production by IL-1Ra was observed across multiple cell types, including CD3+ T cells and CD56+ NK cells. Our findings highlight the extent to which IL-1β regulates the cellular immune response against two common respiratory pathogens. While blocking the IL-1β pathway has the potential to reduce inflammation, this may come at the cost of protective immunity against NTHi and rhinovirus.

Proactive modulation of long-interval intracortical inhibition during response inhibition

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Cowie, Matthew J.; MacDonald, Hayley J.; Cirillo, John

2016-01-01

Daily activities often require sudden cancellation of preplanned movement, termed response inhibition. When only a subcomponent of a whole response must be suppressed (required here on Partial trials), the ensuing component is markedly delayed. The neural mechanisms underlying partial response inhibition remain unclear. We hypothesized that Partial trials would be associated with nonselective corticomotor suppression and that GABAB receptor-mediated inhibition within primary motor cortex might be responsible for the nonselective corticomotor suppression contributing to Partial trial response delays. Sixteen right-handed participants performed a bimanual anticipatory response inhibition task while single- and paired-pulse transcranial magnetic stimulation was delivered to elicit motor evoked potentials in the left first dorsal interosseous muscle. Lift times, amplitude of motor evoked potentials, and long-interval intracortical inhibition were examined across the different trial types (Go, Stop-Left, Stop-Right, Stop-Both). Go trials produced a tight distribution of lift times around the target, whereas those during Partial trials (Stop-Left and Stop-Right) were substantially delayed. The modulation of motor evoked potential amplitude during Stop-Right trials reflected anticipation, suppression, and subsequent reinitiation of movement. Importantly, suppression was present across all Stop trial types, indicative of a “default” nonselective inhibitory process. Compared with blocks containing only Go trials, inhibition increased when Stop trials were introduced but did not differ between trial types. The amount of inhibition was positively correlated with lift times during Stop-Right trials. Tonic levels of inhibition appear to be proactively modulated by task context and influence the speed at which unimanual responses occur after a nonselective “brake” is applied. PMID:27281744

Mimetics of Suppressor of cytokine signalling 3: novel potential therapeutics in triple breast cancer.

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La Manna, Sara; Lee, Eunmi; Ouzounova, Maria; Di Natale, Concetta; Novellino, Ettore; Merlino, Antonello; Korkaya, Hasan; Marasco, Daniela

2018-05-11

Suppressor of cytokine signaling (SOCS) family of proteins plays critical role in the regulation of immune responses controlling JAK/STAT mediated inflammatory cytokines. Among the members, SOCS1 and SOCS3 contain a kinase inhibitory region (KIR) and SOCS3 binds to JAK/STAT/gp130 complex by inhibiting the downstream signaling and suppressing inflammatory cytokines. Loss or reduced levels of SOCS3 have been linked to cancer-associated inflammation and suppressive immunity leading to enhanced tumour growth and metastasis. In line with these reports, we previously demonstrated that proteolytic degradation of SOCS3 in triple negative breast cancer (TNBC) subtype drives the expression of inflammatory cytokines. Therefore, we postulated that SOCS3 mimetics might suppress the inflammatory cytokine production in TNBC subtype and inhibit tumor growth and metastasis. Here we designed and characterized five linear peptides derived from the N-terminal region of SOCS3 encompassing regions that interface with the JAK2/gp130 complex by using the Circular Dichroism and Surface Plasmon Resonance spectroscopies. The KIRESS peptide resulted the sequence containing the most part of the hot-spots required for binding to JAK2 and was further investigated in vivo in mouse xenografts of MDA-MB-231-luci tumours as models of human TNBC subtype. Expectedly, this peptide showed a significant inhibition of primary tumour growth and pulmonary metastasis. Our studies suggest that SOCS3 peptidomimetics may possess a therapeutic potential in aggressive cancers, such as TNBC subtype, with activated inflammatory cytokines. This article is protected by copyright. All rights reserved. © 2018 UICC.

Correlation of cutaneous sensitivity and cytokine response in children with asthma

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Meenu Singh

2017-01-01

Full Text Available Background: Food allergy occurs in a significant portion of pediatric asthma. Various cells and their mediators/cytokines play a pivotal role in orchestrating the airway inflammatory response in asthma. Objective: To study the cutaneous hypersensitivity, Th1, Th2, and Th17 response of pediatric population with asthma and genetic predisposition to atopy, by determining total immunoglobulin E (IgE level in response to various food allergens. Materials and Methods: Fifty asthmatic children with a history of worsening symptoms by various food allergens (study group and twenty healthy children (control group were included. Food allergy was assessed through skin prick test (SPT of various food allergens. Total serum IgE level was measured by sandwich ELISA, and T-cell (Th1, Th2, and Th17-dependent cytokines were measured by flow cytometry. Results: All 50 asthmatic children in the study group showed SPT positivity against various food allergens (rice = 17; banana, fish and groundnut = 10; wheat = 9; milk and orange = 7; egg = 6; and mango = 4. The average total IgE level in the study group was 316.8 ± 189.8 IU/mL. A significant positive correlation of total IgE with interleukin 17 (IL-17 (r = 0.796; P < 0.0001, IL-13 (r = 0.383; P = 0.01, and IL-4 (r = 0.263; P = 0.043 level was noted. A significant negative correlation of total IgE was noted with interferon gamma (r = −0.5823; P < 0.0001 and IL-10 (r = −0.4474; P < 0.001 level and the duration of breastfeeding (r = −0.31, P = 0.03. Conclusions: The present study found a positive correlation between total serum IgE level and Th2, Th17 cytokines in a pediatric population with asthma. A significant negative correlation was found between the duration of breastfeeding and the cytokines.

Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD.

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Hechinger, Anne-Kathrin; Smith, Benjamin A H; Flynn, Ryan; Hanke, Kathrin; McDonald-Hyman, Cameron; Taylor, Patricia A; Pfeifer, Dietmar; Hackanson, Björn; Leonhardt, Franziska; Prinz, Gabriele; Dierbach, Heide; Schmitt-Graeff, Annette; Kovarik, Jiri; Blazar, Bruce R; Zeiser, Robert

2015-01-15

The common γ chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-γ, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common γ-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation. © 2015 by The American Society of Hematology.

Fenoterol inhibits LPS-induced AMPK activation and inflammatory cytokine production through β-arrestin-2 in THP-1 cell line

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Wang, Wei; Zhang, Yuan; Xu, Ming; Zhang, You-Yi; He, Bei

2015-01-01

The AMP-activated protein kinase (AMPK) pathway is involved in regulating inflammation in several cell lines. We reported that fenoterol, a β 2 -adrenergic receptor (β 2 -AR) agonist, had anti-inflammatory effects in THP-1 cells, a monocytic cell line. Whether the fenoterol anti-inflammatory effect involves the AMPK pathway is unknown. In this study, we explored the mechanism of β 2 -AR stimulation with fenoterol in a lipopolysaccharide (LPS)-induced inflammatory cytokine secretion in THP-1 cells. We studied whether fenoterol and β-arrestin-2 or AMPKα1 subunit knockdown could affect LPS-induced AMPK activation, nuclear factor-kappa B (NF-κB) activation and inflammatory cytokine secretion. LPS-induced AMPK activation and interleukin 1β (IL-1β) release were reduced with fenoterol pretreatment of THP-1 cells. SiRNA knockdown of β-arrestin-2 abolished the fenoterol inhibition of LPS-induced AMPK activation and interleukin 1β (IL-1β) release, thus β-arrestin-2 mediated the anti-inflammatory effects of fenoterol on LPS-treated THP-1 cells. In addition, siRNA knockdown of AMPKα1 significantly attenuated the LPS-induced NF-κB activation and IL-1β release, so AMPKα1 was a key signaling molecule involved in LPS-induced inflammatory cytokine production. These results suggested the β 2 -AR agonist fenoterol inhibited LPS-induced AMPK activation and IL-1β release via β-arrestin-2 in THP-1 cells. The exploration of these mechanisms may help optimize therapeutic agents targeting these pathways in inflammatory diseases. - Highlights: • β 2 -AR agonist fenoterol exerts its protective effect on LPS-treated THP-1 cells. • Fenoterol inhibits LPS-induced AMPK activation and IL-1β production. • β-arrestin2 mediates fenoterol-inhibited AMPK activation and IL-1β release. • AMPKα1 is involved in LPS-induced NF-κB activation and IL-1β production

Fenoterol inhibits LPS-induced AMPK activation and inflammatory cytokine production through β-arrestin-2 in THP-1 cell line

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Wang, Wei [Department of Respiratory Medicine, Peking University Third Hospital, Beijing (China); Department of Infectious Diseases, Peking University Third Hospital, Beijing (China); Zhang, Yuan [Department of Respiratory Medicine, Peking University Third Hospital, Beijing (China); Xu, Ming; Zhang, You-Yi [Department of Institute of Vascular Medicine and Beijing Key Laboratory of Cardiovascular Receptors Research, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University Third Hospital, Beijing (China); He, Bei, E-mail: puh3_hb@bjmu.edu.cn [Department of Respiratory Medicine, Peking University Third Hospital, Beijing (China)

2015-06-26

The AMP-activated protein kinase (AMPK) pathway is involved in regulating inflammation in several cell lines. We reported that fenoterol, a β{sub 2}-adrenergic receptor (β{sub 2}-AR) agonist, had anti-inflammatory effects in THP-1 cells, a monocytic cell line. Whether the fenoterol anti-inflammatory effect involves the AMPK pathway is unknown. In this study, we explored the mechanism of β{sub 2}-AR stimulation with fenoterol in a lipopolysaccharide (LPS)-induced inflammatory cytokine secretion in THP-1 cells. We studied whether fenoterol and β-arrestin-2 or AMPKα1 subunit knockdown could affect LPS-induced AMPK activation, nuclear factor-kappa B (NF-κB) activation and inflammatory cytokine secretion. LPS-induced AMPK activation and interleukin 1β (IL-1β) release were reduced with fenoterol pretreatment of THP-1 cells. SiRNA knockdown of β-arrestin-2 abolished the fenoterol inhibition of LPS-induced AMPK activation and interleukin 1β (IL-1β) release, thus β-arrestin-2 mediated the anti-inflammatory effects of fenoterol on LPS-treated THP-1 cells. In addition, siRNA knockdown of AMPKα1 significantly attenuated the LPS-induced NF-κB activation and IL-1β release, so AMPKα1 was a key signaling molecule involved in LPS-induced inflammatory cytokine production. These results suggested the β{sub 2}-AR agonist fenoterol inhibited LPS-induced AMPK activation and IL-1β release via β-arrestin-2 in THP-1 cells. The exploration of these mechanisms may help optimize therapeutic agents targeting these pathways in inflammatory diseases. - Highlights: • β{sub 2}-AR agonist fenoterol exerts its protective effect on LPS-treated THP-1 cells. • Fenoterol inhibits LPS-induced AMPK activation and IL-1β production. • β-arrestin2 mediates fenoterol-inhibited AMPK activation and IL-1β release. • AMPKα1 is involved in LPS-induced NF-κB activation and IL-1β production.

Can Arousal Modulate Response Inhibition?

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Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

2015-01-01

The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

(−-Epigallocatechin gallate inhibits endotoxin-induced expression of inflammatory cytokines in human cerebral microvascular endothelial cells

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Li Jieliang

2012-07-01

Full Text Available Abstract Background (−-Epigallocatechin gallate (EGCG is a major polyphenol component of green tea that has antioxidant activities. Lipopolysaccharide (LPS induces inflammatory cytokine production and impairs blood–brain barrier (BBB integrity. We examined the effect of EGCG on LPS-induced expression of the inflammatory cytokines in human cerebral microvascular endothelial cells (hCMECs and BBB permeability. Methods The expression of TNF-α, IL-1β and monocyte chemotactic protein-1 (MCP-1/CCL2 was determined by quantitative real time PCR (qRT-PCR and ELISA. Intercellular adhesion molecule 1 (ICAM-1 and vascular cell adhesion molecule (VCAM in hCMECs were examined by qRT-PCR and Western blotting. Monocytes that adhered to LPS-stimulated endothelial cells were measured by monocyte adhesion assay. Tight junctional factors were detected by qRT-PCR (Claudin 5 and Occludin and immunofluorescence staining (Claudin 5 and ZO-1. The permeability of the hCMEC monolayer was determined by fluorescence spectrophotometry of transmembrane fluorescin and transendothelial electrical resistance (TEER. NF-kB activation was measured by luciferase assay. Results EGCG significantly suppressed the LPS-induced expression of IL-1β and TNF-α in hCMECs. EGCG also inhibited the expression of MCP-1/CCL2, VCAM-1 and ICAM-1. Functional analysis showed that EGCG induced the expression of tight junction proteins (Occludin and Claudin-5 in hCMECs. Investigation of the mechanism showed that EGCG had the ability to inhibit LPS-mediated NF-κB activation. In addition, 67-kD laminin receptor was involved in the anti-inflammatory effect of EGCG. Conclusions Our results demonstrated that LPS induced inflammatory cytokine production in hCMECs, which could be attenuated by EGCG. These data indicate that EGCG has a therapeutic potential for endotoxin-mediated endothelial inflammation.

Tat-CBR1 inhibits inflammatory responses through the suppressions of NF-κB and MAPK activation in macrophages and TPA-induced ear edema in mice

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Kim, Young Nam [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Kim, Dae Won [Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Kangnung-Wonju National University, Kangneung 210-702 (Korea, Republic of); Jo, Hyo Sang; Shin, Min Jea; Ahn, Eun Hee; Ryu, Eun Ji; Yong, Ji In; Cha, Hyun Ju; Kim, Sang Jin; Yeo, Hyeon Ji; Youn, Jong Kyu; Hwang, Jae Hyeok [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Jeong, Ji-Heon; Kim, Duk-Soo [Department of Anatomy, College of Medicine, Soonchunhyang University, Cheonan-Si 330-090 (Korea, Republic of); Cho, Sung-Woo [Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of); Park, Jinseu [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Eum, Won Sik, E-mail: wseum@hallym.ac.kr [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Choi, Soo Young, E-mail: sychoi@hallym.ac.kr [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of)

2015-07-15

Human carbonyl reductase 1 (CBR1) plays a crucial role in cell survival and protects against oxidative stress response. However, its anti-inflammatory effects are not yet clearly understood. In this study, we examined whether CBR1 protects against inflammatory responses in macrophages and mice using a Tat-CBR1 protein which is able to penetrate into cells. The results revealed that purified Tat-CBR1 protein efficiently transduced into Raw 264.7 cells and inhibited lipopolysaccharide (LPS)-induced cyclooxygenase-2 (COX-2), nitric oxide (NO) and prostaglandin E{sub 2} (PGE{sub 2}) expression levels. In addition, Tat-CBR1 protein leads to decreased pro-inflammatory cytokine expression through suppression of nuclear transcription factor-kappaB (NF-κB) and mitogen activated protein kinase (MAPK) activation. Furthermore, Tat-CBR1 protein inhibited inflammatory responses in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation when applied topically. These findings indicate that Tat-CBR1 protein has anti-inflammatory properties in vitro and in vivo through inhibition of NF-κB and MAPK activation, suggesting that Tat-CBR1 protein may have potential as a therapeutic agent against inflammatory diseases. - Highlights: • Transduced Tat-CBR1 reduces LPS-induced inflammatory mediators and cytokines. • Tat-CBR1 inhibits MAPK and NF-κB activation. • Tat-CBR1 ameliorates inflammation response in vitro and in vivo. • Tat-CBR1 may be useful as potential therapeutic agent for inflammation.

Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines

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Takasawa, Wataru; Ohnuma, Kei; Hatano, Ryo; Endo, Yuko; Dang, Nam H.; Morimoto, Chikao

2010-01-01

Research highlights: → TNF-α or IL-1β induces EC proliferation with reduction of CD26 expression. → CD26 siRNA or DPP-4 inhibition enhances TNF-α or IL-1β-induced EC proliferation. → Loss of CD26/DPP-4 enhances aortic sprouting induced by TNF-α or IL-1β. → Capillary formation induced by TNF-α or IL-1β is enahced in the CD26 -/- mice. -- Abstract: CD26/DPP-4 is abundantly expressed on capillary of inflamed lesion as well as effector T cells. Recently, CD26/dipeptidyl peptidase 4 (DPP-4) inhibition has been used as a novel oral therapeutic approach for patients with type 2 diabetes. While accumulating data indicate that vascular inflammation is a key feature of both micro- and macro-vascular complications in diabetes, the direct role of CD26/DPP-4 in endothelial biology is to be elucidated. We herein showed that proinflammatory cytokines such as tumor necrosis factor or interleukin-1 reduce expression of CD26 on microvascular endothelial cells, and that genetical or pharmacological inhibition of CD26/DPP-4 enhances endothelial growth both in vitro and in vivo. With DPP-4 inhibitors being used widely in the treatment of type 2 diabetes, our data strongly suggest that DPP-4 inhibition plays a pivotal role in endothelial growth and may have a potential role in the recovery of local circulation following diabetic vascular complications.

Epithelial cell pro-inflammatory cytokine response differs across dental plaque bacterial species.

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Stathopoulou, Panagiota G; Benakanakere, Manjunatha R; Galicia, Johnah C; Kinane, Denis F

2010-01-01

The dental plaque is comprised of numerous bacterial species, which may or may not be pathogenic. Human gingival epithelial cells (HGECs) respond to perturbation by various bacteria of the dental plaque by production of different levels of inflammatory cytokines, which is a putative reflection of their virulence. The aim of the current study was to determine responses in terms of interleukin (IL)-1beta, IL-6, IL-8 and IL-10 secretion induced by Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum and Streptococcus gordonii in order to gauge their virulence potential. HGECs were challenged with the four bacterial species, live or heat killed, at various multiplicity of infections and the elicited IL-1beta, IL-6, IL-8 and IL-10 responses were assayed by enzyme-linked immunosorbent assay. Primary HGECs challenged with live P. gingivalis produced high levels of IL-1beta, while challenge with live A. actinomycetemcomitans gave high levels of IL-8. The opportunistic pathogen F. nucleatum induces the highest levels of pro-inflammatory cytokines, while the commensal S. gordonii is the least stimulatory. We conclude that various dental plaque biofilm bacteria induce different cytokine response profiles in primary HGECs that may reflect their individual virulence or commensal status.

Identification of Lactobacillus plantarum genes modulating the cytokine response of human peripheral blood mononuclear cells

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Molenaar Douwe

2010-11-01

Full Text Available Abstract Background Modulation of the immune system is one of the most plausible mechanisms underlying the beneficial effects of probiotic bacteria on human health. Presently, the specific probiotic cell products responsible for immunomodulation are largely unknown. In this study, the genetic and phenotypic diversity of strains of the Lactobacillus plantarum species were investigated to identify genes of L. plantarum with the potential to influence the amounts of cytokines interleukin 10 (IL-10 and IL-12 and the ratio of IL-10/IL-12 produced by peripheral blood mononuclear cells (PBMCs. Results A total of 42 Lactobacillus plantarum strains isolated from diverse environmental and human sources were evaluated for their capacity to stimulate cytokine production in PBMCs. The L. plantarum strains induced the secretion of the anti-inflammatory cytokine IL-10 over an average 14-fold range and secretion of the pro-inflammatory cytokine IL-12 over an average 16-fold range. Comparisons of the strain-specific cytokine responses of PBMCs to comparative genome hybridization profiles obtained with L. plantarum WCFS1 DNA microarrays (also termed gene-trait matching resulted in the identification of 6 candidate genetic loci with immunomodulatory capacities. These loci included genes encoding an N-acetyl-glucosamine/galactosamine phosphotransferase system, the LamBDCA quorum sensing system, and components of the plantaricin (bacteriocin biosynthesis and transport pathway. Deletion of these genes in L. plantarum WCFS1 resulted in growth phase-dependent changes in the PBMC IL-10 and IL-12 cytokine profiles compared with wild-type cells. Conclusions The altered PBMC cytokine profiles obtained with the L. plantarum WCFS1 mutants were in good agreement with the predictions made by gene-trait matching for the 42 L. plantarum strains. This study therefore resulted in the identification of genes present in certain strains of L. plantarum which might be responsible for

Saponin Inhibits Hepatitis C Virus Propagation by Up-regulating Suppressor of Cytokine Signaling 2

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Kang, Sang-Min; Min, Saehong; Son, Kidong; Lee, Han Sol; Park, Eun Mee; Ngo, Huong T. T.; Tran, Huong T. L.; Lim, Yun-Sook; Hwang, Soon B.

2012-01-01

Saponins are a group of naturally occurring plant glycosides which possess a wide range of pharmacological properties, including anti-tumorigenic and antiviral activities. To investigate whether saponin has anti-hepatitis C virus (HCV) activity, we examined the effect of saponin on HCV replication. HCV replication was efficiently inhibited at a concentration of 10 µg/ml of saponin in cell culture grown HCV (HCVcc)-infected cells. Inhibitory effect of saponin on HCV replication was verified by quantitative real-time PCR, reporter assay, and immunoblot analysis. In addition, saponin potentiated IFN-α-induced anti-HCV activity. Moreover, saponin exerted antiviral activity even in IFN-α resistant mutant HCVcc-infected cells. To investigate how cellular genes were regulated by saponin, we performed microarray analysis using HCVcc-infected cells. We demonstrated that suppressor of cytokine signaling 2 (SOCS2) protein level was distinctively increased by saponin, which in turn resulted in inhibition of HCV replication. We further showed that silencing of SOCS2 resurrected HCV replication and overexpression of SOCS2 suppressed HCV replication. These data imply that saponin inhibits HCV replication via SOCS2 signaling pathway. These findings suggest that saponin may be a potent therapeutic agent for HCV patients. PMID:22745742

Antigen-Specific Interferon-Gamma Responses and Innate Cytokine Balance in TB-IRIS

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Goovaerts, Odin; Jennes, Wim; Massinga-Loembé, Marguerite; Ceulemans, Ann; Worodria, William; Mayanja-Kizza, Harriet; Colebunders, Robert; Kestens, Luc

2014-01-01

Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB patients receiving antiretroviral therapy (ART). TB-IRIS could be associated with an exaggerated immune response to TB-antigens. We compared the recovery of IFNγ responses to recall and TB-antigens and explored in vitro innate cytokine production in TB-IRIS patients. Methods In a prospective cohort study of HIV-TB co-infected patients treated for TB before ART initiation, we compared 18 patients who developed TB-IRIS with 18 non-IRIS controls matched for age, sex and CD4 count. We analyzed IFNγ ELISpot responses to CMV, influenza, TB and LPS before ART and during TB-IRIS. CMV and LPS stimulated ELISpot supernatants were subsequently evaluated for production of IL-12p70, IL-6, TNFα and IL-10 by Luminex. Results Before ART, all responses were similar between TB-IRIS patients and non-IRIS controls. During TB-IRIS, IFNγ responses to TB and influenza antigens were comparable between TB-IRIS patients and non-IRIS controls, but responses to CMV and LPS remained significantly lower in TB-IRIS patients. Production of innate cytokines was similar between TB-IRIS patients and non-IRIS controls. However, upon LPS stimulation, IL-6/IL-10 and TNFα/IL-10 ratios were increased in TB-IRIS patients compared to non-IRIS controls. Conclusion TB-IRIS patients did not display excessive IFNγ responses to TB-antigens. In contrast, the reconstitution of CMV and LPS responses was delayed in the TB-IRIS group. For LPS, this was linked with a pro-inflammatory shift in the innate cytokine balance. These data are in support of a prominent role of the innate immune system in TB-IRIS. PMID:25415590

Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

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Kim, Sun Ae [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)

2012-09-07

Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting AMPK

Peripheral Injection of SB203580 Inhibits the Inflammatory-Dependent Synthesis of Proinflammatory Cytokines in the Hypothalamus

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Andrzej P. Herman

2014-01-01

Full Text Available The study was designed to determine the effects of peripheral injection of SB203580 on the synthesis of interleukin- (IL- 1β, IL-6, and tumor necrosis factor (TNF α in the hypothalamus of ewes during prolonged inflammation. Inflammation was induced by the administration of lipopolysaccharide (LPS (400 ng/kg over 7 days. SB203580 is a selective ATP-competitive inhibitor of the p38 mitogen-activated protein kinase (MAPK, which is involved in the regulation of proinflammatory cytokines IL-1β, IL-6 and TNFα synthesis. Intravenous injection of SB203580 successfully inhibited (P<0.01 synthesis of IL-1β and reduced (P<0.01 the production of IL-6 in the hypothalamus. The p38 MAPK inhibitor decreased (P<0.01 gene expression of TNFα but its effect was not observed at the level of TNFα protein synthesis. SB203580 also reduced (P<0.01 LPS-stimulated IL-1 receptor type 1 gene expression. The conclusion that inhibition of p38 MAPK blocks LPS-induced proinflammatory cytokine synthesis seems to initiate new perspectives in the treatment of chronic inflammatory diseases also within the central nervous system. However, potential proinflammatory effects of SB203580 treatment suggest that all therapies using p38 MAPK inhibitors should be introduced very carefully with analysis of all expected and unexpected consequences of treatment.

IFN-γ fails to overcome inhibition of selected macrophage activation events in response to pathogenic mycobacteria.

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Shyamala Thirunavukkarasu

Full Text Available According to most models of mycobacterial infection, inhibition of the pro-inflammatory macrophage immune responses contributes to the persistence of bacteria. Mycobacterium avium subsp. paratuberculosis (MAP is a highly successful pathogen in cattle and sheep and is also implicated as the causative agent of Crohn's disease in humans. Pathogenic mycobacteria such as MAP have developed multiple strategies to evade host defence mechanisms including interfering with the macrophages' capacity to respond to IFN-γ, a feature which might be lacking in non-pathogenic mycobacteria such as M. smegmatis. We hypothesized that pre-sensitisation of macrophages with the pro-inflammatory cytokine IFN-γ would help in overcoming the inhibitory effect of MAP or its antigens on macrophage inflammatory responses. Herein we have compared a series of macrophage activation parameters in response to MAP and M. smegmatis as well as mycobacterial antigens. While IFN-γ did overcome the inhibition in immune suppressive mechanisms in response to MAP antigen as well as M. smegmatis, we could not find a clear role for IFN-γ in overcoming the inhibition of macrophage inflammatory responses to the pathogenic mycobacterium, MAP. We demonstrate that suppression of macrophage defence mechanisms by pathogenic mycobacteria is unlikely to be overcome by prior sensitization with IFN-γ alone. This indicates that IFN-γ signaling pathway-independent mechanisms may exist for overcoming inhibition of macrophage effector functions in response to pathogenic mycobacteria. These findings have important implications in understanding the survival mechanisms of pathogenic mycobacteria directed towards finding better therapeutics and vaccination strategies.

Monitoring bottlenose dolphin leukocyte cytokine mRNA responsiveness by qPCR

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Eberle, Kirsten C.; Venn-Watson, Stephanie K.; Jensen, Eric D.; Porter, Tracy J.; Waters, Theresa E.; Sacco, Randy E.

2017-01-01

Both veterinarians caring for dolphins in managed populations and researchers monitoring wild populations use blood-based diagnostics to monitor bottlenose dolphin (Tursiops truncatus) health. Quantitative PCR (qPCR) can be used to assess cytokine transcription patterns of peripheral blood mononuclear cells (PBMC). This can supplement currently available blood tests with information on immune status. Full realization of this potential requires establishment of normal ranges of cytokine gene transcription levels in bottlenose dolphins. We surveyed four dolphins over the span of seven months by serial bleeds. PBMC were stimulated with phytohaemagglutinin (1, 5, and 10 μg/mL) and concanavalin A (1 μg/mL) for 48 H in vitro. RNA from these cultures was probed by qPCR using Tursiops truncatus-specific primers (IL-1α, IL-1β, IL-1RA, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-13, IL-18, IFN-γ and TNF-α). Two blood samples from an additional bottlenose dolphin diagnosed with acute pulmonary disease add further perspective to the data. We observed that mitogen choice made a significant difference in the magnitude of gene transcription observed. On the other hand, most cytokines tested exhibited limited intra-animal variation. However, IL-6 and IL-12p40 differed between older and younger dolphins. Furthermore, the magnitude of mitogenic response clusters the tested cytokines into three groups. The data provide a reference for the selection of target cytokine mRNAs and their expected range of mitogen-stimulated cytokine gene transcription for future studies. PMID:29272269

Monitoring bottlenose dolphin leukocyte cytokine mRNA responsiveness by qPCR.

Directory of Open Access Journals (Sweden)

Amelia Ruth Hofstetter

Full Text Available Both veterinarians caring for dolphins in managed populations and researchers monitoring wild populations use blood-based diagnostics to monitor bottlenose dolphin (Tursiops truncatus health. Quantitative PCR (qPCR can be used to assess cytokine transcription patterns of peripheral blood mononuclear cells (PBMC. This can supplement currently available blood tests with information on immune status. Full realization of this potential requires establishment of normal ranges of cytokine gene transcription levels in bottlenose dolphins. We surveyed four dolphins over the span of seven months by serial bleeds. PBMC were stimulated with phytohaemagglutinin (1, 5, and 10 μg/mL and concanavalin A (1 μg/mL for 48 H in vitro. RNA from these cultures was probed by qPCR using Tursiops truncatus-specific primers (IL-1α, IL-1β, IL-1RA, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-13, IL-18, IFN-γ and TNF-α. Two blood samples from an additional bottlenose dolphin diagnosed with acute pulmonary disease add further perspective to the data. We observed that mitogen choice made a significant difference in the magnitude of gene transcription observed. On the other hand, most cytokines tested exhibited limited intra-animal variation. However, IL-6 and IL-12p40 differed between older and younger dolphins. Furthermore, the magnitude of mitogenic response clusters the tested cytokines into three groups. The data provide a reference for the selection of target cytokine mRNAs and their expected range of mitogen-stimulated cytokine gene transcription for future studies.

Sulforaphane protects against cytokine- and streptozotocin-induced β-cell damage by suppressing the NF-κB pathway

International Nuclear Information System (INIS)

Song, Mi-Young; Kim, Eun-Kyung; Moon, Woo-Sung; Park, Jin-Woo; Kim, Hyung-Jin; So, Hong-Seob; Park, Raekil; Kwon, Kang-Beom; Park, Byung-Hyun

2009-01-01

Sulforaphane (SFN) is an indirect antioxidant that protects animal tissues from chemical or biological insults by stimulating the expression of several NF-E2-related factor-2 (Nrf2)-regulated phase 2 enzymes. Treatment of RINm5F insulinoma cells with SFN increases Nrf2 nuclear translocation and expression of phase 2 enzymes. In this study, we investigated whether the activation of Nrf2 by SFN treatment or ectopic overexpression of Nrf2 inhibited cytokine-induced β-cell damage. Treatment of RIN cells with IL-1β and IFN-γ induced β-cell damage through a NF-κB-dependent signaling pathway. Activation of Nrf2 by treatment with SFN and induction of Nrf2 overexpression by transfection with Nrf2 prevented cytokine toxicity. The mechanism by which Nrf2 activation inhibited NF-κB-dependent cell death signals appeared to involve the reduction of oxidative stress, as demonstrated by the inhibition of cytokine-induced H 2 O 2 production. The protective effect of SFN was further demonstrated by the restoration of normal insulin secreting responses to glucose in cytokine-treated rat pancreatic islets. Furthermore, pretreatment with SFN blocked the development of type 1 diabetes in streptozotocin-treated mice

Vitamin E γ-Tocotrienol Inhibits Cytokine-Stimulated NF-κB Activation by Induction of Anti-Inflammatory A20 via Stress Adaptive Response Due to Modulation of Sphingolipids.

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Wang, Yun; Park, Na-Young; Jang, Yumi; Ma, Averil; Jiang, Qing

2015-07-01

NF-κB plays a central role in pathogenesis of inflammation and cancer. Many phytochemicals, including γ-tocotrienol (γTE), a natural form of vitamin E, have been shown to inhibit NF-κB activation, but the underlying mechanism has not been identified. In this study, we show that γTE inhibited cytokine-triggered activation of NF-κB and its upstream regulator TGF-β-activated kinase-1 in murine RAW 264.7 macrophages and primary bone marrow-derived macrophages. In these cells, γTE induced upregulation of A20, an inhibitor of NF-κB. Knockout of A20 partially diminished γTE's anti-NF-κB effect, but γTE increased another NF-κB inhibitor, Cezanne, in A20(-/-) cells. In search of the reason for A20 upregulation, we found that γTE treatment increased phosphorylation of translation initiation factor 2, IκBα, and JNK, indicating induction of endoplasmic reticulum stress. Liquid chromatography-tandem mass spectrometry analyses revealed that γTE modulated sphingolipids, including enhancement of intracellular dihydroceramides, sphingoid bases in de novo synthesis of the sphingolipid pathway. Chemical inhibition of de novo sphingolipid synthesis partially reversed γTE's induction of A20 and the anti-NF-κB effect. The importance of dihydroceramide increase is further supported by the observation that C8-dihydroceramide mimicked γTE in upregulating A20, enhancing endoplasmic reticulum stress, and attenuating TNF-triggered NF-κB activation. Our study identifies a novel anti-NF-κB mechanism where A20 is induced by stress-induced adaptive response as a result of modulation of sphingolipids, and it demonstrates an immunomodulatory role of dihydrocermides. Copyright © 2015 by The American Association of Immunologists, Inc.

1,25-Dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level

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Müller, K; Haahr, P M; Diamant, M

1992-01-01

was not caused by impaired production of mRNA. Taken together, the study demonstrates a vitamin D-induced inhibitory effect of LPS-driven monokine production, which is most likely a vitamin D-receptor mediated phenomenon exerted at a post-transcriptional, presecretory level. Impaired monokine production may...... be of importance in 1,25-(OH)2D3-mediated inhibition of lymphocyte functions in vitro.......1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits lymphocyte proliferation and production of antibodies and lymphokines such as interleukin (IL)-2 and interferon gamma. These lymphocyte functions are dependent upon cytokines, including IL-1 alpha, IL-1 beta, IL-6 and tumour necrosis factor alpha...

Cigarette smoke alters the invariant natural killer T cell function and may inhibit anti-tumor responses.

LENUS (Irish Health Repository)

Hogan, Andrew E

2011-09-01

Invariant natural killer T (iNKT) cells are a minor subset of human T cells which express the invariant T cell receptor Vα24 Jα18 and recognize glycolipids presented on CD1d. Invariant NKT cells are important immune regulators and can initiate anti-tumor responses through early potent cytokine production. Studies show that iNKT cells are defective in certain cancers. Cigarette smoke contains many carcinogens and is implicated directly and indirectly in many cancers. We investigated the effects of cigarette smoke on the circulating iNKT cell number and function. We found that the iNKT cell frequency is significantly reduced in cigarette smoking subjects. Invariant NKT cells exposed to cigarette smoke extract (CSE) showed significant defects in cytokine production and the ability to kill target cells. CSE inhibits the upregulation of CD107 but not CD69 or CD56 on iNKT cells. These findings suggest that CSE has a specific effect on iNKT cell anti-tumor responses, which may contribute to the role of smoking in the development of cancer.

Cornuside inhibits mast cell-mediated allergic response by down-regulating MAPK and NF-κB signaling pathways

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Li, Liangchang [Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Yanbian University, Yanji, 133002 (China); Jin, Guangyu [Yanbian University Hospital, Medicine College, Yanbian University, Yanji, 133000 (China); Jiang, Jingzhi [Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Yanbian University, Yanji, 133002 (China); Zheng, Mingyu; Jin, Yan [College of Pharmacy, Yanbian University, Yanji, 133002 (China); Lin, Zhenhua [Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, 133002 (China); Li, Guangzhao [Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Yanbian University, Yanji, 133002 (China); Choi, Yunho, E-mail: why76@jbnu.ac.kr [Department of Anatomy, Medical School, Institute for Medical Sciences, Chonbuk National University, Jeonju, 561-756 (Korea, Republic of); Yan, Guanghai, E-mail: ghyan2015@sina.com [Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Yanbian University, Yanji, 133002 (China)

2016-04-29

Aims: The present study is to investigate the effect of cornuside on mast cell-mediated allergic response, as well as its possible mechanisms of action. Methods: To test the anti-allergic effects of cornuside in vivo, local extravasation was induced by local injection of anti-dinitrophenyl immunoglobulin E (IgE) followed by intravenous antigenic challenge in passive cutaneous anaphylaxis model rats. Mast cell viability was determined using MTT assay. Histamine content from rat peritoneal mast cells was measured by the radioenzymatic method. To investigate the mechanisms by which cornuside affects the reduction of histamine release, the levels of calcium uptake were measured. To examine whether cornuside affects the expression of pro-inflammatory cytokines, Western blotting and ELISA were carried out. Results: Oral administration of cornuside inhibited passive cutaneous anaphylaxis in rats. Presence of cornuside attenuated IgE-induced histamine release from rat peritoneal mast cells. The inhibitory effect of cornuside on histamine release was mediated by the modulation of intracellular calcium. In addition, cornuside decreased phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187-stimulated production and secretion of pro-inflammatory cytokines such as TNF-α and IL-6 in human mast cells. The inhibitory effect of cornuside on pro-inflammatory cytokines was dependent on nuclear factor-κB and p38 mitogen-activated protein kinase. Conclusions: The present study provides evidence that cornuside inhibits mast cell-derived inflammatory allergic reactions by blocking histamine release and pro-inflammatory cytokine expression. Furthermore, in vivo and in vitro anti-allergic effects of cornuside suggest a possible therapeutic application of this agent in inflammatory allergic diseases.

Cornuside inhibits mast cell-mediated allergic response by down-regulating MAPK and NF-κB signaling pathways

International Nuclear Information System (INIS)

Li, Liangchang; Jin, Guangyu; Jiang, Jingzhi; Zheng, Mingyu; Jin, Yan; Lin, Zhenhua; Li, Guangzhao; Choi, Yunho; Yan, Guanghai

2016-01-01

Aims: The present study is to investigate the effect of cornuside on mast cell-mediated allergic response, as well as its possible mechanisms of action. Methods: To test the anti-allergic effects of cornuside in vivo, local extravasation was induced by local injection of anti-dinitrophenyl immunoglobulin E (IgE) followed by intravenous antigenic challenge in passive cutaneous anaphylaxis model rats. Mast cell viability was determined using MTT assay. Histamine content from rat peritoneal mast cells was measured by the radioenzymatic method. To investigate the mechanisms by which cornuside affects the reduction of histamine release, the levels of calcium uptake were measured. To examine whether cornuside affects the expression of pro-inflammatory cytokines, Western blotting and ELISA were carried out. Results: Oral administration of cornuside inhibited passive cutaneous anaphylaxis in rats. Presence of cornuside attenuated IgE-induced histamine release from rat peritoneal mast cells. The inhibitory effect of cornuside on histamine release was mediated by the modulation of intracellular calcium. In addition, cornuside decreased phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187-stimulated production and secretion of pro-inflammatory cytokines such as TNF-α and IL-6 in human mast cells. The inhibitory effect of cornuside on pro-inflammatory cytokines was dependent on nuclear factor-κB and p38 mitogen-activated protein kinase. Conclusions: The present study provides evidence that cornuside inhibits mast cell-derived inflammatory allergic reactions by blocking histamine release and pro-inflammatory cytokine expression. Furthermore, in vivo and in vitro anti-allergic effects of cornuside suggest a possible therapeutic application of this agent in inflammatory allergic diseases.

Inhibition of furin results in increased growth, invasiveness and cytokine production of synoviocytes from patients with rheumatoid arthritis.

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Wu, Changshun; Song, Zezhong; Liu, Huiling; Pan, Jihong; Jiang, Huiyu; Liu, Chao; Yan, Zexing; Feng, Hong; Sun, Shui

2017-07-01

Fibroblast-like synoviocytes derived from patients with rheumatoid arthritis play a key role by local production of cytokines and proteolytic enzymes that degrade the extracellular matrix and cartilage. These synoviocytes acquire phenotypic characteristics commonly observed in transformed cells, like anchorage-independent growth, increased proliferation and invasiveness, and insensitivity to apoptosis. Furin is a ubiquitous proprotein convertase that is capable of cleaving precursors of a wide variety of proteins. In patients with rheumatoid arthritis, furin is reported to be highly expressed in the synovial pannus compared with healthy persons. However, the mechanisms are poorly understood. This study is to explore the effect of furin overexpression in rheumatoid synoviocytes. In this study, RNA interference was used to knock down furin expression and to assess the resultant effects on biological behaviors of synoviocytes, such as cell proliferation, invasion, migration, cell cycle and cell apoptosis. In addition, the production of inflammatory cytokines was evaluated. The results showed that the inhibition of furin enhanced proliferation, invasion, and migration of synoviocytes in vitro. Cell cycle was accelerated and cell death was affected by furin knockdown. Also, the inhibition of furin increased interleukin-1β and tumor necrosis factor-α secretion of synoviocytes. Inhibition of furin enhances invasive phenotype of synoviocytes from patients with rheumatoid arthritis, implying a protective role of furin. Agents targeting upregulation of furin may have therapeutic potential for rheumatoid arthritis. Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Fasting metabolism modulates the interleukin-12/interleukin-10 cytokine axis.

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Johannes J Kovarik

Full Text Available A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR, is responsible for controlling the balance between pro-inflammatory interleukin (IL-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines. Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR-activation and glucose-deprivation or co-treatment with 5'-adenosine monophosphate (AMP-activated protein kinase (AMPK activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10. Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation.

Fasting metabolism modulates the interleukin-12/interleukin-10 cytokine axis

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Kernbauer, Elisabeth; Hölzl, Markus A.; Hofer, Johannes; Gualdoni, Guido A.; Schmetterer, Klaus G.; Miftari, Fitore; Sobanov, Yury; Meshcheryakova, Anastasia; Mechtcheriakova, Diana; Witzeneder, Nadine; Greiner, Georg; Ohradanova-Repic, Anna; Waidhofer-Söllner, Petra; Säemann, Marcus D.; Decker, Thomas

2017-01-01

A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR), is responsible for controlling the balance between pro-inflammatory interleukin (IL)-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines. Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR)-activation and glucose-deprivation or co-treatment with 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG) increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10. Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation. PMID:28742108

Proinflammatory Cytokines IL-6 and TNF-α Increased Telomerase Activity through NF-κB/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells

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Seyung S. Chung

2017-01-01

Full Text Available There are increasing evidences of proinflammatory cytokine involvement in cancer development. Here, we found that two cytokines, IL-6 and TNF-α, activated colorectal cancer cells to be more invasive and stem-like. Combined treatment of IL-6 and TNF-α phosphorylated transcription factors STAT3 in a synergistic manner. STAT3, STAT1, and NF-κB physically interacted upon the cytokine stimulation. STAT3 was bound to the promoter region of human telomerase reverse transcriptase (hTERT. IL-6 and TNF-α stimulation further enhanced STAT3 binding affinity. Stem cell marker Oct-4 was upregulated in colorectal cancer cells upon IL-6 and TNF-α stimulation. Withaferin A, an anti-inflammatory steroidal lactone, inhibited the IL-6- and TNF-α-induced cancer cell invasion and decreased colonosphere formation. Notably, withaferin A inhibited STAT3 phosphorylation and abolished the STAT3, STAT1, and NF-κB interactions. Oct-4 expression was also downregulated by withaferin A inhibition. The binding of STAT3 to the hTERT promoter region and telomerase activity showed reduction with withaferin A treatments. Proinflammatory cytokine-induced cancer cell invasiveness is mediated by a STAT3-regulated mechanism in colorectal cancer cells. Our data suggest that withaferin A could be a promising anticancer agent that effectively inhibits the progression of colorectal cancer.

Regulation of cytokine production in human alveolar macrophages and airway epithelial cells in response to ambient air pollution particles: Further mechanistic studies

International Nuclear Information System (INIS)

Becker, Susanne; Mundandhara, Sailaja; Devlin, Robert B.; Madden, Michael

2005-01-01

In order to better understand how ambient air particulate matter (PM) affect lung health, the two main airway cell types likely to interact with inhaled particles, alveolar macrophages (AM) and airway epithelial cells have been exposed to particles in vitro and followed for endpoints of inflammation, and oxidant stress. Separation of Chapel Hill PM 10 into fine and coarse size particles revealed that the main proinflammatory response (TNF, IL-6, COX-2) in AM was driven by material present in the coarse PM, containing 90-95% of the stimulatory material in PM10. The particles did not affect expression of hemoxygenase-1 (HO-1), a sensitive marker of oxidant stress. Primary cultures of normal human bronchial epithelial cells (NHBE) also responded to the coarse fraction with higher levels of IL-8 and COX-2, than induced by fine or ultrafine PM. All size PM induced oxidant stress in NHBE, while fine PM induced the highest levels of HO-1 expression. The production of cytokines in AM by both coarse and fine particles was blocked by the toll like receptor 4 (TLR4) antagonist E5531 involved in the recognition of LPS and Gram negative bacteria. The NHBE were found to recognize coarse and fine PM through TLR2, a receptor with preference for recognition of Gram positive bacteria. Compared to ambient PM, diesel PM induced only a minimal cytokine response in both AM and NHBE. Instead, diesel suppressed LPS-induced TNF and IL-8 release in AM. Both coarse and fine ambient air PM were also found to inhibit LPS-induced TNF release while silica, volcanic ash or carbon black had no inhibitory effect. Diesel particles did not affect cytokine mRNA induction nor protein accumulation but interfered with the release of cytokine from the cells. Ambient coarse and fine PM, on the other hand, inhibited both mRNA induction and protein production. Exposure to coarse and fine PM decreased the expression of TLR4 in the macrophages. Particle-induced decrease in TLR4 and hyporesponsiveness to LPS

Heroin use is associated with suppressed pro-inflammatory cytokine response after LPS exposure in HIV-infected individuals.

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Hinta Meijerink

Full Text Available Opioid use is associated with increased incidence of infectious diseases. Although experimental studies have shown that opioids affect various functions of immune cells, only limited data are available from human studies. Drug use is an important risk factor for HIV transmission; however no data are available whether heroin and/or methadone modulate immune response. Therefore, we examined the effect of heroin and methadone use among HIV-infected individuals on the production of cytokines after ex vivo stimulation with various pathogens.Treatment naïve HIV-infected individuals from Indonesia were recruited. Several cohorts of individuals were recruited: 1 using heroin 2 receiving methadone opioid substitution 3 using heroin over 1 year ago and 4 controls (never used opioids. Whole blood was stimulated with Mycobacterium tuberculosis, Candida albicans and LPS for 24 to 48 hours. Cytokine production (IL-1 β, IL-6, IL-10, IFN-α, IFN-γ and TNF-α was determined using multiplex beads assay.Among 82 individuals, the cytokine levels in unstimulated samples did not differ between groups. Overall, heroin users had significantly lower cytokine response after exposure to LPS (p<0.05. After stimulation with either M. tuberculosis or C. albicans the cytokine production of all groups were comparable.The cytokine production after exposure to LPS is significantly down-regulated in HIV-infected heroin users. Interesting, methadone use did not suppress cytokine response, which could have implications guidelines of opioid substitution.

Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response.

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Hempstead, Andrew D; Isberg, Ralph R

2015-12-08

Cells of the innate immune system recognize bacterial pathogens by detecting common microbial patterns as well as pathogen-specific activities. One system that responds to these stimuli is the IRE1 branch of the unfolded protein response (UPR), a sensor of endoplasmic reticulum (ER) stress. Activation of IRE1, in the context of Toll-like receptor (TLR) signaling, induces strong proinflammatory cytokine induction. We show here that Legionella pneumophila, an intravacuolar pathogen that replicates in an ER-associated compartment, blocks activation of the IRE1 pathway despite presenting pathogen products that stimulate this response. L. pneumophila TLR ligands induced the splicing of mRNA encoding XBP1s, the main target of IRE1 activity. L. pneumophila was able to inhibit both chemical and bacterial induction of XBP1 splicing via bacterial translocated proteins that interfere with host protein translation. A strain lacking five translocated translation elongation inhibitors was unable to block XBP1 splicing, but this could be rescued by expression of a single such inhibitor, consistent with limitation of the response by translation elongation inhibitors. Chemical inhibition of translation elongation blocked pattern recognition receptor-mediated XBP1 splicing, mimicking the effects of the bacterial translation inhibitors. In contrast, host cell-promoted inhibition of translation initiation in response to the pathogen was ineffective in blocking XBP1 splicing, demonstrating the need for the elongation inhibitors for protection from the UPR. The inhibition of host translation elongation may be a common strategy used by pathogens to limit the innate immune response by interfering with signaling via the UPR.

Impaired Cytokine Responses to Epstein-Barr Virus Antigens in Systemic Lupus Erythematosus Patients

DEFF Research Database (Denmark)

Draborg, Anette Holck; Sandhu, Noreen; Larsen, Nanna

2016-01-01

We analyzed cytokine responses against latent and lytic Epstein-Barr virus (EBV) antigens in systemic lupus erythematosus (SLE) patients and healthy controls (HCs) to obtain an overview of the distinctive immune regulatory response in SLE patients and to expand the previously determined impaired...

Caspase-8 regulates the expression of pro- and anti-inflammatory cytokines in human bone marrow-derived mesenchymal stromal cells.

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Moen, Siv H; Westhrin, Marita; Zahoor, Muhammad; Nørgaard, Nikolai N; Hella, Hanne; Størdal, Berit; Sundan, Anders; Nilsen, Nadra J; Sponaas, Anne-Marit; Standal, Therese

2016-09-01

Mesenchymal stem cells, also called mesenchymal stromal cells, MSCs, have great potential in stem cell therapy partly due to their immunosuppressive properties. How these cells respond to chronic inflammatory stimuli is therefore of importance. Toll-like receptors (TLR)s are innate immune receptors that mediate inflammatory signals in response to infection, stress, and damage. Caspase-8 is involved in activation of NF-kB downstream of TLRs in immune cells. Here we investigated the role of caspase-8 in regulating TLR-induced cytokine production from human bone marrow-derived mesenchymal stromal cells (hBMSCs). Cytokine expression in hBMCs in response to poly(I:C) and LPS was evaluated by PCR, multiplex cytokine assay, and ELISA. TLR3, TRIF, and caspase-8 were silenced using siRNA. Caspase-8 was also inhibited using a caspase-8 inhibitor, z-IEDT. We found that TLR3 agonist poly(I:C) and TLR4 agonist LPS induced secretion of several pro-inflammatory cytokines in a TLR-dependent manner which required the TLR signaling adaptor molecule TRIF. Further, poly(I:C) reduced the expression of anti-inflammatory cytokines HGF and TGFβ whereas LPS reduced HGF expression only. Notably, caspase-8 was involved in the induction of IL- IL-1β, IL-6, CXCL10, and in the inhibition of HGF and TGFβ. Caspase-8 appears to modulate hBMSCs into gaining a pro-inflammatory phenotype. Therefore, inhibiting caspase-8 in hBMSCs might promote an immunosuppressive phenotype which could be useful in clinical applications to treat inflammatory disorders.

Caspase‐8 regulates the expression of pro‐ and anti‐inflammatory cytokines in human bone marrow‐derived mesenchymal stromal cells

Science.gov (United States)

Moen, Siv H.; Westhrin, Marita; Zahoor, Muhammad; Nørgaard, Nikolai N.; Hella, Hanne; Størdal, Berit; Sundan, Anders; Nilsen, Nadra J.; Sponaas, Anne‐Marit

2016-01-01

Abstract Introduction Mesenchymal stem cells, also called mesenchymal stromal cells, MSCs, have great potential in stem cell therapy partly due to their immunosuppressive properties. How these cells respond to chronic inflammatory stimuli is therefore of importance. Toll‐like receptors (TLR)s are innate immune receptors that mediate inflammatory signals in response to infection, stress, and damage. Caspase‐8 is involved in activation of NF‐kB downstream of TLRs in immune cells. Here we investigated the role of caspase‐8 in regulating TLR‐induced cytokine production from human bone marrow‐derived mesenchymal stromal cells (hBMSCs). Methods Cytokine expression in hBMCs in response to poly(I:C) and LPS was evaluated by PCR, multiplex cytokine assay, and ELISA. TLR3, TRIF, and caspase‐8 were silenced using siRNA. Caspase‐8 was also inhibited using a caspase‐8 inhibitor, z‐IEDT. Results We found that TLR3 agonist poly(I:C) and TLR4 agonist LPS induced secretion of several pro‐inflammatory cytokines in a TLR‐dependent manner which required the TLR signaling adaptor molecule TRIF. Further, poly(I:C) reduced the expression of anti‐inflammatory cytokines HGF and TGFβ whereas LPS reduced HGF expression only. Notably, caspase‐8 was involved in the induction of IL‐ IL‐1β, IL‐6, CXCL10, and in the inhibition of HGF and TGFβ. Conclusion Caspase‐8 appears to modulate hBMSCs into gaining a pro‐inflammatory phenotype. Therefore, inhibiting caspase‐8 in hBMSCs might promote an immunosuppressive phenotype which could be useful in clinical applications to treat inflammatory disorders. PMID:27621815

Cytokine profiles show heterogeneity of interferon-β response in multiple sclerosis patients

DEFF Research Database (Denmark)

Hegen, Harald; Adrianto, Indra; Lessard, Christopher J

2016-01-01

OBJECTIVE: To evaluate serum cytokine profiles for their utility to determine the heterogeneous responses to interferon (IFN)-β treatment in patients with multiple sclerosis (MS). METHODS: Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome receiving de novo IFN-β treatment...... were included in this prospective, observational study. Number of relapses and changes in disability were assessed 2 years prior to and 2 years after initiation of treatment. Sera were collected at baseline and after 3 months on therapy. Cytokine levels in sera were assessed by Luminex multiplex assays...

Ursodeoxycholic acid inhibits TNFα-induced IL-8 release from monocytes.

Science.gov (United States)

O'Dwyer, Aoife M; Lajczak, Natalia K; Keyes, Jennifer A; Ward, Joseph B; Greene, Catherine M; Keely, Stephen J

2016-08-01

Monocytes are critical to the pathogenesis of inflammatory bowel disease (IBD) as they infiltrate the mucosa and release cytokines that drive the inflammatory response. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid with anti-inflammatory actions, has been proposed as a potential new therapy for IBD. However, its effects on monocyte function are not yet known. Primary monocytes from healthy volunteers or cultured U937 monocytes were treated with either the proinflammatory cytokine, TNFα (5 ng/ml) or the bacterial endotoxin, lipopolysaccharide (LPS; 1 μg/ml) for 24 h, in the absence or presence of UDCA (25-100 μM). IL-8 release into the supernatant was measured by ELISA. mRNA levels were quantified by qPCR and changes in cell signaling proteins were determined by Western blotting. Toxicity was assessed by measuring lactate dehydrogenase (LDH) release. UDCA treatment significantly attenuated TNFα-, but not LPS-driven, release of IL-8 from both primary and cultured monocytes. UDCA inhibition of TNFα-driven responses was associated with reduced IL-8 mRNA expression. Both TNFα and LPS stimulated NFκB activation in monocytes, while IL-8 release in response to both cytokines was attenuated by an NFκB inhibitor, BMS-345541. Interestingly, UDCA inhibited TNFα-, but not LPS-stimulated, NFκB activation. Finally, TNFα, but not LPS, induced phosphorylation of TNF receptor associated factor (TRAF2), while UDCA cotreatment attenuated this response. We conclude that UDCA specifically inhibits TNFα-induced IL-8 release from monocytes by inhibiting TRAF2 activation. Since such actions would serve to dampen mucosal immune responses in vivo, our data support the therapeutic potential of UDCA for IBD. Copyright © 2016 the American Physiological Society.

Differing House Finch Cytokine Expression Responses to Original and Evolved Isolates of Mycoplasma gallisepticum.

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Vinkler, Michal; Leon, Ariel E; Kirkpatrick, Laila; Dalloul, Rami A; Hawley, Dana M

2018-01-01

The recent emergence of the poultry bacterial pathogen Mycoplasma gallisepticum (MG) in free-living house finches ( Haemorhous mexicanus ), which causes mycoplasmal conjunctivitis in this passerine bird species, resulted in a rapid coevolutionary arms-race between MG and its novel avian host. Despite extensive research on the ecological and evolutionary dynamics of this host-pathogen system over the past two decades, the immunological responses of house finches to MG infection remain poorly understood. We developed seven new probe-based one-step quantitative reverse transcription polymerase chain reaction assays to investigate mRNA expression of house finch cytokine genes ( IL1B, IL6, IL10, IL18, TGFB2, TNFSF15 , and CXCLi2 , syn. IL8L ). These assays were then used to describe cytokine transcription profiles in a panel of 15 house finch tissues collected at three distinct time points during MG infection. Based on initial screening that indicated strong pro-inflammatory cytokine expression during MG infection at the periorbital sites in particular, we selected two key house finch tissues for further characterization: the nictitating membrane, i.e., the internal eyelid in direct contact with MG, and the Harderian gland, the secondary lymphoid tissue responsible for regulation of periorbital immunity. We characterized cytokine responses in these two tissues for 60 house finches experimentally inoculated either with media alone (sham) or one of two MG isolates: the earliest known pathogen isolate from house finches (VA1994) or an evolutionarily more derived isolate collected in 2006 (NC2006), which is known to be more virulent. We show that the more derived and virulent isolate NC2006, relative to VA1994, triggers stronger local inflammatory cytokine signaling, with peak cytokine expression generally occurring 3-6 days following MG inoculation. We also found that the extent of pro-inflammatory interleukin 1 beta signaling was correlated with conjunctival MG loads

Differing House Finch Cytokine Expression Responses to Original and Evolved Isolates of Mycoplasma gallisepticum

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Michal Vinkler

2018-01-01

Full Text Available The recent emergence of the poultry bacterial pathogen Mycoplasma gallisepticum (MG in free-living house finches (Haemorhous mexicanus, which causes mycoplasmal conjunctivitis in this passerine bird species, resulted in a rapid coevolutionary arms-race between MG and its novel avian host. Despite extensive research on the ecological and evolutionary dynamics of this host–pathogen system over the past two decades, the immunological responses of house finches to MG infection remain poorly understood. We developed seven new probe-based one-step quantitative reverse transcription polymerase chain reaction assays to investigate mRNA expression of house finch cytokine genes (IL1B, IL6, IL10, IL18, TGFB2, TNFSF15, and CXCLi2, syn. IL8L. These assays were then used to describe cytokine transcription profiles in a panel of 15 house finch tissues collected at three distinct time points during MG infection. Based on initial screening that indicated strong pro-inflammatory cytokine expression during MG infection at the periorbital sites in particular, we selected two key house finch tissues for further characterization: the nictitating membrane, i.e., the internal eyelid in direct contact with MG, and the Harderian gland, the secondary lymphoid tissue responsible for regulation of periorbital immunity. We characterized cytokine responses in these two tissues for 60 house finches experimentally inoculated either with media alone (sham or one of two MG isolates: the earliest known pathogen isolate from house finches (VA1994 or an evolutionarily more derived isolate collected in 2006 (NC2006, which is known to be more virulent. We show that the more derived and virulent isolate NC2006, relative to VA1994, triggers stronger local inflammatory cytokine signaling, with peak cytokine expression generally occurring 3–6 days following MG inoculation. We also found that the extent of pro-inflammatory interleukin 1 beta signaling was correlated with conjunctival

Thioredoxin ameliorates cutaneous inflammation by regulating the epithelial production and release of pro-Inflammatory cytokines

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Hai eTian

2013-09-01

Full Text Available Human thioredoxin-1 (TRX is a 12-kDa protein with redox-active dithiol in the active site -Cys-Gly-Pro-Cys-. It has been demonstrated that systemic administration and transgenic overexpression of TRX ameliorate inflammation in various animal models, but its anti-inflammatory mechanism is not well characterized. We investigated the anti-inflammatory effects of topically applied recombinant human TRX (rhTRX in a murine irritant contact dermatitis (ICD induced by croton oil. Topically applied rhTRX was distributed only in the skin tissues under both non-inflammatory and inflammatory conditions, and significantly suppressed the inflammatory response by inhibiting the production of cytokines and chemokines, such as TNF-α, Il-1β, IL-6, CXCL-1, and MCP-1. In an in vitro study, rhTRX also significantly inhibited the formation of cytokines and chemokines produced by keratinocytes after exposure to croton oil and phorbol 12-myristate 13-acetate. These results indicate that TRX prevents skin inflammation via the inhibition of local formation of inflammatory cytokines and chemokines. As a promising new approach, local application of TRX may be useful for the treatment of various skin and mucosal inflammatory disorders.

Cytokine balance in human malaria: does Plasmodium vivax elicit more inflammatory responses than Plasmodium falciparum?

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Raquel M Gonçalves

Full Text Available BACKGROUND: The mechanisms by which humans regulate pro- and anti-inflammatory responses on exposure to different malaria parasites remains unclear. Although Plasmodium vivax usually causes a relatively benign disease, this parasite has been suggested to elicit more host inflammation per parasitized red blood cell than P. falciparum. METHODOLOGY/PRINCIPAL FINDINGS: We measured plasma concentrations of seven cytokines and two soluble tumor necrosis factor (TNF-α receptors, and evaluated clinical and laboratory outcomes, in Brazilians with acute uncomplicated infections with P. vivax (n = 85, P. falciparum (n = 30, or both species (n = 12, and in 45 asymptomatic carriers of low-density P. vivax infection. Symptomatic vivax malaria patients, compared to those infected with P. falciparum or both species, had more intense paroxysms, but they had no clear association with a pro-inflammatory imbalance. To the contrary, these patients had higher levels of the regulatory cytokine interleukin (IL-10, which correlated positively with parasite density, and elevated IL-10/TNF-α, IL-10/interferon (IFN-γ, IL-10/IL-6 and sTNFRII/TNF-α ratios, compared to falciparum or mixed-species malaria patient groups. Vivax malaria patients had the highest levels of circulating soluble TNF-α receptor sTNFRII. Levels of regulatory cytokines returned to normal values 28 days after P. vivax clearance following chemotherapy. Finally, asymptomatic carriers of low P. vivax parasitemias had substantially lower levels of both inflammatory and regulatory cytokines than did patients with clinical malaria due to either species. CONCLUSIONS: Controlling fast-multiplying P. falciparum blood stages requires a strong inflammatory response to prevent fulminant infections, while reducing inflammation-related tissue damage with early regulatory cytokine responses may be a more cost-effective strategy in infections with the less virulent P. vivax parasite. The early induction

Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells

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Meyer-Siegler, Katherine L; Leifheit, Erica C; Vera, Pedro L

2004-01-01

The importance of various inflammatory cytokines in maintaining tumor cell growth and viability is well established. Increased expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) has previously been associated with various types of adenocarcinoma. MIF IHC was used to localize MIF in human bladder tissue. ELISA and Western blot analysis determined the synthesis and secretion of MIF by human bladder transitional cell carcinoma cells. The effects of MIF inhibitors (high molecular weight hyaluronate (HA), anti-MIF antibody or MIF anti-sense) on cell growth and cytokine expression were analyzed. Human bladder cancer cells (HT-1376) secrete detectable amounts of MIF protein. Treatment with HA, anti-MIF antibody and MIF anti-sense reduced HT-1376 cell proliferation, MIF protein secretion, MIF gene expression and secreted inflammatory cytokines. Our evidence suggests MIF interacts with the invariant chain, CD74 and the major cell surface receptor for HA, CD44. This study is the first to report MIF expression in the human bladder and these findings support a role for MIF in tumor cell proliferation. Since MIF participates in the inflammatory response and bladder cancer is associated with chronic inflammatory conditions, these new findings suggest that neutralizing bladder tumor MIF may serve as a novel therapeutic treatment for bladder carcinoma

Andrographolide Ameliorates Abdominal Aortic Aneurysm Progression by Inhibiting Inflammatory Cell Infiltration through Downregulation of Cytokine and Integrin Expression

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Ren, Jun; Liu, Zhenjie; Wang, Qiwei; Giles, Jasmine; Greenberg, Jason; Sheibani, Nader; Kent, K. Craig

2016-01-01

Abdominal aortic aneurysm (AAA), characterized by exuberant inflammation and tissue deterioration, is a common aortic disease associated with a high mortality rate. There is currently no established pharmacological therapy to treat this progressive disease. Andrographolide (Andro), a major bioactive component of the herbaceous plant Andrographis paniculata, has been found to exhibit potent anti-inflammatory properties by inhibiting nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity in several disease models. In this study, we investigated the ability of Andro to suppress inflammation associated with aneurysms, and whether it may be used to block the progression of AAA. Whereas diseased aortae continued to expand in the solvent-treated group, daily administration of Andro to mice with small aneurysms significantly attenuated aneurysm growth, as measured by the diminished expansion of aortic diameter (165.68 ± 15.85% vs. 90.62 ± 22.91%, P < 0.05). Immunohistochemistry analyses revealed that Andro decreased infiltration of monocytes/macrophages and T cells. Mechanistically, Andro inhibited arterial NF-κB activation and reduced the production of proinflammatory cytokines [CCL2, CXCL10, tumor necrosis factor α, and interferon-γ] in the treated aortae. Furthermore, Andro suppressed α4 integrin expression and attenuated the ability of monocytes/macrophages to adhere to activated endothelial cells. These results indicate that Andro suppresses progression of AAA, likely through inhibition of inflammatory cell infiltration via downregulation of NF-κB–mediated cytokine production and α4 integrin expression. Thus, Andro may offer a pharmacological therapy to slow disease progression in patients with small aneurysms. PMID:26483397

Th9 cytokines response and its possible implications in the immunopathogenesis of leprosy.

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de Sousa, Jorge Rodrigues; Pagliari, Carla; de Almeida, Dandara Simone Maia; Barros, Luiz Fernando Lima; Carneiro, Francisca Regina Oliveira; Dias, Leonidas Braga; de Souza Aarão, Tinara Leila; Quaresma, Juarez Antonio Simões

2017-06-01

Leprosy is an infectious-contagious disease whose clinical evolution depends on the interaction of the infectious agent with the immune response of the host, leading to a clinical spectrum that ranges from lepromatous leprosy (susceptibility, LL) to tuberculoid leprosy (resistance, TT). The immune response profile will depend on the pattern of cytokine production and on the activity of macrophages during infection. Classically, the clinical evolution of leprosy has been associated with Th1/Th2 cytokine profiles, but the role of new cytokine profiles such as T helper 9 (Th9) remains to be elucidated. To evaluate the tissue expression profile of these cytokines, a cross-sectional study was conducted using a sample of 30 leprosy skin lesion biopsies obtained from patients with leprosy, 16 TT and 14 lepromatous LL. Immunohistochemical analysis revealed a significant difference in interleukin (IL)-9, IL-4 transforming growth factor (TGF)-β and IL-10 levels between the two groups. IL-9 was more expressed in TT lesions compared with LL lesions. Higher expression of IL-4, IL-10 and TGF-β was observed in LL compared with TT. IL-4, IL-10 and TGF-β tended to be negatively correlated with the expression of IL-9, indicating a possible antagonistic activity in tissue. The results suggest that Th9 lymphocytes may be involved in the response to Mycobacterium leprae , positively or negatively regulating microbicidal activity of the local immune system in the disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Aloin Suppresses Lipopolysaccharide-Induced Inflammatory Response and Apoptosis by Inhibiting the Activation of NF-κB

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Xuan Luo

2018-02-01

Full Text Available Numerous herbal-derived natural products are excellent anti-inflammatory agents. Several studies have reported that aloin, the major anthraquinone glycoside obtained from the Aloe species, exhibits anti-inflammatory activity. However, the molecular mechanism of this activity is not well understood. In this report, we found that aloin suppresses lipopolysaccharide-induced pro-inflammatory cytokine secretion and nitric oxide production, and downregulates the expression of tumor necrosis factor alpha (TNF-α, interleukin 6 (IL-6, inducible nitric oxide synthase (iNOS, and cyclooxygenase-2 (COX-2. Aloin inhibits the phosphorylation and acetylation of the NF-κB p65 subunit by suppressing the upstream kinases p38 and Msk1, preventing LPS-induced p65 translocation to the nucleus. We have also shown that aloin inhibits LPS-induced caspase-3 activation and apoptotic cell death. Collectively, these findings suggest that aloin effectively suppresses the inflammatory response, primarily through the inhibition of NF-κB signaling.

Human leukocyte antigen and cytokine receptor gene polymorphisms associated with heterogeneous immune responses to mumps viral vaccine.

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Ovsyannikova, Inna G; Jacobson, Robert M; Dhiman, Neelam; Vierkant, Robert A; Pankratz, V Shane; Poland, Gregory A

2008-05-01

Mumps outbreaks continue to occur throughout the world, including in highly vaccinated populations. Vaccination against mumps has been successful; however, humoral and cellular immune responses to mumps vaccines vary significantly from person to person. We set out to assess whether HLA and cytokine gene polymorphisms are associated with variations in the immune response to mumps viral vaccine. To identify genetic factors that might contribute to variations in mumps vaccine-induced immune responses, we performed HLA genotyping in a group of 346 healthy schoolchildren (12-18 years of age) who previously received 2 doses of live mumps vaccine. Single-nucleotide polymorphisms (minor allele frequency of >5%) in cytokine and cytokine receptor genes were genotyped for a subset of 118 children. Median values for mumps-specific antibody titers and lymphoproliferative stimulation indices were 729 IU/mL and 4.8, respectively. Girls demonstrated significantly higher mumps antibody titers than boys, indicating gender-linked genetic differences in humoral immune response. Significant associations were found between the HLA-DQB1*0303 alleles and lower mumps-specific antibody titers. An interesting finding was the association of several HLA class II alleles with mumps-specific lymphoproliferation. Alleles of the DRB1 (*0101, *0301, *0801, *1001, *1201, and *1302), DQA1 (*0101, *0105, *0401, and *0501), and DQB1 (*0201, *0402, and *0501) loci were associated with significant variations in lymphoproliferative immune responses to mumps vaccine. Additional associations were observed with single-nucleotide polymorphisms in the interleukin-10RA, interleukin-12RB1, and interleukin-12RB2 cytokine receptor genes. Minor alleles for 4 single-nucleotide polymorphisms within interleukin-10RA and interleukin-12RB genes were associated with variations in humoral and cellular immune responses to mumps vaccination. These data suggest the important role of HLA and immunoregulatory cytokine receptor

Heavy metal mediated innate immune responses of the Indian green frog, Euphlyctis hexadactylus (Anura: Ranidae): Cellular profiles and associated Th1 skewed cytokine response

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Jayawardena, Uthpala A.; Ratnasooriya, Wanigasekara D.; Wickramasinghe, Deepthi D.; Udagama, Preethi V.

2016-01-01

Immune cell and cytokine profiles in relation to metal exposure though much studied in mammals has not been adequately investigated in amphibians, due mainly to lack of suitable reagents for cytokine profiling in non-model species. However, interspecies cross reactivity of cytokines permitted us to assay levels of IFNγ, TNFα, IL6 and IL10in a common anuran, the Indian green frog (Euphlyctis hexadactylus), exposed to heavy metals (Cd, Cr, Cu, Zn and Pb, at ~ 5 ppm each) under field and laboratory settings in Sri Lanka. Enumeration of immune cells in blood and melanomacrophages in the liver, assay of serum and hepatic cytokines, and Th1/Th2 cytokine polarisation were investigated. Immune cell counts indicated overall immunosuppression with decreasing total WBC and splenocyte counts while neutrophil/lymphocyte ratio increased with metal exposure, indicating metal mediated stress. Serum IL6 levels of metal exposed frogs reported the highest (~ 9360 pg/mL) of all cytokines tested. Significantly elevated IFNγ production (P < 0.05) was evident in heavy metal exposed frogs. Th1/Th2 cytokine ratio in both serum and liver tissue homogenates was Th1 skewed due to significantly higher production of pro-inflammatory cytokines, IFNγ in serum and TNFα in the liver (P < 0.01).Metal mediated aggregations of melanomacrophages in the liver were positively and significantly (P < 0.05) correlated with the hepatic expression of TNFα, IL6 and IL10 activity. Overall, Th1 skewed response may well be due to oxidative stress mediated nuclear factor κ-light chain enhancer of activated B cells (NFκB) which enhances the transcription of pro-inflammatory cytokines. Xenobiotic stress has recently imposed an unprecedented level of threat to wildlife, particularly to sensitive species such as amphibians. Therefore, understanding the interactions between physiological stress and related immune responses is fundamental to conserve these environmental sentinels in the face of emerging eco

Heavy metal mediated innate immune responses of the Indian green frog, Euphlyctis hexadactylus (Anura: Ranidae): Cellular profiles and associated Th1 skewed cytokine response

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Jayawardena, Uthpala A.; Ratnasooriya, Wanigasekara D.; Wickramasinghe, Deepthi D.; Udagama, Preethi V., E-mail: dappvr@yahoo.com

2016-10-01

Immune cell and cytokine profiles in relation to metal exposure though much studied in mammals has not been adequately investigated in amphibians, due mainly to lack of suitable reagents for cytokine profiling in non-model species. However, interspecies cross reactivity of cytokines permitted us to assay levels of IFNγ, TNFα, IL6 and IL10in a common anuran, the Indian green frog (Euphlyctis hexadactylus), exposed to heavy metals (Cd, Cr, Cu, Zn and Pb, at ~ 5 ppm each) under field and laboratory settings in Sri Lanka. Enumeration of immune cells in blood and melanomacrophages in the liver, assay of serum and hepatic cytokines, and Th1/Th2 cytokine polarisation were investigated. Immune cell counts indicated overall immunosuppression with decreasing total WBC and splenocyte counts while neutrophil/lymphocyte ratio increased with metal exposure, indicating metal mediated stress. Serum IL6 levels of metal exposed frogs reported the highest (~ 9360 pg/mL) of all cytokines tested. Significantly elevated IFNγ production (P < 0.05) was evident in heavy metal exposed frogs. Th1/Th2 cytokine ratio in both serum and liver tissue homogenates was Th1 skewed due to significantly higher production of pro-inflammatory cytokines, IFNγ in serum and TNFα in the liver (P < 0.01).Metal mediated aggregations of melanomacrophages in the liver were positively and significantly (P < 0.05) correlated with the hepatic expression of TNFα, IL6 and IL10 activity. Overall, Th1 skewed response may well be due to oxidative stress mediated nuclear factor κ-light chain enhancer of activated B cells (NFκB) which enhances the transcription of pro-inflammatory cytokines. Xenobiotic stress has recently imposed an unprecedented level of threat to wildlife, particularly to sensitive species such as amphibians. Therefore, understanding the interactions between physiological stress and related immune responses is fundamental to conserve these environmental sentinels in the face of emerging eco

Lemongrass and citral effect on cytokines production by murine macrophages.

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Bachiega, Tatiana Fernanda; Sforcin, José Maurício

2011-09-01

Cymbopogon citratus (DC) Stapf (Poaceae-Gramineae), an herb commonly known as lemongrass (LG), is an important source of ethnomedicines as well as citral, the major constituent of Cymbopogon citratus, used in perfumery, cosmetic and pharmaceutical industries for controlling pathogens. Thus, the goal of this work was to analyze the effect of LG and citral on cytokines production (IL-1β, IL-6 and IL-10) in vitro, as well as before or after LPS incubation. Peritoneal macrophages from BALB/c mice were treated with LG or citral in different concentrations for 24h. The concentrations that inhibited cytokines production were tested before or after macrophages challenge with LPS, in order to evaluate a possible anti-inflammatory action. Supernatants of cell cultures were used for cytokines determination by ELISA. As to IL-1β, only citral inhibited its release, exerting an efficient action before LPS challenge. LG and citral inhibited IL-6 release. Cymbopogon citratus showed inhibitory effects only after LPS challenge, whereas citral prevented efficiently LPS effects before and after LPS addition. Citral inhibited IL-10 production and although LG did not inhibit its production, the concentration of 100 μg/well was tested in the LPS-challenge protocol, because it inhibited IL-6 production. LG inhibited LPS action after macrophages incubation with LPS, while citral counteracted LPS action when added before or after LPS incubation. LG exerted an anti-inflammatory action and citral may be involved in its inhibitory effects on cytokines production. We suggest that a possible mechanism involved in such results could be the inhibition of the transcription factor NF-κB. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Inhibition of cytokine gene expression and induction of chemokine genes in non-lymphatic cells infected with SARS coronavirus

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Weber Friedemann

2006-03-01

Full Text Available Abstract Background SARS coronavirus (SARS-CoV is the etiologic agent of the severe acute respiratory syndrome. SARS-CoV mainly infects tissues of non-lymphatic origin, and the cytokine profile of those cells can determine the course of disease. Here, we investigated the cytokine response of two human non-lymphatic cell lines, Caco-2 and HEK 293, which are fully permissive for SARS-CoV. Results A comparison with established cytokine-inducing viruses revealed that SARS-CoV only weakly triggered a cytokine response. In particular, SARS-CoV did not activate significant transcription of the interferons IFN-α, IFN-β, IFN-λ1, IFN-λ2/3, as well as of the interferon-induced antiviral genes ISG56 and MxA, the chemokine RANTES and the interleukine IL-6. Interestingly, however, SARS-CoV strongly induced the chemokines IP-10 and IL-8 in the colon carcinoma cell line Caco-2, but not in the embryonic kidney cell line 293. Conclusion Our data indicate that SARS-CoV suppresses the antiviral cytokine system of non-immune cells to a large extent, thus buying time for dissemination in the host. However, synthesis of IP-10 and IL-8, which are established markers for acute-stage SARS, escapes the virus-induced silencing at least in some cell types. Therefore, the progressive infiltration of immune cells into the infected lungs observed in SARS patients could be due to the production of these chemokines by the infected tissue cells.

Mucorales spores induce a proinflammatory cytokine response in human mononuclear phagocytes and harbor no rodlet hydrophobins.

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Wurster, Sebastian; Thielen, Vanessa; Weis, Philipp; Walther, Paul; Elias, Johannes; Waaga-Gasser, Ana Maria; Dragan, Mariola; Dandekar, Thomas; Einsele, Hermann; Löffler, Jürgen; Ullmann, Andrew J

2017-11-17

Mucormycoses are life-threatening infections in immunocompromised patients. This study characterizes the response of human mononuclear cells to different Mucorales and Ascomycota. PBMC, monocytes, and monocyte derived dendritic cells (moDCs) from healthy donors were stimulated with resting and germinated stages of Mucorales and Ascomycota. Cytokine response and expression of activation markers were studied. Both inactivated germ tubes and resting spores of Rhizopus arrhizus and other human pathogenic Mucorales species significantly stimulated mRNA synthesis and secretion of proinflammatory cytokines. Moreover, R. arrhizus spores induced the upregulation of co-stimulatory molecules on moDCs and a specific T-helper cell response. Removal of rodlet hydrophobins by hydrofluoric acid treatment of A. fumigatus conidia resulted in enhanced immunogenicity, whereas the cytokine response of PBMCs to dormant R. arrhizus spores was not influenced by hydrofluoric acid. Scanning electron micrographs of Mucorales spores did not exhibit any morphological correlates of rodlet hydrophobins. Taken together, this study revealed striking differences in the response of human mononuclear cells to resting stages of Ascomycota and Mucorales, which may be explained by absence of an immunoprotective hydrophobin layer in Mucorales spores.

Diclofenac enhances proinflammatory cytokine-induced nitric oxide production through NF-κB signaling in cultured astrocytes

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Kakita, Hiroki; Aoyama, Mineyoshi; Hussein, Mohamed Hamed; Kato, Shin; Suzuki, Satoshi; Ito, Tetsuya; Togari, Hajime; Asai, Kiyofumi

2009-01-01

Recently, the number of reports of encephalitis/encephalopathy associated with influenza virus has increased. In addition, the use of a non-steroidal anti-inflammatory drug, diclofenac sodium (DCF), is associated with a significant increase in the mortality rate of influenza-associated encephalopathy. Activated astrocytes are a source of nitric oxide (NO), which is largely produced by inducible NO synthase (iNOS) in response to proinflammatory cytokines. Therefore, we investigated whether DCF enhances nitric oxide production in astrocytes stimulated with proinflammatory cytokines. We stimulated cultured rat astrocytes with three cytokines, interleukin-1β, tumor necrosis factor-α and interferon-γ, and then treated the astrocytes with DCF or acetaminophen (N-acetyl-p-aminophenol: APAP). iNOS and NO production in astrocyte cultures were induced by proinflammatory cytokines. The addition of DCF augmented NO production, but the addition of APAP did not. NF-κB inhibitors SN50 and MG132 inhibited iNOS gene expression in cytokine-stimulated astrocytes with or without DCF. Similarly, NF-κB p65 Stealth small interfering RNA suppressed iNOS gene expression in cytokine-stimulated astrocytes with or without DCF. LDH activity and DAPI staining showed that DCF induces cell damage in cytokine-stimulated astrocytes. An iNOS inhibitor, L-NMMA, inhibited the cytokine- and DCF-induced cell damage. In conclusion, this study demonstrates that iNOS and NO are induced in astrocyte cultures by proinflammatory cytokines. Addition of DCF further augments NO production. This effect is mediated via NF-κB signaling and leads to cell damage. The enhancement of DCF on NO production may explain the significant increase in the mortality rate of influenza-associated encephalopathy in patients treated with DCF.

Virulent Type A Francisella tularensis actively suppresses cytokine responses in human monocytes

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Gillette, Devyn D.; Curry, Heather M.; Cremer, Thomas; Ravneberg, David; Fatehchand, Kavin; Shah, Prexy A.; Wewers, Mark D.; Schlesinger, Larry S.; Butchar, Jonathan P.; Tridandapani, Susheela; Gavrilin, Mikhail A.

2014-01-01

Background: Human monocyte inflammatory responses differ between virulent and attenuated Francisella infection. Results: A mixed infection model showed that the virulent F. tularensis Schu S4 can attenuate inflammatory cytokine responses to the less virulent F. novicida in human monocytes. Conclusion: F. tularensis dampens inflammatory response by an active process. Significance: This suppression may contribute to enhanced pathogenicity of F. tularensis. Francisella tularensis is a Gram-negative facultative bacterium that can cause the disease tularemia, even upon exposure to low numbers of bacteria. One critical characteristic of Francisella is its ability to dampen or subvert the host immune response. Previous work has shown that monocytes infected with highly virulent F. tularensis subsp. tularensis strain Schu S4 responded with a general pattern of quantitatively reduced pro-inflammatory signaling pathway genes and cytokine production in comparison to those infected with the less virulent related F. novicida. However, it has been unclear whether the virulent Schu S4 was merely evading or actively suppressing monocyte responses. By using mixed infection assays with F. tularensis and F. novicida, we show that F. tularensis actively suppresses monocyte pro-inflammatory responses. Additional experiments show that this suppression occurs in a dose-dependent manner and is dependent upon the viability of F. tularensis. Importantly, F. tularensis was able to suppress pro-inflammatory responses to earlier infections with F. novicida. These results lend support that F. tularensis actively dampens human monocyte responses and this likely contributes to its enhanced pathogenicity. PMID:24783062

Inhibition of macrophage migration inhibitory factor decreases proliferation and cytokine expression in bladder cancer cells

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Leifheit Erica C

2004-07-01

Full Text Available Abstract Background The importance of various inflammatory cytokines in maintaining tumor cell growth and viability is well established. Increased expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF has previously been associated with various types of adenocarcinoma. Methods MIF IHC was used to localize MIF in human bladder tissue. ELISA and Western blot analysis determined the synthesis and secretion of MIF by human bladder transitional cell carcinoma cells. The effects of MIF inhibitors (high molecular weight hyaluronate (HA, anti-MIF antibody or MIF anti-sense on cell growth and cytokine expression were analyzed. Results Human bladder cancer cells (HT-1376 secrete detectable amounts of MIF protein. Treatment with HA, anti-MIF antibody and MIF anti-sense reduced HT-1376 cell proliferation, MIF protein secretion, MIF gene expression and secreted inflammatory cytokines. Our evidence suggests MIF interacts with the invariant chain, CD74 and the major cell surface receptor for HA, CD44. Conclusions This study is the first to report MIF expression in the human bladder and these findings support a role for MIF in tumor cell proliferation. Since MIF participates in the inflammatory response and bladder cancer is associated with chronic inflammatory conditions, these new findings suggest that neutralizing bladder tumor MIF may serve as a novel therapeutic treatment for bladder carcinoma.

Cytokine profiles in tears accompanying the secondary conjunctival responses induced by nasal allergy.

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Pelikan, Zdenek

2014-02-01

Allergic conjunctivitis (AC) occurs either in a primary form, due to the allergic reaction localized in the conjunctivae or in a secondary form, induced by an allergic reaction initiated primarily in the nasal mucosa. The purpose of this study was to investigate the cytokine profiles in tears associated with the secondary conjunctival response (SCR) types. In 47 AC patients developing 16 immediate (SICR; p tears. The SCRs were associated with significant concentration changes of particular cytokines in tears (p tears during the phosphate-buffered saline controls or negative SCRs. Different cytokine profiles in the tears accompanying the immediate, late and delayed types of SCR, induced by nasal allergy, would indicate involvement of different hypersensitivity mechanisms in the particular SCR types. The low cytokine concentrations in tears recorded during the SCRs may suggest their origin from the nasal mucosa. These results emphasize the diagnostic value of NPTs with allergens combined with monitoring of various ocular features in patients suffering from the secondary form of AC. These results may also have an impact on the therapeutical approach to this clinical entity.

Involvement of three mechanisms in the alteration of cytokine responses by sodium methyldithiocarbamate

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Pruett, Stephen B.; Fan, Ruping; Zheng, Qiang

2006-01-01

Sodium methyldithiocarbamate (SMD) is the third most abundantly used conventional pesticide in the U.S. We recently reported that it alters the induction of cytokine production mediated though Toll-like receptor (TLR) 4 at relevant dosages in mice. Its chemical properties and evidence from the literature suggest thee potential mechanisms of action for this compound. It could either act as a free radical scavenger (by means of its free S - group) or promote oxidation by breaking down to form methylisothiocyanate, which can deplete glutathione. It is a potent copper chelator and may affect the availability of copper to a number of copper-dependent enzymes (including some signaling molecules). SMD induces a classical neuroendocrine stress response characterized by elevated serum corticosterone concentrations, which could affect cytokine production. Although each of these mechanisms could potentially contribute to altered cytokine responses, direct evidence is lacking. The present study was conducted to obtain such evidence. The role of redox balance was investigated by pretreating mice with N-acetyl cysteine (NAC), which increases cellular glutathione concentrations, before administration of SMD. NAC exacerbated the SMD-induced suppression of IL-12 and the SMD-induced enhancement of IL-10 in the serum. The role of copper chelation was investigated by comparing the effects of SMD with an equimolar dose to SMD that was administered in the form of a copper chelation complex. Addition of copper significantly decreased the action of SMD on IL-12 production but not on IL-10 production. The role of the stress response was investigated by pretreating mice with antagonists of corticosterone and catecholamines. This treatment partially prevented the action of SMD on IL-10 and IL-12 in the peritoneal fluid. The results suggest that all of the proposed mechanisms have some role in the alteration of cytokine production by SMD

Direct contact between dendritic cells and bronchial epithelial cells inhibits T cell recall responses towards mite and pollen allergen extracts in vitro

DEFF Research Database (Denmark)

Papazian, Dick; Wagtmann, Valery R; Hansen, Soren

2015-01-01

(DCs), we have investigated recall T cell responses in allergic patients sensitized to house dust mite, grass, and birch pollen. Conclusions: Using allergen extract-loaded DCs to stimulate autologous allergen-specific T cell lines, we show that AEC-imprinted DCs inhibit T cell proliferation...... production of both Th1 and Th2 cytokines upon re-challenge. The inhibitory effects of AECs' contact with DCs were absent when allergen extract-loaded DCs had only been exposed to AECs supernatants, but present after direct contact with AECs. We conclude that direct contact between DCs and AECs inhibits T...

Ganoderma lucidum ethanol extract inhibits the inflammatory response by suppressing the NF-κB and toll-like receptor pathways in lipopolysaccharide-stimulated BV2 microglial cells.

Science.gov (United States)

Yoon, Hyun-Min; Jang, Kyung-Jun; Han, Min Seok; Jeong, Jin-Woo; Kim, Gi Young; Lee, Jai-Heon; Choi, Yung Hyun

2013-03-01

Ganoderma lucidum is a traditional Oriental medicine that has been widely used as a tonic to promote longevity and health in Korea and other Asian countries. Although a great deal of work has been carried out on the therapeutic potential of this mushroom, the pharmacological mechanisms of its anti-inflammatory actions remain unclear. In this study, we evaluated the inhibitory effects of G. lucidum ethanol extract (EGL) on the production of inflammatory mediators and cytokines in lipopolysaccharide (LPS)-stimulated murine BV2 microglia. We also investigated the effects of EGL on the LPS-induced activation of nuclear factor kappaB (NF-κB) and upregulation of toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). Elevated levels of nitric oxide (NO), prostaglandin E(2) (PGE(2)) and pro-inflammatory cytokine production were detected in BV2 microglia following LPS stimulation. We identifed that EGL significantly inhibits the excessive production of NO, PGE(2) and pro-inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor-α in a concentration-dependent manner without causing cytotoxicity. In addition, EGL suppressed NF-κB translocation and transcriptional activity by blocking IκB degradation and inhibiting TLR4 and MyD88 expression in LPS-stimulated BV2 cells. Our results indicate that the inhibitory effects of EGL on LPS-stimulated inflammatory responses in BV2 microglia are associated with the suppression of the NF-κB and TLR signaling pathways. Therefore, EGL may be useful in the treatment of neurodegenerative diseases by inhibiting inflammatory mediator responses in activated microglia.

The cytomegalovirus homolog of interleukin-10 requires phosphatidylinositol 3-kinase activity for inhibition of cytokine synthesis in monocytes.

Science.gov (United States)

Spencer, Juliet V

2007-02-01

Human cytomegalovirus (CMV) has evolved numerous strategies for evading host immune defenses, including piracy of cellular cytokines. A viral homolog of interleukin-10, designated cmvIL-10, binds to the cellular IL-10 receptor and effects potent immune suppression. The signaling pathways employed by cmvIL-10 were investigated, and the classic IL-10R/JAK1/Stat3 pathway was found to be activated in monocytes. However, inhibition of JAK1 had little effect on cmvIL-10-mediated suppression of tumor necrosis factor alpha (TNF-alpha) production. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway had a more significant impact on TNF-alpha levels but did not completely relieve the immune suppression, demonstrating that cmvIL-10 stimulates multiple signaling pathways to modulate cell function.

Fasting and meal-stimulated residual beta cell function is positively associated with serum concentrations of proinflammatory cytokines and negatively associated with anti-inflammatory and regulatory cytokines in patients with longer term type 1 diabetes

DEFF Research Database (Denmark)

Pham, Minh-Long; Kolb, H; Battelino, T

2013-01-01

Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes.......Cytokines may promote or inhibit disease progression in type 1 diabetes. We investigated whether systemic proinflammatory, anti-inflammatory and regulatory cytokines associated differently with fasting and meal-stimulated beta cell function in patients with longer term type 1 diabetes....

Cytokine Responses to Acute Exercise in Healthy Older Adults: The Effect of Cardiorespiratory Fitness

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Mark T. Windsor

2018-03-01

Full Text Available Markers of chronic inflammation increase with aging, and are associated with cardiovascular disease prevalence and mortality. Increases in fitness with exercise training have been associated with lower circulating concentrations of cytokines known to have pro-inflammatory actions (such as interleukin-6 [IL-6] and higher circulating concentrations of anti-inflammatory cytokines (interleukin-10 [IL-10]. However, the effect of cardiorespiratory fitness on acute cytokine responses to a single bout of exercise in healthy older individuals is unknown. We compared the response of plasma cytokines IL-6, tumor necrosis factor-alpha (TNF-α and IL-10 to a bout of moderate-intensity continuous and higher-intensity interval exercise between older individuals with higher and lower levels of cardiorespiratory fitness. Sixteen lower-fit (VO2peak: 22.6±2.8 mL.kg−1.min−1 and fourteen higher-fit participants (VO2peak: 37.4±5.9 mL.kg−1.min−1 completed three 24 min experimental protocols in a randomized order: (1 moderate-intensity continuous exercise (40% of peak power output [PPO]; (2 higher-intensity interval exercise (12 × 1 min intervals at 70% PPO separated by 1 min periods at 10% PPO; or (3 non-exercise control. Plasma cytokines were measured at rest, immediately after, and during 90 min of recovery following exercise or control. Plasma IL-6 concentrations at baseline were greater in the higher-fit compared to the lower-fit group (P = 0.02, with no difference in plasma IL-10 or TNF-α concentrations at baseline between groups. Plasma IL-6 and IL-10 concentrations in both groups increased immediately after all protocols (IL-6: P = 0.02, IL-10: P < 0.01. However, there was no difference in the IL-6 and IL-10 response between the exercise and non-exercise (control protocols. After all protocols, no changes in plasma TNF-α concentrations were observed in either the higher- or lower-fit groups. In this study, basal concentrations of circulating IL-6

The peri-operative cytokine response in infants and young children following major surgery

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Hansen, Tom Giedsing; Tønnesen, Else Kirstine; Andersen, J B

1998-01-01

The peri-operative cytokine response was studied in 13 infants and young children undergoing major surgery. All children were anaesthetized with a combined general and epidural anaesthetic technique, followed by post-operative epidural analgesia with bupivacaine and fentanyl. Blood samples were...... taken before and after surgery, 24 h post-operatively, and finally, when the children were mobilized and had regained gastrointestinal function. Plasma samples were analysed for tumour necrosis factor-alpha, interleukin-1 alpha, interleukin-1 beta, interleukin-6, interferon-gamma, interleukin-10...... and the interleukin-1 receptor antagonist. The cytokine responses were highly variable. Overall, no significant changes between pre- and post-operative plasma concentrations were found. Tumour necrosis factor-alpha and the interleukin-1 receptor antagonist were detectable in all children, and a trend towards an early...

St. John's wort attenuates irinotecan-induced diarrhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis

International Nuclear Information System (INIS)

Hu Zeping; Yang Xiaoxia; Chan Suiyung; Xu Anlong; Duan Wei; Zhu Yizhun; Sheu, F.-S.; Boelsterli, Urs Alex; Chan, Eli; Zhang Qiang; Wang, J.-C.; Ee, Pui Lai Rachel; Koh, H.L.; Huang Min; Zhou Shufeng

2006-01-01

Diarrhea is a common dose-limiting toxicity associated with cancer chemotherapy, in particular for drugs such as irinotecan (CPT-11), 5-fluouracil, oxaliplatin, capecitabine and raltitrexed. St. John's wort (Hypericum perforatum, SJW) has anti-inflammatory activity, and our preliminary study in the rat and a pilot study in cancer patients found that treatment of SJW alleviated irinotecan-induced diarrhea. In the present study, we investigated whether SJW modulated various pro-inflammatory cytokines including interleukins (IL-1β, IL-2, IL-6), interferon (IFN-γ) and tumor necrosis factor-α (TNF-α) and intestinal epithelium apoptosis in rats. The rats were treated with irinotecan at 60 mg/kg for 4 days in combination with oral SJW or SJW-free control vehicle at 400 mg/kg for 8 days. Diarrhea, tissue damage, body weight loss, various cytokines including IL-1β, IL-2, IL-6, IFN-γ and TNF-α and intestinal epithelial apoptosis were monitored over 11 days. Our studies demonstrated that combined SJW markedly reduced CPT-11-induced diarrhea and intestinal lesions. The production of pro-inflammatory cytokines such as IL-1β, IFN-γ and TNF-α was significantly up-regulated in intestine. In the mean time, combined SJW significantly suppressed the intestinal epithelial apoptosis induced by CPT-11 over days 5-11. In particular, combination of SJW significantly inhibited the expression of TNF-α mRNA in the intestine over days 5-11. In conclusion, inhibition of pro-inflammatory cytokines and intestinal epithelium apoptosis partly explained the protective effect of SJW against the intestinal toxicities induced by irinotecan. Further studies are warranted to explore the potential for STW as an agent in combination with chemotherapeutic drugs to lower their dose-limiting toxicities

Exogenously triggered response inhibition in developmental stuttering.

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Eggers, Kurt; De Nil, Luc F; Van den Bergh, Bea R H

2018-06-01

The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering. Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (±3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008). Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered. Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition. Copyright © 2018 Elsevier Inc. All rights reserved.

Cytokine Responses in Gills of Capoeta umbla as Biomarkers of Environmental Pollution.

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Danabas, Durali; Yildirim, Nuran Cikcikoglu; Yildirim, Numan; Onal, Ayten Oztufekci; Uslu, Gulsad; Unlu, Erhan; Danabas, Seval; Ergin, Cemil; Tayhan, Nilgun

2016-03-01

Immunological biomarkers reflect the effects of exposure to environmental contaminants. In this study, the suitability and sensitivity of cytokine responses, interleukin1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) in gill tissues of Capoeta umbla (Heckel, 1843), collected from different regions, as early warning indices of environmental pollution and ecosystem health was evaluated. Fish and water samples were taken from ten stations in March and September 2011 and 2012. Tumor necrosis factor-α, IL-1β and IL-6 levels were determined in samples of the gill tissues by using an ELISA kit. Significant variations of TNF-α, IL-1β and IL-6 levels observed between stations and seasons. The results of this study show that seasonal variations of cytokine responses in gills of Capoeta umbla are sensitive to the contaminants present in Uzuncayir Dam Lake (Tunceli, Turkey) water and are valuable biomarkers for environmental pollution and ecosystem health.

Tanshinone IIA attenuates neuropathic pain via inhibiting glial activation and immune response.

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Cao, Fa-Le; Xu, Min; Wang, Yan; Gong, Ke-Rui; Zhang, Jin-Tao

2015-01-01

Neuropathic pain, characterized by spontaneous pain, hyperalgesia and allodynia, is a devastating neurological disease that seriously affects patients' quality of life. We have previously shown that tanshinone IIA (TIIA), an important lipophilic component of Danshen, had significant anti-nociceptive effect in somatic and visceral pain, it is surprisingly noted that few pharmacological studies have been carried out to explore the possible analgesic action of TIIA on neuropathic pain and the underlying mechanisms. Therefore, in the present study, by using spinal nerve ligation (SNL) pain model, the antinociceptive and antihyperalgesic effects of TIIA on neuropathic pain were evaluated by intraperitoneal administration in rats. The results indicated that TIIA dose-dependently inhibited SNL-induced mechanical hyperalgesia. As revealed by OX42 levels, TIIA effectively repressed the activation of spinal microglial activation in SNL-induced neuropathic pain. Meanwhile, TIIA also decreased the expressions of inflammatory cytokines TNF-α and IL-1β in the spinal cord. Furthermore, TIIA inhibited oxidative stress by significantly rescuing the superoxide dismutase (SOD) activity and decreasing the malondialdehyde (MDA). Moreover, TIIA depressed SNL-induced MAPKs activation in spinal cord. Taken together, our study provides evidence that TIIA inhibited SNL-induced neuropathic pain through depressing microglial activation and immune response by the inhibition of mitogen-activated protein kinases (MAPKs) pathways. Our findings suggest that TIIA might be a promising agent in the treatment of neuropathic pain. Copyright © 2014 Elsevier Inc. All rights reserved.

Activated factor X signaling via protease-activated receptor 2 suppresses pro-inflammatory cytokine production from LPS-stimulated myeloid cells.

LENUS (Irish Health Repository)

Gleeson, Eimear M

2013-07-19

Vitamin K-dependent proteases generated in response to vascular injury and infection enable fibrin clot formation, but also trigger distinct immuno-regulatory signaling pathways on myeloid cells. Factor Xa, a protease crucial for blood coagulation, also induces protease-activated receptor-dependent cell signaling. Factor Xa can bind both monocytes and macrophages, but whether factor Xa-dependent signaling stimulates or suppresses myeloid cell cytokine production in response to Toll-like receptor activation is not known. In this study, exposure to factor Xa significantly impaired pro-inflammatory cytokine production from lipopolysaccharide-treated peripheral blood mononuclear cells, THP-1 monocytic cells and murine macrophages. Furthermore, factor Xa inhibited nuclear factor-kappa B activation in THP-1 reporter cells, requiring phosphatidylinositide 3-kinase activity for its anti-inflammatory effect. Active-site blockade, γ-carboxyglutamic acid domain truncation and a peptide mimic of the factor Xa inter-epidermal growth factor-like region prevented factor Xa inhibition of lipopolysaccharide-induced tumour necrosis factor-α release. In addition, factor Xa anti-inflammatory activity was markedly attenuated by the presence of an antagonist of protease-activated receptor 2, but not protease-activated receptor 1. The key role of protease-activated receptor 2 in eliciting factor Xa-dependent anti-inflammatory signaling on macrophages was further underscored by the inability of factor Xa to mediate inhibition of tumour necrosis factor-α and interleukin-6 release from murine bone marrow-derived protease-activated receptor 2-deficient macrophages. We also show for the first time that, in addition to protease-activated receptor 2, factor Xa requires a receptor-associated protein-sensitive low-density lipoprotein receptor to inhibit lipopolysaccharide-induced cytokine production. Collectively, this study supports a novel function for factor Xa as an endogenous, receptor

Psychological stress exerts effects on pathogenesis of hepatitis B via type-1/type-2 cytokines shift toward type-2 cytokine response.

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YingLi He

Full Text Available BACKGROUND: Psychological and physical stress has been demonstrated to have an impact on health through modulation of immune function. Despite high prevalence of stress among patients with hepatitis B virus (HBV infection, little is known about whether and how stress exerts an effect on the course of hepatitis B. METHODS: Eighty patients with chronic hepatitis B(CHB completed the Perceived Stress Scale-10(PSS-10 and State-Trait Anxiety Inventory(STAI. Fresh whole blood was subject to flow cytometry for lymphocytes count. Plasma samples frozen at -80 °C were thawed for cytokines, alanine aminotransferase (ALT, and virus load. These patients were grouped into high or low perceived stress, state anxiety and trait anxiety groups according to the scale score. Sociodemographic, disease-specific characteristics, lymphocytes count and cytokines were compared. RESULTS: Firstly, a negative association between ALT and stress (t =  -4.308; p =  .000, state anxiety (t =  -3.085; p =  .003 and trait anxiety (t =  -4.925; p =  .000 were found. As ALT is a surrogate marker of hepatocytes injury, and liver injury is a consequence of immune responses. Next, we tested the relationship between stress/anxiety and lymphocytes. No statistical significance were found with respect to counts of total T cells, CD4+ T cell, CD8+ T cell, NK cell, and B cell count between high and low stress group. Type-2 cytokine interleukin-10 (IL-10 level was significantly higher in high stress group relative to lower counterpart (t = 6.538; p = 0.000, and type-1 cytokine interferon-gamma (IFN-γ level shown a decreased tendency in high stress group (t =  -1.702; p = 0.093. Finally, INF-γ:IL-10 ratio displayed significant decrease in high perceived stress(t =  -4.606; p = 0.000, state anxiety(t =  -5.126; p = 0.000 and trait anxiety(t =  -4.670; p = 0.000 groups relative to low counterparts. CONCLUSION: Our data show stress is not related to the lymphocyte cells

Protective Role of Complement C3 Against Cytokine-Mediated beta-Cell Apoptosis

DEFF Research Database (Denmark)

Dos Santos, Reinaldo S.; Marroqui, Laura; Grieco, Fabio A.

2017-01-01

silencing exacerbates apoptosis under both basal condition and following exposure to cytokines, and it increases chemokine expression upon cytokine treatment. C3 exerts its prosurvival effects via AKT activation and c-Jun N-terminal kinase inhibition. Exogenously added C3 also protects against cytokine...

Influence of HMB supplementation and resistance training on cytokine responses to resistance exercise.

Science.gov (United States)

Kraemer, William J; Hatfield, Disa L; Comstock, Brett A; Fragala, Maren S; Davitt, Patrick M; Cortis, Cristina; Wilson, Jacob M; Lee, Elaine C; Newton, Robert U; Dunn-Lewis, Courtenay; Häkkinen, Keijo; Szivak, Tunde K; Hooper, David R; Flanagan, Shawn D; Looney, David P; White, Mark T; Volek, Jeff S; Maresh, Carl M

2014-01-01

The purpose of this study was to determine the effects of a multinutritional supplement including amino acids, β-hydroxy-β-methylbutyrate (HMB), and carbohydrates on cytokine responses to resistance exercise and training. Seventeen healthy, college-aged men were randomly assigned to a Muscle Armor™ (MA; Abbott Nutrition, Columbus, OH) or placebo supplement group and 12 weeks of resistance training. An acute resistance exercise protocol was administered at 0, 6, and 12 weeks of training. Venous blood samples at pre-, immediately post-, and 30-minutes postexercise were analyzed via bead multiplex immunoassay for 17 cytokines. After 12 weeks of training, the MA group exhibited decreased interferon-gamma (IFN-γ) and interleukin (IL)-10. IL-1β differed by group at various times. Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, IL-7, IL-8, IL-12p70, IL-13, IL-17, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1β) changed over the 12-week training period but did not differ by group. Twelve weeks of resistance training alters the cytokine response to acute resistance exercise, and supplementation with HMB and amino acids appears to further augment this result.

Leucocytes, cytokines and satellite cells

DEFF Research Database (Denmark)

Paulsen, Gøran; Mikkelsen, Ulla Ramer; Raastad, Truls

2012-01-01

uncertain. The COX enzymes regulate satellite cell activity, as demonstrated in animal models; however the roles of the COX enzymes in human skeletal muscle need further investigation. We suggest using the term 'muscle damage' with care. Comparisons between studies and individuals must consider changes......-damaging exercise', primarily eccentric exercise. We review the evidence for the notion that the degree of muscle damage is related to the magnitude of the cytokine response. In the third and final section, we look at the satellite cell response to a single bout of eccentric exercise, as well as the role...... variation in individual responses to a given exercise should, however be expected. The link between cytokine and satellite cell responses and exercise-induced muscle damage is not so clear The systemic cytokine response may be linked more closely to the metabolic demands of exercise rather than muscle...

Porcine blood mononuclear cell cytokine responses to PAMP molecules: comparison of mRNA and protein production

DEFF Research Database (Denmark)

Sørensen, Nanna Skall; Skovgaard, Kerstin; Heegaard, Peter M. H.

2011-01-01

Pathogen-associated molecular patterns (PAMPs) are conserved molecules of microorganisms inducing innate immune cells to secrete distinct patterns of cytokines. In veterinary species, due to a lack of specific antibodies, cytokines are often monitored as expressed mRNA only. This study investigated...... the induction of IFN-α, IL-12 p40, IL-1β, TNF-α, IL-6 and IL-10 by PAMP-molecules [CpG oligonucleotide D19 (CpG), peptidoglycan (PGN), lipopolysaccharide (LPS), Pam3Cys and poly-U] in porcine blood mononuclear cells (BMC) within a 24h period. As expected, cytokine responses were PAMP-specific, CpG inducing IFN...

STIR: Assessing and Training Response Inhibition Abilities

Science.gov (United States)

2014-07-30

Learning to stop responding to alcohol cues reduces alcohol intake via reduced affective associations rather than increased response inhibition. Addiction ...requires an abstract application of the core learning principle1,2, and viable examples are often hard to find and/or assess. If exposure to non...inhibition training that expands upon previous successful “near transfer” response inhibition training efforts—such as treating alcohol addictions by

Cytokine-mediated FOXO3a phosphorylation suppresses FasL expression in hemopoietic cell lines: investigations of the role of Fas in apoptosis due to cytokine starvation.

Science.gov (United States)

Behzad, Hayedeh; Jamil, Sarwat; Denny, Trisha A; Duronio, Vincent

2007-05-01

We have investigated phosphatidylinositol 3-kinase (PI3K)-dependent survival signalling pathways using several cytokines in three different hemopoietic cell lines, MC/9, FDC-P1, and TF-1. Cytokines caused PI3K- and PKB-dependent phosphorylation of FOXO3a (previously known as FKHRL1) at three distinct sites. Following cytokine withdrawal or PI3K inhibition, both of which are known to lead to apoptosis, there was a loss of FOXO3a phosphorylation, and a resulting increase in forkhead transcriptional activity, along with increased expression of Fas Ligand (FasL), which could be detected at the cell surface. Concurrently, an increase in cell surface expression of Fas was also detected. Despite the presence of both FasL and Fas, there was no detectable evidence that activation of Fas-mediated apoptotic events was contributing to apoptosis resulting from cytokine starvation or inhibition of PI3K activity. Thus, inhibition of FOXO3a activity is mediated by the PI3K-PKB pathway, but regulation of FasL is not the primary means by which cell survival is regulated in cytokine-dependent hemopoietic cells. We were also able to confirm increased expression of known FOXO3a targets, Bim and p27kip1. Together, these results support the conclusion that mitochondrial-mediated signals play the major role in apoptosis of hemopoietic cells due to loss of cytokine signalling.

Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor

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Qureshi Asaf A

2012-07-01

Full Text Available Abstract Background Altered immune function during ageing results in increased production of nitric oxide (NO and other inflammatory mediators. Recently, we have reported that NO production was inhibited by naturally-occurring proteasome inhibitors (quercetin, δ-tocotrienol, and riboflavin in lipopolysaccharide (LPS-stimulated RAW264.7 cells, and thioglycolate-elicited peritoneal macrophages from C57BL/6 mice. In a continuous effort to find more potent, non-toxic, commercially available, naturally-occurring proteasome inhibitors that suppress inflammation, the present study was carried out to describe the inhibition of NF-κB activation and NO, TNF-α, IL-6, IL-1β, and iNOS expression by trans-resveratrol, trans-pterostilbene, morin hydrate, and nicotinic acid in LPS-induced RAW 264.7 cells and thioglycolate-elicited peritoneal macrophages from C57BL/6 and BALB/c mice. Results The present results indicate that resveratrol, pterostilbene, and morin hydrate caused significant inhibition (>70% to 90%; P 40%; P 60%; P 40%; P P  Conclusions The present results clearly demonstrate that resveratrol and pterostilbene are particularly potent proteasome inhibitors that suppress expression of genes, and production of inflammatory products in LPS-stimulated RAW 264.7 cells, and macrophages from C57BL/6 and BALB/c mice. Resveratrol and pterostilbene which are present in grapes, blueberries, and red wine, have been implicated as contributing factors to the lower incidence of cardiovascular disease in the French population, despite their relatively high dietary fat intake. Consequently, it appears likely that the beneficial nutritional effects of resveratrol and pterostilbene are due at least in part, to their ability to inhibit NF-κB activation by the proteasome, thereby suppressing activation of pro-inflammatory cytokines and iNOS genes, resulting in decreased secretion of TNF-α, IL-1β, IL-6, and NO levels, in response to inflammatory stimuli

Andrographolide sulfonate ameliorates experimental colitis in mice by inhibiting Th1/Th17 response.

Science.gov (United States)

Liu, Wen; Guo, Wenjie; Guo, Lele; Gu, Yanhong; Cai, Peifen; Xie, Ning; Yang, Xiaoling; Shu, Yongqian; Wu, Xuefeng; Sun, Yang; Xu, Qiang

2014-06-01

Inflammatory bowel disease (IBD) is a chronic, relapsing and remitting condition of inflammation involves overproduction of pro-inflammatory cytokines and excessive functions of inflammatory cells. However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma. Therefore new therapies for the treatment of IBD are desperately needed. In the present study, we aimed to examine the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on murine experimental colitis induced by 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Andrographolide sulfonate was administrated through intraperitoneal injection to mice with TNBS-induced colitis. TNBS-induced body weight loss, myeloperoxidase activity, shortening of the colon and colonic inflammation were significantly ameliorated by andrographolide sulfonate. Both the mRNA and protein levels of pro-inflammatory cytokines were reduced by andrographolide sulfonate administration. Moreover, andrographolide sulfonate markedly suppressed the activation of p38 mitogen-activated protein kinase as well as p65 subunit of nuclear factor-κB (NF-κB). Furthermore, CD4(+) T cell infiltration as well as the differentiation of Th1 (CD4(+)IFN-γ(+)) and Th17 (CD4(+)IL17A(+)) subset were inhibited by andrographolide sulfonate. In summary, these results suggest that andrographolide sulfonate ameliorated TNBS-induced colitis in mice through inhibiting Th1/Th17 response. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating gastrointestinal inflammatory disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

NF-κB Mediates the Stimulation of Cytokine and Chemokine Expression by Human Articular Chondrocytes in Response to Fibronectin Fragments1

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Pulai, Judit I.; Chen, Hong; Im, Hee-Jeong; Kumar, Sanjay; Hanning, Charles; Hegde, Priti S.; Loeser, Richard F.

2010-01-01

Fibronectin fragments (FN-f) that bind to the α5β1 integrin stimulate chondrocyte-mediated cartilage destruction and could play an important role in the progression of arthritis. The objective of this study was to identify potential cytokine mediators of cartilage inflammation and destruction induced by FN-f and to investigate the mechanism of their stimulation. Human articular chondrocytes, isolated from normal ankle cartilage obtained from tissue donors, were treated with a 110-kDa FN-f in serum-free culture, and expression of various cytokine genes was analyzed by cDNA microarray and by a cytokine protein array. Compared with untreated control cultures, stimulation by FN-f resulted in a >2-fold increase in IL-6, IL-8, MCP-1, and growth-related oncogene β (GRO-β). Constitutive and FN-f-inducible expression of GRO-α and GRO-γ were also noted by RT-PCR and confirmed by immunoblotting. Previous reports of IL-1β expression induced by FN-f were also confirmed, while TNF expression was found to be very low. Inhibitor studies revealed that FN-f-induced stimulation of chondrocyte chemokine expression was dependent on NF-κB activity, but independent of IL-1 autocrine signaling. The ability of FN-f to stimulate chondrocyte expression of multiple proinflammatory cytokines and chemokines suggests that damage to the cartilage matrix is capable of inducing a proinflammatory state responsible for further progressive matrix destruction, which also includes the chemoattraction of inflammatory cells. Targeting the signaling pathways activated by FN-f may be an effective means of inhibiting production of multiple mediators of cartilage destruction. PMID:15843581

Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function

DEFF Research Database (Denmark)

Backe, Marie Balslev; Andersson, Jan Legaard; Bacos, Karl

2018-01-01

) protects β cells from cytokine-induced apoptosis and reduces type 1 diabetes incidence in animals. We hypothesized that also lysine demethylases (KDMs) regulate β-cell fate in response to inflammatory stress. Expression of the demethylase Kdm6B was upregulated by proinflammatory cytokines suggesting......Transcriptional changes control β-cell survival in response to inflammatory stress. Posttranslational modifications of histone and non-histone transcriptional regulators activate or repress gene transcription, but the link to cell-fate signaling is unclear. Inhibition of lysine deacetylases (KDACs...

Short communication: Cytokine profiles from blood mononuclear cells of dairy cows classified with divergent immune response phenotypes.

Science.gov (United States)

Martin, C E; Paibomesai, M A; Emam, S M; Gallienne, J; Hine, B C; Thompson-Crispi, K A; Mallard, B A

2016-03-01

Genetic selection for enhanced immune response has been shown to decrease disease occurrence in dairy cattle. Cows can be classified as high (H), average, or low responders based on antibody-mediated immune response (AMIR), predominated by type-2 cytokine production, and cell-mediated immune response (CMIR) through estimated breeding values for these traits. The purpose of this study was to identify in vitro tests that correlate with in vivo immune response phenotyping in dairy cattle. Blood mononuclear cells (BMC) isolated from cows classified as H-AMIR and H-CMIR through estimated breeding values for immune response traits were stimulated with concanavalin A (ConA; Sigma Aldrich, St. Louis, MO) and gene expression, cytokine production, and cell proliferation was determined at multiple time points. A repeated measures model, which included the effects of immune response group, parity, and stage of lactation, was used to compare differences between immune response phenotype groups. The H-AMIR cows produced more IL-4 protein than H-CMIR cows at 48 h; however, no difference in gene expression of type-2 transcription factor GATA3 or IL4 was noted. The BMC from H-CMIR cows had increased production of IFN-γ protein at 48, 72, and 96 h compared with H-AMIR animals. Further, H-CMIR cows had increased expression of the IFNG gene at 16, 24, and 48 h post-treatment with ConA, although expression of the type-1 transcription factor gene TBX21 did not differ between immune response groups. Although proliferation of BMC increased from 24 to 72 h after ConA stimulation, no differences were found between the immune response groups. Overall, stimulation of H-AMIR and H-CMIR bovine BMC with ConA resulted in distinct cytokine production profiles according to genetically defined groups. These distinct cytokine profiles could be used to define disease resistance phenotypes in dairy cows according to stimulation in vitro; however, other immune response phenotypes should be assessed

Neonatal plasma polarizes TLR4-mediated cytokine responses towards low IL-12p70 and high IL-10 production via distinct factors.

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Mirjam E Belderbos

Full Text Available Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP or soluble CD14 (sCD14. The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection.

Neonatal Plasma Polarizes TLR4-Mediated Cytokine Responses towards Low IL-12p70 and High IL-10 Production via Distinct Factors

Science.gov (United States)

Belderbos, Mirjam E.; Levy, Ofer; Stalpers, Femke; Kimpen, Jan L.; Meyaard, Linde; Bont, Louis

2012-01-01

Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR) responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs) produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP) or soluble CD14 (sCD14). The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection. PMID:22442690

Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1beta-mediated toxicity through inhibition of multiple nuclear factor-kappaB-regulated proapoptotic pathways

DEFF Research Database (Denmark)

Karlsen, Allan Ertman; Heding, P E; Frobøse, H

2004-01-01

The proinflammatory cytokine IL-1beta induces apoptosis in pancreatic beta cells via pathways dependent on nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinase, and protein kinase C. We recently showed suppressor of cytokine signalling (SOCS)-3 to be a natural negative feedback reg...... regulator of IL-1beta- and IFN-gamma-mediated signalling in rat islets and beta cell lines, preventing their deleterious effects. However, the mechanisms underlying SOCS-3 inhibition of IL-1beta signalling and prevention against apoptosis remain unknown....

Inhibition of cathepsin X enzyme influences the immune response of THP-1 cells and dendritic cells infected with Helicobacter pylori

International Nuclear Information System (INIS)

Skvarc, Miha; Stubljar, David; Kopitar, Andreja Natasa; Jeverica, Samo; Tepes, Bojan; Kos, Janko; Ihan, Alojz

2013-01-01

The immune response to Helicobacter pylori importantly determines the outcome of infection as well as the success of eradication therapy. We demonstrate the role of a cysteine protease cathepsin X in the immune response to H. pylori infection. We analysed how the inhibition of cathepsin X influenced the immune response in experiments when THP-1 cells or dendritic cells isolated from patients were stimulated with 48 strains of H. pylori isolated from gastric biopsy samples of patients which had problems with the eradication of bacteria. The experiments, performed with the help of a flow cytometer, showed that the expression of Toll-like receptors (TLRs), especially TLR-4 molecules, on the membranes of THP-1 cells or dendritic cells was higher when we stimulated cells with H. pylori together with inhibitor of cathepsin X 2F12 compared to THP-1 cells or dendritic cells stimulated with H. pylori only, and also in comparison with negative control samples. We also demonstrated that when we inhibited the action of cathepsin X in THP-1 cells, the concentrations of pro-inflammatory cytokines were lower than when THP-1 cell were stimulated with H. pylori only. We demonstrated that inhibition of cathepsin X influences the internalization of TLR-2 and TLR-4. TLR-2 and TLR-4 redistribution to intra-cytoplasmic compartments is hampered if cathepsin X is blocked. The beginning of a successful immune response against H. pylori in the case of inhibition of cathepsin X is delayed

Cytokines and the Inception of CD8 T Cell Responses

Science.gov (United States)

Cox, Maureen A.; Harrington, Laurie E.; Zajac, Allan J.

2011-01-01

The activation and differentiation of CD8 T cells is a necessary first step that endows these cells with the phenotypic and functional properties required for the control of intracellular pathogens. The induction of the CD8 T cell responses typically results in the development of a massive overall population of effector cells, comprised of both highly functional but short-lived terminally differentiated cells, as well as a smaller subset of precursors that are predisposed to survive and transition into the memory T cell pool. In this article we discuss how inflammatory cytokines and IL-2 bias the initial response towards short-lived effector generation and also highlight the potential counterbalancing role of IL-21. PMID:21371940

Cytokine responses in relation to age, gender, body mass index, Mycobacterium tuberculosis infection, and otitis media among inuit in greenland

DEFF Research Database (Denmark)

Nielsen, Nina Odgaard; Soborg, Bolette; Børresen, Malene

2013-01-01

To evaluate the cytokine response pattern in Inuit in Greenland in relation to age, gender, body mass index (BMI), Mycobacterium tuberculosis infection (MTI), and otitis media (OM) to assess whether Inuit may have signs of impaired immune responsiveness to infection.......To evaluate the cytokine response pattern in Inuit in Greenland in relation to age, gender, body mass index (BMI), Mycobacterium tuberculosis infection (MTI), and otitis media (OM) to assess whether Inuit may have signs of impaired immune responsiveness to infection....

Both very low- and very high in vitro cytokine responses were associated with infant death in low-birth-weight children from Guinea Bissau.

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Andreas Andersen

Full Text Available The mechanisms behind heterologous immunity and non-specific effects of vaccines on mortality are not well understood. We examined associations between cytokine responses and subsequent mortality in low-birth-weight infants in Guinea-Bissau.A low-birth-weight trial randomized children to Bacille Calmette-Guérin (BCG at birth or later according to local policy. Blood samples were obtained from a sub-group at age 6 weeks. Interleukin (IL-5, IL-10, IL-13, interferon (IFN-γ, and tumor necrosis factor (TNF-α were measured in whole-blood cell cultures stimulated with lipopolysaccharide (LPS, phytohaemagglutinin (PHA, or purified protein derivative (PPD. The outcome was mortality between bleeding and 1 year of age. Non-linear associations between cytokine responses and mortality were examined.Cytokine measurements were available from 390 children. The mortality rate (MR was high (6.8/100 person-years-observation (PYO. Both low and high cytokine responses to LPS and PHA were associated with high mortality (MR up to 25/100 PYO in the lowest 10% and 9.2/100 PYO in the highest 10%. In BCG-vaccinated children, higher IFN-γ responses to PPD were associated with better survival (MR ratio = 0.43 (0.24-0.77.Data presented a rare opportunity to explore associations between cytokine responses and mortality. Both low and high cytokine responses were associated with high mortality; a balanced response to invading pathogens seems preferable.

Both very low- and very high in vitro cytokine responses were associated with infant death in low-birth-weight children from Guinea Bissau.

Science.gov (United States)

Andersen, Andreas; Jensen, Kristoffer J; Erikstrup, Christian; Ravn, Henrik; Fisker, Ane B; Lisse, Ida M; Sartono, Erliyani; Aaby, Peter; Yazdanbakhsh, Maria; Benn, Christine S

2014-01-01

The mechanisms behind heterologous immunity and non-specific effects of vaccines on mortality are not well understood. We examined associations between cytokine responses and subsequent mortality in low-birth-weight infants in Guinea-Bissau. A low-birth-weight trial randomized children to Bacille Calmette-Guérin (BCG) at birth or later according to local policy. Blood samples were obtained from a sub-group at age 6 weeks. Interleukin (IL)-5, IL-10, IL-13, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were measured in whole-blood cell cultures stimulated with lipopolysaccharide (LPS), phytohaemagglutinin (PHA), or purified protein derivative (PPD). The outcome was mortality between bleeding and 1 year of age. Non-linear associations between cytokine responses and mortality were examined. Cytokine measurements were available from 390 children. The mortality rate (MR) was high (6.8/100 person-years-observation (PYO)). Both low and high cytokine responses to LPS and PHA were associated with high mortality (MR up to 25/100 PYO in the lowest 10% and 9.2/100 PYO in the highest 10%). In BCG-vaccinated children, higher IFN-γ responses to PPD were associated with better survival (MR ratio = 0.43 (0.24-0.77)). Data presented a rare opportunity to explore associations between cytokine responses and mortality. Both low and high cytokine responses were associated with high mortality; a balanced response to invading pathogens seems preferable.

DNA repair and cytokines: TGF-beta, IL-6, and thrombopoietin as different biomarkers of radioresistance

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Francesca Bianca Aiello

2016-07-01

Full Text Available Double strand breaks (DSBs induced by radiotherapy are highly cytotoxic lesions, leading to chromosomal aberrations and cell death. ATM-dependent DNA-damage response, non-homologous end joining, and homologous recombination pathways coordinately contribute to repairing DSBs in higher eukaryotes. It is known that the expression of DSB repair genes is increased in tumors which is one of the main reasons for radioresistance. The inhibition of DSB repair pathways may be useful to increase tumor cell radiosensitivity and may target stem cell-like cancer cells, known to be the most radioresistant tumor components. Commonly overexpressed in neoplastic cells, cytokines confer radioresistance by promoting proliferation, survival, invasion, and angiogenesis. Unfortunately, tumor irradiation increases the expression of various cytokines displaying these effects, including transforming growth factor-beta and interlukin-6. Recently the capabilities of these cytokines to support DNA repair pathways and the ATM-dependent DNA response have been demonstrated. Thrombopoietin, essential for megakaryopoiesis and very important for hematopoietic stem cell homeostasis, has also been found to promote DNA repair in a highly selective manner. These findings reveal a novel mechanism underlying cytokine-related radioresistance, which may be clinically relevant. Therapies targeting specific cytokines may be used to improve radiosensitivity. Specific inhibitors may be chosen in consideration of different tumor microenvironments. Thrombopoietin may be useful in fending off irradiation-induced loss of hematopoietic stem cells.

Severe Malaria Infections Impair Germinal Center Responses by Inhibiting T Follicular Helper Cell Differentiation

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Victoria Ryg-Cornejo

2016-01-01

Full Text Available Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the establishment of germinal centers (GCs in the spleen. We demonstrate that infection induces high frequencies of T follicular helper (Tfh cell precursors but results in impaired Tfh cell differentiation. Despite high expression of Bcl-6 and IL-21, precursor Tfh cells induced during infection displayed low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3. Blockade of the inflammatory cytokines TNF and IFN-γ or T-bet deletion restored Tfh cell differentiation and GC responses to infection. Thus, this study demonstrates that the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of protective B cell responses.

Thrombomodulin inhibits the activation of eosinophils and mast cells.

Science.gov (United States)

Roeen, Ziaurahman; Toda, Masaaki; D'Alessandro-Gabazza, Corina N; Onishi, Masahiro; Kobayashi, Tetsu; Yasuma, Taro; Urawa, Masahito; Taguchi, Osamu; Gabazza, Esteban C

2015-01-01

Eosinophils and mast cells play critical roles in the pathogenesis of bronchial asthma. Activation of both cells leads to the release of pro-inflammatory mediators in the airway of asthmatic patients. Recently, we have shown that inhaled thrombomodulin inhibits allergic bronchial asthma in a mouse model. In the present study, we hypothesize that thrombomodulin can inhibit the activation of eosinophils and mast cells. The effect of thrombomodulin on the activation and release of inflammatory mediators from eosinophils and mast cells was evaluated. Thrombomodulin inhibited the eotaxin-induced chemotaxis, upregulation of CD11b and degranulation of eosinophils. Treatment with thrombomodulin also significantly suppressed the degranulation and synthesis of inflammatory cytokines and chemokines in eosinophils and mast cells. Mice treated with a low-dose of inhaled thrombomodulin have decreased number of eosinophils and activated mast cells and Th2 cytokines in the lungs compared to untreated mice. The results of this study suggest that thrombomodulin may modulate allergic responses by inhibiting the activation of both eosinophils and mast cells. Copyright © 2014 Elsevier Inc. All rights reserved.

Photoperiodic Regulation of Behavioral Responsiveness to Proinflammatory Cytokines

OpenAIRE

Wen, Jarvi C.; Prendergast, Brian J.

2007-01-01

Symptoms of bacterial infection include decreases in body mass (cachexia), induction of depressive-like hedonic tone (anhedonia), decreases in food intake (anorexia), and increases in body temperature (fever). Recognition of bacteria by the innate immune system triggers the release of proinflammatory cytokines which induce these sickness behaviors via central and peripheral substrates. In Siberian hamsters, exposure to short day lengths decreases both the production of proinflammatory cytokin...

Bojesodok-eum, a Herbal Prescription, Ameliorates Acute Inflammation in Association with the Inhibition of NF-κB-Mediated Nitric Oxide and ProInflammatory Cytokine Production

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Kook Ho Sohn

2012-01-01

Full Text Available Bojesodok-eum (BSE is a herbal prescription consisting of Coptidis Rhizoma and Scutellariae Radix as main components. This paper investigated the effects of BSE on the induction of nitric oxide (NO, prostaglandin E2 (PGE2, and proinflammatory cytokines that are caused by lipopolysaccharide (LPS in murine macrophage cell line and on the paw edema formation in animals. Administration of BSE (0.3 g/kg and 1 g/kg in rats significantly inhibited carrageenan-induced paw edema formation, as did dexamethasone, an anti-inflammatory positive control drug. In cell model, treatment of BSE decreased the production of NO and PGE2 in RAW264.7 cells stimulated by LPS. BSE also inhibited the expression of iNOS and COX-2 protein as well as COX activity in a concentration-dependent manner. Consistently, BSE suppressed the ability of LPS to produce TNF-α, interleukin-1β, and interleukin-6. LPS treatment induced nuclear NF-κB level and I-κBα phosphorylation, which were inhibited subsequent treatment of BSE, suggesting its repression of LPS-inducible NF-κB activation. BSE abrogated the induction of NO, PGE2, and proinflammatory cytokines, as well as iNOS and COX-2 protein expression in RAW264.7 cells stimulated by LPS as mediated with NF-κB inhibition.

Tomatidine Attenuates Airway Hyperresponsiveness and Inflammation by Suppressing Th2 Cytokines in a Mouse Model of Asthma

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Chieh-Ying Kuo

2017-01-01

Full Text Available Tomatidine is isolated from the fruits of tomato plants and found to have anti-inflammatory effects in macrophages. In the present study, we investigated whether tomatidine suppresses airway hyperresponsiveness (AHR and eosinophil infiltration in asthmatic mice. BALB/c mice were sensitized with ovalbumin and treated with tomatidine by intraperitoneal injection. Airway resistance was measured by intubation analysis as an indication of airway responsiveness, and histological studies were performed to evaluate eosinophil infiltration in lung tissue. Tomatidine reduced AHR and decreased eosinophil infiltration in the lungs of asthmatic mice. Tomatidine suppressed Th2 cytokine production in bronchoalveolar lavage fluid. Tomatidine also blocked the expression of inflammatory and Th2 cytokine genes in lung tissue. In vitro, tomatidine inhibited proinflammatory cytokines and CCL11 production in inflammatory BEAS-2B bronchial epithelial cells. These results indicate that tomatidine contributes to the amelioration of AHR and eosinophil infiltration by blocking the inflammatory response and Th2 cell activity in asthmatic mice.

N-acetylcysteine attenuates hexavalent chromium-induced hypersensitivity through inhibition of cell death, ROS-related signaling and cytokine expression.

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Yu-Hsuan Lee

Full Text Available Chromium hypersensitivity (chromium-induced allergic contact dermatitis is an important issue in occupational skin disease. Hexavalent chromium (Cr (VI can activate the Akt, Nuclear factor κB (NF-κB, and Mitogen-activated protein kinase (MAPK pathways and induce cell death, via the effects of reactive oxygen species (ROS. Recently, cell death stimuli have been proposed to regulate the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α and interleukin-1 (IL-1. However, the exact effects of ROS on the signaling molecules and cytotoxicity involved in Cr(VI-induced hypersensitivity have not yet been fully demonstrated. N-acetylcysteine (NAC could increase glutathione levels in the skin and act as an antioxidant. In this study, we investigated the effects of NAC on attenuating the Cr(VI-triggered ROS signaling in both normal keratinocyte cells (HaCaT cells and a guinea pig (GP model. The results showed the induction of apoptosis, autophagy and ROS were observed after different concentrations of Cr(VI treatment. HaCaT cells pretreated with NAC exhibited a decrease in apoptosis and autophagy, which could affect cell viability. In addition, Cr (VI activated the Akt, NF-κB and MAPK pathways thereby increasing IL-1α and TNF-α production. However, all of these stimulation phenomena could be inhibited by NAC in both of in vitro and in vivo studies. These novel findings indicate that NAC may prevent the development of chromium hypersensitivity by inhibiting of ROS-induced cell death and cytokine expression.

Gemfibrozil, a Lipid-lowering Drug, Inhibits the Induction of Nitric-oxide Synthase in Human Astrocytes*

Science.gov (United States)

Pahan, Kalipada; Jana, Malabendu; Liu, Xiaojuan; Taylor, Bradley S.; Wood, Charles; Fischer, Susan M.

2007-01-01

Gemfibrozil, a lipid-lowering drug, inhibited cytokine-induced production of NO and the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astrocytes. Similar to gemfibrozil, clofibrate, another fibrate drug, also inhibited the expression of iNOS. Inhibition of human iNOS promoter-driven luciferase activity by gemfibrozil in cytokine-stimulated U373MG astroglial cells suggests that this compound inhibits the transcription of iNOS. Since gemfibrozil is known to activate peroxisome proliferator-activated receptor-α (PPAR-α), we investigated the role of PPAR-α in gemfibrozil-mediated inhibition of iNOS. Gemfibrozil induced peroxisome proliferator-responsive element (PPRE)-dependent luciferase activity, which was inhibited by the expression of ΔhPPAR-α, the dominant-negative mutant of human PPAR-α. However, ΔhPPAR-α was unable to abrogate gemfibrozil-mediated inhibition of iNOS suggesting that gemfibrozil inhibits iNOS independent of PPAR-α. The human iNOS promoter contains consensus sequences for the binding of transcription factors, including interferon-γ (IFN-γ) regulatory factor-1 (IRF-1) binding to interferon-stimulated responsive element (ISRE), signal transducer and activator of transcription (STAT) binding to γ-activation site (GAS), nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and CCAAT/enhancer-binding protein β (C/EBPβ); therefore, we investigated the effect of gemfibrozil on the activation of these transcription factors. The combination of interleukin (IL)-1β and IFN-γ induced the activation of NF-κB, AP-1, C/EBPβ, and GAS but not that of ISRE, suggesting that IRF-1 may not be involved in cytokine-induced expression of iNOS in human astrocytes. Interestingly, gemfibrozil strongly inhibited the activation of NF-κB, AP-1, and C/EBPβ but not that of GAS in cytokine-stimulated astroglial cells. These results suggest that gemfibrozil inhibits the induction of iNOS probably by

Immunologic Characterization of Cytokine Responses to Enterovirus 71 and Coxsackievirus A16 Infection in Children.

Science.gov (United States)

Zhang, Shu-Yan; Xu, Mei-Yan; Xu, Hong-Mei; Li, Xiu-Jun; Ding, Shu-Jun; Wang, Xian-Jun; Li, Ting-Yu; Lu, Qing-Bin

2015-07-01

Viral encephalitis is a serious complication of hand, foot, and mouth disease (HFMD), but characteristics of cytokines response in enterovirus 71 (EV-71) and/or coxsackievirus A16 (CV-A16) associated HFMD with or without viral encephalitis remained unclear.We performed a multigroup retrospective study and compared the serum cytokines concentrations among 16 encephalitis patients infected with EV-71 and CV-A16, 24 encephalitis patients with single EV-71 infection, 34 mild HFMD patients with EV-71 infection, 18 mild HFMD patients with CV-A16 infection, and 39 healthy control subjects.Serum levels of interleukin (IL)-4, IL-5, IL-22, and IL-23 were significantly higher in encephalitis patients than in HFMD-alone patients when adjusting for age and sex; IL-2, tumor necrosis factor (TNF)-α, IL-4, IL-22, and IL-1β were significantly higher in HFMD-alone patients of EV-71 infection than in CV-A16 infected HFMD patients; cerebrospinal fluid level of IL-6 was lower in the EV-71/CV-A16 associated encephalitis than that in the EV-71 alone associated encephalitis patients.Over or low expression of the cytokines cascade in HFMD patients appears to play an important role in the elicitation of the immune response to EV-71 and CV-A16. These data will be used to define a cytokine profile, which might help to recognize HFMD patients with the high risk of developing encephalitis.

Contrasting neural effects of aging on proactive and reactive response inhibition

NARCIS (Netherlands)

Bloemendaal, Mirjam; Zandbelt, Bram; Wegman, Joost; Rest, van de O.; Cools, Roshan; Aarts, Esther

2016-01-01

Two distinct forms of response inhibition may underlie observed deficits in response inhibition in aging. We assessed whether age-related neurocognitive impairments in response inhibition reflect deficient reactive inhibition (outright stopping) or also deficient proactive inhibition

Variability in tuberculosis granuloma T cell responses exists, but a balance of pro- and anti-inflammatory cytokines is associated with sterilization.

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Hannah Priyadarshini Gideon

2015-01-01

Full Text Available Lung granulomas are the pathologic hallmark of tuberculosis (TB. T cells are a major cellular component of TB lung granulomas and are known to play an important role in containment of Mycobacterium tuberculosis (Mtb infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB with clinically active disease, latent infection or early infection, to understand functional characteristics and dynamics of T cells in individual granulomas. We sought to correlate T cell cytokine response and bacterial burden of each granuloma, as well as granuloma and systemic responses in individual animals. Our results support that each granuloma within an individual host is independent with respect to total cell numbers, proportion of T cells, pattern of cytokine response, and bacterial burden. The spectrum of these components overlaps greatly amongst animals with different clinical status, indicating that a diversity of granulomas exists within an individual host. On average only about 8% of T cells from granulomas respond with cytokine production after stimulation with Mtb specific antigens, and few "multi-functional" T cells were observed. However, granulomas were found to be "multi-functional" with respect to the combinations of functional T cells that were identified among lesions from individual animals. Although the responses generally overlapped, sterile granulomas had modestly higher frequencies of T cells making IL-17, TNF and any of T-1 (IFN-γ, IL-2, or TNF and/or T-17 (IL-17 cytokines than non-sterile granulomas. An inverse correlation was observed between bacterial burden with TNF and T-1/T-17 responses in individual granulomas, and a combinatorial analysis of pair-wise cytokine responses indicated that granulomas with T cells producing both pro- and anti-inflammatory cytokines (e.g. IL-10 and IL-17 were associated with clearance of Mtb. Preliminary evaluation suggests that systemic responses in the blood do not

Human metapneumovirus M2-2 protein inhibits innate immune response in monocyte-derived dendritic cells.

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Junping Ren

Full Text Available Human metapneumovirus (hMPV is a leading cause of lower respiratory infection in young children, the elderly and immunocompromised patients. Repeated hMPV infections occur throughout life. However, immune evasion mechanisms of hMPV infection are largely unknown. Recently, our group has demonstrated that hMPV M2-2 protein, an important virulence factor, contributes to immune evasion in airway epithelial cells by targeting the mitochondrial antiviral-signaling protein (MAVS. Whether M2-2 regulates the innate immunity in human dendritic cells (DC, an important family of immune cells controlling antigen presenting, is currently unknown. We found that human DC infected with a virus lacking M2-2 protein expression (rhMPV-ΔM2-2 produced higher levels of cytokines, chemokines and IFNs, compared to cells infected with wild-type virus (rhMPV-WT, suggesting that M2-2 protein inhibits innate immunity in human DC. In parallel, we found that myeloid differentiation primary response gene 88 (MyD88, an essential adaptor for Toll-like receptors (TLRs, plays a critical role in inducing immune response of human DC, as downregulation of MyD88 by siRNA blocked the induction of immune regulatory molecules by hMPV. Since M2-2 is a cytoplasmic protein, we investigated whether M2-2 interferes with MyD88-mediated antiviral signaling. We found that indeed M2-2 protein associated with MyD88 and inhibited MyD88-dependent gene transcription. In this study, we also identified the domains of M2-2 responsible for its immune inhibitory function in human DC. In summary, our results demonstrate that M2-2 contributes to hMPV immune evasion by inhibiting MyD88-dependent cellular responses in human DC.

Sex differences in the pro-inflammatory cytokine response to endotoxin unfold in vivo but not ex vivo in healthy humans.

Science.gov (United States)

Wegner, Alexander; Benson, Sven; Rebernik, Laura; Spreitzer, Ingo; Jäger, Marcus; Schedlowski, Manfred; Elsenbruch, Sigrid; Engler, Harald

2017-07-01

Clinical data indicate that inflammatory responses differ across sexes, but the mechanisms remain elusive. Herein, we assessed in vivo and ex vivo cytokine responses to bacterial endotoxin in healthy men and women to elucidate the role of systemic and cellular factors underlying sex differences in inflammatory responses. Participants received an i.v. injection of low-dose endotoxin (0.4 ng/kg body mass), and plasma TNF-α and IL-6 responses were analyzed over a period of 6 h. In parallel, ex vivo cytokine production was measured in endotoxin-stimulated blood samples obtained immediately before in vivo endotoxin administration. As glucocorticoids (GCs) play an important role in the negative feedback regulation of the inflammatory response, we additionally analyzed plasma cortisol concentrations and ex vivo GC sensitivity of cytokine production. Results revealed greater in vivo pro-inflammatory responses in women compared with men, with significantly higher increases in plasma TNF-α and IL-6 concentrations. In addition, the endotoxin-induced rise in plasma cortisol was more pronounced in women. In contrast, no sex differences in ex vivo cytokine production and GC sensitivity were observed. Together, these findings demonstrate major differences in in vivo and ex vivo responses to endotoxin and underscore the importance of systemic factors underlying sex differences in the inflammatory response.

Maysin and Its Flavonoid Derivative from Centipedegrass Attenuates Amyloid Plaques by Inducting Humoral Immune Response with Th2 Skewed Cytokine Response in the Tg (APPswe, PS1dE9 Alzheimer's Mouse Model.

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Yuno Song

Full Text Available Alzheimer's disease (AD is a slow, progressive neurodegenerative disease and the most common type of dementia in the elderly. The etiology of AD and its underlying mechanism are still not clear. In a previous study, we found that an ethyl acetate extract of Centipedegrass (CG (i.e., EA-CG contained 4 types of Maysin derivatives, including Luteolin, Isoorientin, Rhamnosylisoorientin, and Derhamnosylmaysin, and showed protective effects against Amyloid beta (Aβ by inhibiting oligomeric Aβ in cellular and in vitro models. Here, we examined the preventative effects of EA-CG treatment on the Aβ burden in the Tg (Mo/Hu APPswe PS1dE9 AD mouse model. We have investigated the EA-CG efficacy as novel anti-AD likely preventing amyloid plaques using immunofluorescence staining to visually analyze Aβ40/42 and fibril formation with Thioflavin-S or 6E10 which are the profile of immunoreactivity against epitope Aβ1-16 or neuritic plaque, the quantitation of humoral immune response against Aβ, and the inflammatory cytokine responses (Th1 and Th2 using ELISA and QRT-PCR. To minimize the toxicity of the extracted CG, we addressed the liver toxicity in response to the CG extract treatment in Tg mice using relevant markers, such as aspartate aminotransferase (AST/ alanine aminotransferase (ALT measurements in serum. The EA-CG extract significantly reduced the Aβ burden, the concentration of soluble Aβ40/42 protein, and fibril formation in the hippocampus and cortex of the Tg mice treated with EA-CG (50 mg/kg BW/day for 6 months compared with the Tg mice treated with a normal diet. Additionally, the profile of anti-inflammatory cytokines revealed that the levels of Th2 (interleukin-4 (IL-4 and interleukin-10 (IL-10 cytokines are more significantly increased than Th1 (interferon-γ (IFN-γ, interleukin-2(IL-2 in the sera. These results suggest that the EA-CG fraction induces IL-4/IL-10-dependent anti-inflammatory cytokines (Th2 rather than pro

Antibiotic-Mediated Inhibition of Porcine Reproductive and Respiratory Syndrome Virus (PRRSV Infection: A Novel Quinolone Function Which Potentiates the Antiviral Cytokine Response in MARC-145 Cells and Pig Macrophages

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William A. Cafruny

2008-01-01

Full Text Available Porcine reproductive and respiratory syndrome virus (PRRSV is an economically significant agent for which there currently are no effective treatments. Development of antiviral agents for PRRSV as well as many other viruses has been limited by toxicity of known antiviral compounds. In contrast, antibiotics for non-virus microbial infections have been widely useful, in part because of their acceptable toxicity in animals. We report here the discovery that the quinolonecontaining compound Plasmocin™, as well as the quinolones nalidixic acid and ciprofloxacin, have potent anti-PRRSV activity in vitro. PRRSV replication was inhibited by these antibiotics in both cultured MARC-145 cells and cultured primary alveolar porcine macrophages (PAMs. Furthermore, sub-optimal concentrations of nalidixic acid synergized with antiviral cytokines (AK-2 or IFN-γ to quantitatively and qualitatively inhibit PRRSV replication in MARC-145 cells or PAMs. The antiviral activity of Plasmocin and nalidixic acid correlated with reduced actin expression in MARC-145 cells. Replication of the related lactate dehydrogenase-elevating virus (LDV was also inhibited in primary mouse macrophages by Plasmocin. These results are significant to the development of antiviral strategies with potentially reduced toxicity, and provide a model system to better understand regulation of arterivirus replication.

Cytokine, antibody and proliferative cellular responses elicited by Taenia solium calreticulin upon experimental infection in hamsters.

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Fela Mendlovic

Full Text Available Taenia solium causes two diseases in humans, cysticercosis and taeniosis. Tapeworm carriers are the main risk factor for neurocysticercosis. Limited information is available about the immune response elicited by the adult parasite, particularly the induction of Th2 responses, frequently associated to helminth infections. Calreticulin is a ubiquitous, multifunctional protein involved in cellular calcium homeostasis, which has been suggested to play a role in the regulation of immune responses. In this work, we assessed the effect of recombinant T. solium calreticulin (rTsCRT on the cytokine, humoral and cellular responses upon experimental infection in Syrian Golden hamsters (Mesocricetus auratus. Animals were infected with T. solium cysticerci and euthanized at different times after infection. Specific serum antibodies, proliferative responses in mesenteric lymph nodes and spleen cells, as well as cytokines messenger RNA (mRNA were analyzed. The results showed that one third of the infected animals elicited anti-rTsCRT IgG antibodies. Interestingly, mesenteric lymph node (MLN cells from either infected or non-infected animals did not proliferate upon in vitro stimulation with rTsCRT. Additionally, stimulation with a tapeworm crude extract resulted in increased expression of IL-4 and IL-5 mRNA. Upon stimulation, rTsCRT increased the expression levels of IL-10 in spleen and MLN cells from uninfected and infected hamsters. The results showed that rTsCRT favors a Th2-biased immune response characterized by the induction of IL-10 in mucosal and systemic lymphoid organs. Here we provide the first data on the cytokine, antibody and cellular responses to rTsCRT upon in vitro stimulation during taeniasis.

Acrolein inhalation suppresses lipopolysaccharide-induced inflammatory cytokine production but does not affect acute airways neutrophilia.

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Kasahara, David Itiro; Poynter, Matthew E; Othman, Ziryan; Hemenway, David; van der Vliet, Albert

2008-07-01

Acrolein is a reactive unsaturated aldehyde that is produced during endogenous oxidative processes and is a major bioactive component of environmental pollutants such as cigarette smoke. Because in vitro studies demonstrate that acrolein can inhibit neutrophil apoptosis, we evaluated the effects of in vivo acrolein exposure on acute lung inflammation induced by LPS. Male C57BL/6J mice received 300 microg/kg intratracheal LPS and were exposed to acrolein (5 parts per million, 6 h/day), either before or after LPS challenge. Exposure to acrolein either before or after LPS challenge did not significantly affect the overall extent of LPS-induced lung inflammation, or the duration of the inflammatory response, as observed from recovered lung lavage leukocytes and histology. However, exposure to acrolein after LPS instillation markedly diminished the LPS-induced production of several inflammatory cytokines, specifically TNF-alpha, IL-12, and the Th1 cytokine IFN-gamma, which was associated with reduction in NF-kappaB activation. Our data demonstrate that acrolein exposure suppresses LPS-induced Th1 cytokine responses without affecting acute neutrophilia. Disruption of cytokine signaling by acrolein may represent a mechanism by which smoking contributes to chronic disease in chronic obstructive pulmonary disease and asthma.

Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway

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Pavlov, Valentin A.; Parrish, William R.; Rosas-Ballina, Mauricio; Ochani, Mahendar; Puerta, Margot; Ochani, Kanta; Chavan, Sangeeta; Al-Abed, Yousef; Tracey, Kevin J.

2015-01-01

The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “cholinergic anti-inflammatory pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the alpha7 subunit-containing nicotinic acetylcholine receptor (α7nAChR). Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks, but despite considerable importance, little is known about the molecular basis for central regulation of the vagus nerve-based cholinergic anti-inflammatory pathway. Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF production during endotoxemia. Peripheral administration of the acetylcholinesterase inhibitor galantamine significantly reduced serum TNF levels through vagus nerve signaling, and protected against lethality during murine endotoxemia. Administration of a centrally-acting muscarinic receptor antagonist abolished the suppression of TNF by galantamine, indicating that suppressing acetylcholinesterase activity, coupled with central muscarinic receptors, controls peripheral cytokine responses. Administration of galantamine to α7nAChR knockout mice failed to suppress TNF levels, indicating that the α7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of galantamine. These findings show that inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal- and α7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor can be utilized to suppress abnormal inflammation to therapeutic advantage. PMID:18639629

Activation of farnesoid X receptor increases the expression of cytokine inducible SH2-containing protein in HepG2 cells.

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Xu, Zhizhen; Huang, Gang; Gong, Wei; Zhao, Yuanyin; Zhou, Peng; Zeng, Yijun; He, Fengtian

2012-11-01

Cytokine inducible SH2-containing protein (CISH), which negatively regulates cytokine signaling by inhibiting JAK2/STAT5 activity, is regarded as a therapeutic target for inflammatory diseases. Farnesoid X receptor (FXR), a ligand-activated transcription factor, has been proposed to play a protective function in the inflammatory responses. However, the role of FXR in modulation of CISH expression is unknown. In the present study, we for the first time identified that in human hepatoma cell line HepG2 the activation of FXR by the natural agonist chenodeoxycholic acid (CDCA) and the synthetic specific agonist GW4064 upregulated CISH at both transcriptional and translational levels, and inhibited interleukin (IL)6-induced STAT5 activation. Moreover, the in vivo experiment demonstrated that gavaging mice with CDCA increased CISH expression and reduced basal STAT5 phosphorylation in liver tissues. Reporter assay showed that FXR agonists enhanced the transcriptional activity of CISH promoter. These data suggest that FXR may serve as a novel molecular target for manipulating CISH expression in hepatocytes. FXR-mediated upregulation of CISH may play an important role in the homeostasis of cytokine signal networks and be beneficial to control cytokine-associated inflammatory diseases.

Salivary cytokine response in the aftermath of stress: An emotion regulation perspective.

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Newton, Tamara L; Fernandez-Botran, Rafael; Lyle, Keith B; Szabo, Yvette Z; Miller, James J; Warnecke, Ashlee J

2017-09-01

Elevated inflammation in the context of stress has been implicated in mental and physical health. Approaching this from an emotion regulation perspective, we tested whether the salivary cytokine response to stress is dampened by using distraction to minimize opportunity for poststressor rumination. Healthy young adults were randomized to an acute stressor: modified Trier Social Stress Test (TSST, Study 1) or angry memory retrieval (Study 2). Within each study, participants were randomized to poststressor condition-rest or distraction-at a 3:1 ratio. Saliva, collected before and 40 min after the end of each stressor, was assayed for proinflammatory cytokines (PICs): interleukin-1β (IL-1β), TNF-α, and IL-6. Both stressors increased all PICs, and both provoked negative emotion. At 40 min post-TSST, salivary PIC increases did not differ between distraction and rest, but correlated positively with emotional reactivity to stress. At 40 min after memory retrieval, IL-1β increases and intrusive rumination were lower during distraction than rest, but did not correlate with emotional reactivity. Trait rumination and interference control mechanisms, also measured, played little role in PIC increases. Overall, after some stressors, some salivary cytokine responses are lower during distraction than rest. The roles of specific emotions, emotional intensity, and poststressor timing of saliva collection in this finding require clarification. Furthermore, the possibility of two affective paths to inflammation in the context of stress-one sensitive to opportunities for early occurring emotion regulation (as reflected in emotional reactivity), and one sensitive to late-occurring emotion regulation (as reflected in distraction after stress)-deserves attention. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Response inhibition in motor conversion disorder.

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Voon, Valerie; Ekanayake, Vindhya; Wiggs, Edythe; Kranick, Sarah; Ameli, Rezvan; Harrison, Neil A; Hallett, Mark

2013-05-01

Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups. © 2013 Movement Disorder Society. Copyright © 2013 Movement Disorder Society.

IL-12p35 Inhibits Neuroinflammation and Ameliorates Autoimmune Encephalomyelitis

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Jin Kyeong Choi

2017-10-01

Full Text Available Multiple sclerosis (MS is an inflammatory demyelinating disease in which cytokines produced by immune cells that infiltrate the brain and spinal cord play a central role. We show here that the IL-12p35, the alpha subunit of IL-12 or IL-35 cytokine, might be an effective biologic for suppressing neuroinflammatory responses and ameliorating the pathology of experimental autoimmune encephalomyelitis (EAE, the mouse model of human MS. We further show that IL-12p35 conferred protection from neuropathy by inhibiting the expansion of pathogenic Th17 and Th1 cells and inhibiting trafficking of inflammatory cells into the brain and spinal cord. In addition, in vitro exposure of encephalitogenic cells to IL-12p35 suppressed their capacity to induce EAE by adoptive transfer. Importantly, the IL-12p35-mediated expansion of Treg and Breg cells and its amelioration of EAE correlated with inhibition of cytokine-induced activation of STAT1/STAT3 pathways. Moreover, IL-12p35 inhibited lymphocyte proliferation by suppressing the expressions of cell-cycle regulatory proteins. Taken together, these results suggest that IL-12p35 can be exploited as a novel biologic for treating central nervous system autoimmune diseases and offers the promise of ex vivo production of large amounts of Tregs and Bregs for immunotherapy.

Neural Synchrony during Response Production and Inhibition

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Müller, Viktor; Anokhin, Andrey P.

2012-01-01

Inhibition of irrelevant information (conflict monitoring) and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs) elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG) recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300–600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations. PMID:22745691

Neural synchrony during response production and inhibition.

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Viktor Müller

Full Text Available Inhibition of irrelevant information (conflict monitoring and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300-600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations.

An investigation of the anti-inflammatory effects and a potential biomarker of PI3Kδ inhibition in COPD T cells.

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Khan, Abid; Southworth, Thomas; Worsley, Sally; Sriskantharajah, Srividya; Amour, Augustin; Hessel, Edith M; Singh, Dave

2017-09-01

Lymphocyte numbers are increased in the lungs of chronic obstructive pulmonary disease (COPD) patients. Phosphatidylinositol-3-kinase delta (PI3Kδ) is involved in lymphocyte activation. We investigated the effect of PI3Kδ inhibition on cytokine release from COPD lymphocytes. We also evaluated phosphorylated ribosomal S6 protein (rS6) as a potential biomarker of PI3Kδ activation. Peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage (BAL) cells isolated from healthy never smokers (HNS), smokers (S) and COPD patients were stimulated to induce a T cell receptor response. The effects of a PI3Kδ specific inhibitor (GSK045) on cytokine release and rS6 phosphorylation were measured by Luminex and flow cytometry respectively. The effects of GSK045 on cytokine production from PHA stimulated chopped lung samples were investigated. GSK045 reduced cytokine release from PBMCs, BAL cells and chopped lung. Inhibition was greatest in the chopped lung model, with approximately 80% inhibition of interferon (IFN) γ, interleukin (IL)-2, IL-17 and IL-10. PI3Kδ inhibition suppressed rS6 phosphorylation in unstimulated airway T-lymphocytes by up to 60%. Inhibition of PI3Kδ suppressed T cell cytokine production in COPD patients. rS6 phosphorylation shows potential as a biomarker to assess PI3Kδ activity. © 2017 John Wiley & Sons Australia, Ltd.

Effects of corticosteroid on the expressions of neuropeptide and cytokine mRNA and on tenocyte viability in lateral epicondylitis

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Han Soo

2012-10-01

Full Text Available Abstract Background The purpose of this study was to determine the reaction mechanism of corticosteroid by analyzing the expression patterns of neuropeptides (substance P (SP, calcitonin gene related peptide (CGRP and of cytokines (interleukin (IL-1α, tumor growth factor (TGF-β after corticosteroid treatment in lateral epicondylitis. In addition, we also investigated whether corticosteroid influenced tenocyte viability. Methods The corticosteroid triamcinolone acetonide (TAA was applied to cultured tenocytes of lateral epicondylitis, and the changes in the mRNA expressions of neuropeptides and cytokines and tenocyte viabilities were analyzed at seven time points. Quantitative real-time polymerase chain reaction and an MTT assay were used. Results The expression of SP mRNA was maximally inhibited by TAA at 24 hours but recovered at 72 hours, and the expressions of CGRP mRNA and IL-1α mRNA were inhibited at 24 and 3 hours, respectively. The expression of TGF-β mRNA was not significant. Tenocyte viability was significantly reduced by TAA at 24 hours. Conclusions We postulate that the reaction mechanism predominantly responsible for symptomatic relief after a corticosteroid injection involves the inhibitions of neuropeptides and cytokines, such as, CGRP and IL-1α. However the tenocyte viability was compromised by a corticosteroid.

Transcriptome dynamics of the microRNA inhibition response

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Wen, Jiayu; Leucci, Elenora; Vendramin, Roberto

2015-01-01

We report a high-resolution time series study of transcriptome dynamics following antimiR-mediated inhibition of miR-9 in a Hodgkin lymphoma cell-line-the first such dynamic study of the microRNA inhibition response-revealing both general and specific aspects of the physiological response. We show...... validate the key observations with independent time series qPCR and we experimentally validate key predicted miR-9 targets. Methodologically, we developed sensitive functional data analytic predictive methods to analyse the weak response inherent in microRNA inhibition experiments. The methods...... of this study will be applicable to similar high-resolution time series transcriptome analyses and provides the context for more accurate experimental design and interpretation of future microRNA inhibition studies....

Both very low- and very high in vitro cytokine responses were associated with infant death in low-birth-weight children from Guinea bissau

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Andersen, Andreas; Jensen, Kristoffer J; Erikstrup, Christian

2014-01-01

with lipopolysaccharide (LPS), phytohaemagglutinin (PHA), or purified protein derivative (PPD). The outcome was mortality between bleeding and 1 year of age. Non-linear associations between cytokine responses and mortality were examined. RESULTS: Cytokine measurements were available from 390 children. The mortality rate...... (MR) was high (6.8/100 person-years-observation (PYO)). Both low and high cytokine responses to LPS and PHA were associated with high mortality (MR up to 25/100 PYO in the lowest 10% and 9.2/100 PYO in the highest 10%). In BCG-vaccinated children, higher IFN-γ responses to PPD were associated...

Clinical Studies Applying Cytokine-Induced Killer Cells for the Treatment of Renal Cell Carcinoma

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Clara E. Jäkel

2012-01-01

Full Text Available Metastatic renal cell carcinoma (RCC seems to be resistant to conventional chemo- and radiotherapy and the general treatment regimen of cytokine therapy produces only modest responses while inducing severe side effects. Nowadays standard of care is the treatment with VEGF-inhibiting agents or mTOR inhibition; nevertheless, immunotherapy can induce complete remissions and long-term survival in selected patients. Among different adoptive lymphocyte therapies, cytokine-induced killer (CIK cells have a particularly advantageous profile as these cells are easily available, have a high proliferative rate, and exhibit a high antitumor activity. Here, we reviewed clinical studies applying CIK cells, either alone or with standard therapies, for the treatment of RCC. The adverse events in all studies were mild, transient, and easily controllable. In vitro studies revealed an increased antitumor activity of peripheral lymphocytes of participants after CIK cell treatment and CIK cell therapy was able to induce complete clinical responses in RCC patients. The combination of CIK cell therapy and standard therapy was superior to standard therapy alone. These studies suggest that CIK cell immunotherapy is a safe and competent treatment strategy for RCC patients and further studies should investigate different treatment combinations and schedules for optimal application of CIK cells.

Anti-WASP intrabodies inhibit inflammatory responses induced by Toll-like receptors 3, 7, and 9, in macrophages

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Sakuma, Chisato; Sato, Mitsuru; Oshima, Takuma; Takenouchi, Takato; Chiba, Joe; Kitani, Hiroshi

2015-01-01

Wiskott-Aldrich syndrome protein (WASP) is an adaptor molecule in immune cells. Recently, we showed that the WASP N-terminal domain interacted with the SH3 domain of Bruton's tyrosine kinase (Btk), and that the complex formed by WASP and Btk was important for TLR2 and TLR4 signaling in macrophages. Several other studies have shown that Btk played important roles in modulating innate immune responses through TLRs in immune cells. Here, we evaluated the significance of the interaction between WASP and Btk in TLR3, TLR7, and TLR9 signaling. We established bone marrow–derived macrophage cell lines from transgenic (Tg) mice that expressed intracellular antibodies (intrabodies) that specifically targeted the WASP N-terminal domain. One intrabody comprised the single-chain variable fragment and the other comprised the light-chain variable region single domain of an anti-WASP N-terminal monoclonal antibody. Both intrabodies inhibited the specific interaction between WASP and Btk, which impaired the expression of TNF-α, IL-6, and IL-1β in response to TLR3, TLR7, or TLR9 stimulation. Furthermore, the intrabodies inhibited the phosphorylation of both nuclear factor (NF)-κB and WASP in response to TLR3, TLR7, or TLR9 stimulation, in the Tg bone marrow-derived macrophages. These results suggested that WASP plays important roles in TLR3, TLR7, and TLR9 signaling by associating with Btk in macrophages. - Highlights: • The interaction between WASP and Btk is critical for TLR3, TLR7, and TLR9 signaling. • Anti-WASP intrabodies inhibited several TLR pathways that led to cytokine expression. • Phosphorylation of NF-κB via TLR signaling was inhibited by anti-WASP intrabodies. • WASP phosphorylation via several TLR ligands was inhibited by anti-WASP intrabodies

Anti-WASP intrabodies inhibit inflammatory responses induced by Toll-like receptors 3, 7, and 9, in macrophages

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Sakuma, Chisato [Animal Immune and Cell Biology Research Unit, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki, 305-8634 (Japan); Sato, Mitsuru, E-mail: mitsuru.sato@affrc.go.jp [Animal Immune and Cell Biology Research Unit, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki, 305-8634 (Japan); Oshima, Takuma [Department of Biological Science and Technology, Graduate School of Faculty of Industrial Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510 (Japan); Takenouchi, Takato [Animal Immune and Cell Biology Research Unit, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki, 305-8634 (Japan); Chiba, Joe [Department of Biological Science and Technology, Graduate School of Faculty of Industrial Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba, 278-8510 (Japan); Kitani, Hiroshi [Animal Immune and Cell Biology Research Unit, National Institute of Agrobiological Sciences, 1-2 Ohwashi, Tsukuba, Ibaraki, 305-8634 (Japan)

2015-02-27

Wiskott-Aldrich syndrome protein (WASP) is an adaptor molecule in immune cells. Recently, we showed that the WASP N-terminal domain interacted with the SH3 domain of Bruton's tyrosine kinase (Btk), and that the complex formed by WASP and Btk was important for TLR2 and TLR4 signaling in macrophages. Several other studies have shown that Btk played important roles in modulating innate immune responses through TLRs in immune cells. Here, we evaluated the significance of the interaction between WASP and Btk in TLR3, TLR7, and TLR9 signaling. We established bone marrow–derived macrophage cell lines from transgenic (Tg) mice that expressed intracellular antibodies (intrabodies) that specifically targeted the WASP N-terminal domain. One intrabody comprised the single-chain variable fragment and the other comprised the light-chain variable region single domain of an anti-WASP N-terminal monoclonal antibody. Both intrabodies inhibited the specific interaction between WASP and Btk, which impaired the expression of TNF-α, IL-6, and IL-1β in response to TLR3, TLR7, or TLR9 stimulation. Furthermore, the intrabodies inhibited the phosphorylation of both nuclear factor (NF)-κB and WASP in response to TLR3, TLR7, or TLR9 stimulation, in the Tg bone marrow-derived macrophages. These results suggested that WASP plays important roles in TLR3, TLR7, and TLR9 signaling by associating with Btk in macrophages. - Highlights: • The interaction between WASP and Btk is critical for TLR3, TLR7, and TLR9 signaling. • Anti-WASP intrabodies inhibited several TLR pathways that led to cytokine expression. • Phosphorylation of NF-κB via TLR signaling was inhibited by anti-WASP intrabodies. • WASP phosphorylation via several TLR ligands was inhibited by anti-WASP intrabodies.

Cytokine response patterns in severe pandemic 2009 H1N1 and seasonal influenza among hospitalized adults.

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Nelson Lee

Full Text Available BACKGROUND: Studying cytokine/chemokine responses in severe influenza infections caused by different virus subtypes may improve understanding on pathogenesis. METHODS: Adults hospitalized for laboratory-confirmed seasonal and pandemic 2009 A/H1N1 (pH1N1 influenza were studied. Plasma concentrations of 13 cytokines/chemokines were measured at presentation and then serially, using cytometric-bead-array with flow-cytometry and ELISA. PBMCs from influenza patients were studied for cytokine/chemokine expression using ex-vivo culture (Whole Blood Assay,±PHA/LPS stimulation. Clinical variables were prospectively recorded and analyzed. RESULTS: 63 pH1N1 and 53 seasonal influenza patients were studied. pH1N1 patients were younger (mean±S.D. 42.8±19.2 vs 70.5±16.7 years, and fewer had comorbidities. Respiratory/cardiovascular complications were common in both groups (71.4% vs 81.1%, although severe pneumonia with hypoxemia (54.0% vs 28.3% and ICU admissions (25.4% vs 1.9% were more frequent with pH1N1. Hyperactivation of the proinflammatory cytokines IL-6, CXCL8/IL-8, CCL2/MCP-1 and sTNFR-1 was found in pH1N1 pneumonia (2-15 times normal and in complicated seasonal influenza, but not in milder pH1N1 infections. The adaptive-immunity (Th1/Th17-related CXCL10/IP-10, CXCL9/MIG and IL-17A however, were markedly suppressed in severe pH1N1 pneumonia (2-27 times lower than seasonal influenza; P-values<0.01. This pattern was further confirmed with serial measurements. Hypercytokinemia tended to be sustained in pH1N1 pneumonia, associated with a slower viral clearance [PCR-negativity: day 3-4, 55% vs 85%; day 6-7, 67% vs 100%]. Elevated proinflammatory cytokines, particularly IL-6, predicted ICU admission (adjusted OR 12.6, 95%CI 2.6-61.5, per log(10unit increase; P = 0.002, and correlated with fever, tachypnoea, deoxygenation, and length-of-stay (Spearman's rho, P-values<0.01 in influenza infections. PBMCs in seasonal influenza patients were activated and

Regulation of human cytokines by Cordyceps militaris

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Yong Sun

2014-12-01

Full Text Available Cordyceps (Cordyceps militaris exhibits many biological activities including antioxidant, inhibition of inflammation, cancer prevention, hypoglycemic, and antiaging properties, etc. However, a majority of studies involving C. militaris have focused only on in vitro and animal models, and there is a lack of direct translation and application of study results to clinical practice (e.g., health benefits. In this study, we investigated the regulatory effects of C. militaris micron powder (3 doses on the human immune system. The study results showed that administration of C. militaris at various dosages reduced the activity of cytokines such as eotaxin, fibroblast growth factor-2, GRO, and monocyte chemoattractant protein-1. In addition, there was a significant decrease in the activity of various cytokines, including GRO, sCD40L, and tumor necrosis factor-α, and a significant downregulation of interleukin-12(p70, interferon-γ inducible protein 10, and macrophage inflammatory protein-1β activities, indicating that C. militaris at all three dosages downregulated the activity of cytokines, especially inflammatory cytokines and chemokines. Different dosages of C. militaris produced different changes in cytokines.

Angiogenic Factors and Cytokines in Diabetic Retinopathy

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Abcouwer, Steven F.

2013-01-01

Diabetic retinopathy (DR) is a sight-threatening complication of both type-1 and type-2 diabetes. The recent success of treatments inhibiting the function of vascular endothelial growth factor (VEGF) demonstrates that specific targeting of a growth factor responsible for vascular permeability and growth is an effective means of treating DR-associated vascular dysfunction, edema and angiogenesis. This has stimulated research of alternative therapeutic targets involved in the control of retinal vascular function. However, additional treatment options and preventative measures are still needed and these require a greater understanding of the pathological mechanisms leading to the disturbance of retinal tissue homeostasis in DR. Although severe DR can be treated as a vascular disease, abundant data suggests that inflammation is also occurring in the diabetic retina.Thus, anti-inflammatory therapies may also be useful for treatment and prevention of DR. Herein, the evidence for altered expression of angiogenic factors and cytokines in DR is reviewed and possible mechanisms by which the expression of VEGF and cytokines may be increased in the diabetic retina are examined. In addition, the potential role for microglial activation in diabetic retinal neuroinflammation is explored. PMID:24319628

Andrographolide Inhibits Inflammatory Cytokines Secretion in LPS-Stimulated RAW264.7 Cells through Suppression of NF-κB/MAPK Signaling Pathway.

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Li, Yu; He, Shengnan; Tang, Jishun; Ding, Nana; Chu, Xiaoyan; Cheng, Lianping; Ding, Xuedong; Liang, Ting; Feng, Shibin; Rahman, Sajid Ur; Wang, Xichun; Wu, Jinjie

2017-01-01

Andrographolide, the main active component extracted from Andrographis paniculata (Burm.f.) Wall. ex Nees, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the molecular mechanisms of Andrographolide in modifying lipopolysaccharide- (LPS-) induced signaling pathway in RAW264.7 cells. An in vitro model of inflammation was induced by LPS in mouse RAW264.7 cells in the presence of Andrographolide. The concentration and expression levels of proinflammatory cytokines were determined by an enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. The nuclear level of NF- κ B was measured by an electrophoretic mobility shift assay (EMSA). The expression levels of NF- κ B, p38, ERK, and JNK were determined by western blot. Andrographolide dose-dependently inhibited the release and mRNA expression of TNF- α , IL-6, and IL-1 β in LPS-stimulated RAW264.7 cells. The nuclear level of p65 protein was decreased in Andrographolide treatment group. Western blot analysis showed that Andrographolide suppressed LPS-induced NF- κ B activation and the phosphorylation of IkBa, ERK1/2, JNK, and p38. These results suggest that Andrographolide exerts an anti-inflammatory effect by inhibiting the activation of NF- κ B/MAPK signaling pathway and the induction of proinflammatory cytokines.

Andrographolide Inhibits Inflammatory Cytokines Secretion in LPS-Stimulated RAW264.7 Cells through Suppression of NF-κB/MAPK Signaling Pathway

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Yu Li

2017-01-01

Full Text Available Andrographolide, the main active component extracted from Andrographis paniculata (Burm.f. Wall. ex Nees, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the molecular mechanisms of Andrographolide in modifying lipopolysaccharide- (LPS- induced signaling pathway in RAW264.7 cells. An in vitro model of inflammation was induced by LPS in mouse RAW264.7 cells in the presence of Andrographolide. The concentration and expression levels of proinflammatory cytokines were determined by an enzyme-linked immunosorbent assay (ELISA and quantitative real-time polymerase chain reaction (qRT-PCR, respectively. The nuclear level of NF-κB was measured by an electrophoretic mobility shift assay (EMSA. The expression levels of NF-κB, p38, ERK, and JNK were determined by western blot. Andrographolide dose-dependently inhibited the release and mRNA expression of TNF-α, IL-6, and IL-1β in LPS-stimulated RAW264.7 cells. The nuclear level of p65 protein was decreased in Andrographolide treatment group. Western blot analysis showed that Andrographolide suppressed LPS-induced NF-κB activation and the phosphorylation of IkBa, ERK1/2, JNK, and p38. These results suggest that Andrographolide exerts an anti-inflammatory effect by inhibiting the activation of NF-κB/MAPK signaling pathway and the induction of proinflammatory cytokines.

Sulfur mustard primes human neutrophils for increased degranulation and stimulates cytokine release via TRPM2/p38 MAPK signaling

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Ham, Hwa-Yong [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of); Hong, Chang-Won, E-mail: chyj7983@hallym.ac.kr [Department of Chemical and Biological Warfare Research, The Armed Forces Medical Research Institute, Daejeon (Korea, Republic of); Lee, Si-Nae [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of); Kwon, Min-Soo [Department of Pharmacology, School of Medicine, CHA University, Seongnam (Korea, Republic of); Kim, Yeon-Ja [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of); Song, Dong-Keun, E-mail: dksong@hallym.ac.kr [Department of Pharmacology, Infectious Diseases Medical Research Center, College of Medicine, Hallym University, Chuncheon (Korea, Republic of)

2012-01-01

Sulfur mustard (2,2′-bis-chloroethyl-sulfide; SM) has been a military threat since the World War I. The emerging threat of bioterrorism makes SM a major threat not only to military but also to civilian world. SM injury elicits an inflammatory response characterized by infiltration of neutrophils. Although SM was reported to prime neutrophils, the mechanism has not been identified yet. In the present study, we investigated the mechanism of SM-induced priming in human neutrophils. SM increased [Ca{sup 2+}]{sub i} in human neutrophils in a concentration-dependent fashion. Transient receptor potential melastatin (TRPM) 2 inhibitors (clotrimazole, econazole and flufenamic acid) and silencing of TRPM2 by shRNA attenuated SM-induced [Ca{sup 2+}]{sub i} increase. SM primed degranulation of azurophil and specific granules in response to activation by fMLP as previously reported. SB203580, an inhibitor of p38 MAPK, inhibited SM-induced priming. Neither PD98057, an ERK inhibitor, nor SP600215, a JNK inhibitor, inhibited SM-induced priming. In addition, SM enhanced phosphorylation of NF-kB p65 and release of TNF-α, interleukin (IL)-6 and IL-8. SB203580 inhibited SM-induced NF-kB phosphorylation and cytokine release. These results suggest the involvement of TRPM2/p38 MAPK pathway in SM-induced priming and cytokines release in neutrophils. -- Highlights: ► SM increased [Ca{sup 2+}]{sub i} in human neutrophils through TPRM2-mediated calcium influx. ► SM primed degranulation of azurophil and specific granules. ► SM enhanced p38 MAPK and NF-κB p65 phosphorylation in human neutrophils. ► SM enhanced release of TNF-α, interleukin (IL)-6 and IL-8 from human neutrophils. ► SB203580 inhibited SM-induced priming, NF-κB p65 phosphorylation and cytokine release.

The role of factor inhibiting HIF (FIH-1 in inhibiting HIF-1 transcriptional activity in glioblastoma multiforme.

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Enfeng Wang

Full Text Available Glioblastoma multiforme (GBM accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1, which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF-mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis.

Biphasic Effect of Curcumin on Morphine Tolerance: A Preliminary Evidence from Cytokine/Chemokine Protein Array Analysis

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Jui-An Lin

2011-01-01

Full Text Available The aim of this study was to evaluate the effect of curcumin on morphine tolerance and the corresponding cytokine/chemokine changes. Male ICR mice were made tolerant to morphine by daily subcutaneous injection for 7 days. Intraperitoneal injections of vehicle, low-dose or high-dose curcumin were administered 15 min after morphine injection, either acutely or chronically for 7 days to test the effect of curcumin on morphine-induced antinociception and development of morphine tolerance. On day 8, cumulative dose-response curves were generated and the 50% of maximal analgesic dose values were calculated and compared among groups. Corresponding set of mice were used for analyzing the cytokine responses by antibody-based cytokine protein array. Acute, high-dose curcumin enhanced morphine-induced antinociception. While morphine tolerance was attenuated by administration of low-dose curcumin following morphine injections for 7 days, it was aggravated by chronic high-dose curcumin following morphine injection, suggesting a biphasic effect of curcumin on morphine-induced tolerance. Of the 96 cytokine/chemokines analyzed by mouse cytokine protein array, 14 cytokines exhibited significant changes after the different 7-day treatments. Mechanisms for the modulatory effects of low-dose and high-dose curcumin on morphine tolerance were discussed. Even though curcumin itself is a neuroprotectant and low doses of the compound serve to attenuate morphine tolerance, high-doses of curcumin might cause neurotoxicity and aggravate morphine tolerance by inhibiting the expression of antiapoptotic cytokines and neuroprotective factors. Our results indicate that the effect of curcumin on morphine tolerance may be biphasic, and therefore curcumin should be used cautiously.

Behavioral inhibition in rhesus monkeys (Macaca mulatta is related to the airways response, but not immune measures, commonly associated with asthma.

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Katie Chun

Full Text Available Behavioral inhibition reflects a disposition to react warily to novel situations, and has been associated with atopic diseases such as asthma. Retrospective work established the relationship between behavioral inhibition in rhesus monkeys (Macaca mulatta and airway hyperresponsiveness, but not atopy, and the suggestion was made that behavioral inhibition might index components of asthma that are not immune-related. In the present study, we prospectively examined the relationship between behavioral inhibition and airway hyperresponsiveness, and whether hormonal and immune measures often associated with asthma were associated with behavioral inhibition and/or airway hyperresponsiveness. In a sample of 49 yearling rhesus monkeys (mean=1.25 years, n=24 behaviorally inhibited animals, we measured in vitro cytokine levels (IL-4, IL-10, IL-12, IFN-γ in response to stimulation, as well as peripheral blood cell percentages, cortisol levels, and percentage of regulatory T-cells (CD3+CD4+CD25+FOXP3+. Airway reactivity was assessed using an inhaled methacholine challenge. Bronchoalveolar lavage was performed and the proportion of immune cells was determined. Behaviorally inhibited monkeys had airway hyperresponsiveness as indicated by the methacholine challenge (p=0.031, confirming our earlier retrospective result. Airway hyperresponsiveness was also associated with lower lymphocyte percentages in lavage fluid and marginally lower plasma cortisol concentrations. However, none of the tested measures was significantly related to both behavioral inhibition and airway hyperresponsiveness, and so could not mediate their relationship. Airway hyperresponsiveness is common to atopic and non-atopic asthma and behavioral inhibition has been related to altered autonomic activity in other studies. Our results suggest that behavioral inhibition might index an autonomically mediated reactive airway phenotype, and that a variety of stimuli (including inflammation within

Cytokines in tears during the secondary keratoconjunctival responses induced by allergic reaction in the nasal mucosa.

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Pelikan, Zdenek

2014-01-01

Allergic keratoconjunctivitis (KC) can occur in a primary form due to an allergic reaction taking place in the conjunctivae or in a secondary form induced by nasal allergy. To search for the cytokine changes in tears accompanying the secondary keratoconjunctival response types (SKCR), caused by the nasal allergy. In 43 KC patients developing 15 immediate (SIKCR), 16 late (SLKCR) and 12 delayed (SDYKCR) responses to nasal provocation tests with allergens (NPT), the NPTs were repeated with subsequent recording of cytokine concentrations in tears up to 72 h. The SIKCRs (ptears, suggesting involvement of different hypersensitivity mechanisms. These results also stress the diagnostic usefulness of NPTs combined with monitoring of ocular features in KC patients who did not respond satisfactorily to the topical ophthalmological treatment. © 2014 S. Karger AG, Basel.

Pro-inflammatory Cytokine Response and Genetic Diversity in Merozoite Surface Protein 2 of Plasmodium falciparum Isolates from Nigeria.

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Ajibaye, Olusola; Osuntoki, Akinniyi A; Ebuehi, Albert Ot; Iwalokun, Bamidele A; Balogun, Emmanuel O; Egbuna, Kathleen N

2017-01-01

Polymorphisms in Plasmodium falciparum merozoite surface protein-2 ( msp -2) and associated parasite genetic diversity which varies between malaria-endemic regions remain a limitation in malaria vaccine development. Pro-inflammatory cytokines are important in immunity against malaria, understanding the influence of genetic diversity on cytokine response is important for effective vaccine design. P. falciparum isolates obtained from 300 Nigerians with uncomplicated falciparum malaria at Ijede General Hospital, Ijede (IJE), General Hospital Ajeromi, Ajeromi (AJE) and Saint Kizito Mission Hospital, Lekki, were genotyped by nested polymerase chain reaction of msp -2 block 3 while ELISA was used to determine the pro-inflammatory cytokine response to describe the genetic diversity of P. falciparum . Eighteen alleles were observed for msp -2 loci. Of the 195 isolates, 61 (31.0%) had only FC27-type alleles, 38 (19.7%) had only 3D7-type alleles, and 49.3% had multiple parasite lines with both alleles. Band sizes were 275-625 bp for FC27 and 150-425 bp for 3D7. Four alleles were observed from LEK, 2 (375-425 bp) and 2 (275-325 bp) of FC27-and 3D7-types, respectively; 12 alleles from AJE, 9 (275-625 bp) and 3 (325-425 bp) of FC27-types and 3D7-types, respectively; while IJE had a total of 12 alleles, 9 (275-625 bp) and 3 (325-425 bp) of FC27-types and 3D7-types, respectively. Mean multiplicity of infection (MOI) was 1.54. Heterozygosity ( H E ) ranged from 0.77 to 0.87 and was highest for IJE (0.87). Cytokine response was higher among 0.05) but with neither parasite density nor infection type. P. falciparum genetic diversity is extensive in Nigeria, protection via pro-inflammatory cytokines have little or no interplay with infection multiplicity.

Comparison of cytokine immune responses to Brucella abortus and Yersinia enterocolitica serotype O:9 infections in BALB/c mice.

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Gu, Wenpeng; Wang, Xin; Qiu, Haiyan; Cui, Buyun; Zhao, Shiwen; Zheng, Han; Xiao, Yuchun; Liang, Junrong; Duan, Ran; Jing, Huaiqi

2013-12-01

Brucella abortus and Yersinia enterocolitica serotype O:9 serologically cross-react in the immune response with the host; therefore, our aim was to compare the immune responses to these two pathogens. We selected typical B. abortus and Y. enterocolitica O:9 strains to study the cytokine immune response and the histopathological changes in livers and spleens of BALB/c mice. The data showed the cytokine responses to the two strains of pathogens were different, where the average levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma interferon (IFN-γ), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNF-α) were higher with B. abortus infections than with Y. enterocolitica O:9 infections, especially for IFN-γ, while the IL-10 level was lower and the levels of IL-1β, IL-4, IL-5, and IL-6 were similar. The histopathological effects in the livers and spleens of the BALB/c mice with B. abortus and Y. enterocolitica O:9 infections were similar; however, the pathological changes in the liver were greater with B. abortus infections, while damage in the spleen was greater with Y. enterocolitica O:9 infections. These observations show that different cytokine responses and histopathological changes occur with B. abortus and Y. enterocolitica O:9 infections.

Antibody-cytokine fusion proteins for treatment of cancer: engineering cytokines for improved efficacy and safety.

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Young, Patricia A; Morrison, Sherie L; Timmerman, John M

2014-10-01

The true potential of cytokine therapies in cancer treatment is limited by the inability to deliver optimal concentrations into tumor sites due to dose-limiting systemic toxicities. To maximize the efficacy of cytokine therapy, recombinant antibody-cytokine fusion proteins have been constructed by a number of groups to harness the tumor-targeting ability of monoclonal antibodies. The aim is to guide cytokines specifically to tumor sites where they might stimulate more optimal anti-tumor immune responses while avoiding the systemic toxicities of free cytokine therapy. Antibody-cytokine fusion proteins containing interleukin (IL)-2, IL-12, IL-21, tumor necrosis factor (TNF)α, and interferons (IFNs) α, β, and γ have been constructed and have shown anti-tumor activity in preclinical and early-phase clinical studies. Future priorities for development of this technology include optimization of tumor targeting, bioactivity of the fused cytokine, and choice of appropriate agents for combination therapies. This review is intended to serve as a framework for engineering an ideal antibody-cytokine fusion protein, focusing on previously developed constructs and their clinical trial results. Copyright © 2014 Elsevier Inc. All rights reserved.

Protection against inflammatory β-cell damage by lysine deacetylase inhibition and microRNA expression?

DEFF Research Database (Denmark)

Vestergaard, Anna Lindeløv; Pallesen, Emil Marek Heymans; Novotny, Guy Wayne

Background and aims: Pro-inflammatory cytokines contribute to pancreatic β-cell apoptosis in type 1 and 2 diabetes mellitus. The detrimental effects resulting from cytokine-induced signaling in the β cell can be reduced by inhibition of class I classical lysine deacetylases (KDACi), especially HDAC...... of oxidative stress proteins responsible for β-cell death. The aim of the study is to identify novel and specific therapeutic targets for β-cell protection by mapping the miR profile of β cells rescued from inflammatory assault by inhibition of lysine deacetylation, thereby identifying miR that repress....... The perspective of this study is to develop novel anti-diabetic drugs targeting HDAC1 and/or associated miR....

Atractylenolide I restores HO-1 expression and inhibits Ox-LDL-induced VSMCs proliferation, migration and inflammatory responses in vitro

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Li, Weifeng, E-mail: liwf@mail.xjtu.edu.cn; Zhi, Wenbing; Liu, Fang; He, Zehong; Wang, Xiuei; Niu, Xiaofeng, E-mail: niuxf@mail.xjtu.edu.cn

2017-04-01

Pathogenesis of atherosclerosis is characterized by the proliferation and migration of vascular smooth muscle cells (VSMCs) and inflammatory lesions. The aim of this study is to elucidate the effect of atractylenolide I (AO-I) on smooth muscle cell inflammation, proliferation and migration induced by oxidized modified low density lipoprotein (Ox-LDL). Here, We found that atractylenolide I inhibited Ox-LDL-induced VSMCs proliferation and migration in a dose-dependent manner, and decreased the production of inflammatory cytokines and the expression of monocyte chemoattractant protein-1 (MCP-1) in VSMCs. The study also identified that AO-I prominently inhibited p38-MAPK and NF-κB activation. More importantly, the specific heme oxygenase-1 (HO-1) inhibitor zinc protoporphyrin (ZnPP) IX partially abolished the beneficial effects of atractylenolide I on Ox-LDL-induced VSMCs. Furthermore, atractylenolide I blocked the foam cell formation in macrophages induced by Ox-LDL. In summary, inhibitory roles of AO-I in VSMCs proliferation and migration, lipid peroxidation and subsequent inflammatory responses might contribute to the anti-atherosclerotic property of AO-I. - Highlights: • AO-I inhibited Ox-LDL-induced VSMCs proliferation and migration. • AO-I alleviated inflammatory response via inhibiting TNF-α, IL-6 and NO production. • AO-I restored HO-1 expression and down-regulated PCNA expression. • MCP-1 overexpression is potentially regulated by NF-κB and p38 MAPK pathway. • AO-I possesses strong anti-lipid peroxidation effect.

Cytokine responses to the anti-schistosome vaccine candidate antigen glutathione-S-transferase vary with host age and are boosted by praziquantel treatment.

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Claire D Bourke

2014-05-01

Full Text Available Improved helminth control is required to alleviate the global burden of schistosomiasis and schistosome-associated pathologies. Current control efforts rely on the anti-helminthic drug praziquantel (PZQ, which enhances immune responses to crude schistosome antigens but does not prevent re-infection. An anti-schistosome vaccine based on Schistosoma haematobium glutathione-S-transferase (GST is currently in Phase III clinical trials, but little is known about the immune responses directed against this antigen in humans naturally exposed to schistosomes or how these responses change following PZQ treatment.Blood samples from inhabitants of a Schistosoma haematobium-endemic area were incubated for 48 hours with or without GST before (n = 195 and six weeks after PZQ treatment (n = 107. Concentrations of cytokines associated with innate inflammatory (TNFα, IL-6, IL-8, type 1 (Th1; IFNγ, IL-2, IL-12p70, type 2 (IL-4, IL-5, IL-13, type 17 (IL-17A, IL-21, IL-23p19 and regulatory (IL-10 responses were quantified in culture supernatants via enzyme-linked immunosorbent assay (ELISA. Factor analysis and multidimensional scaling were used to analyse multiple cytokines simultaneously.A combination of GST-specific type 2 (IL-5 and IL-13 and regulatory (IL-10 cytokines was significantly lower in 10-12 year olds, the age group at which S. haematobium infection intensity and prevalence peak, than in 4-9 or 13+ year olds. Following PZQ treatment there was an increase in the number of participants producing detectable levels of GST-specific cytokines (TNFα, IL-6, IL-8, IFNγ, IL-12p70, IL-13 and IL-23p19 and also a shift in the GST-specific cytokine response towards a more pro-inflammatory phenotype than that observed before treatment. Participant age and pre-treatment infection status significantly influenced post-treatment cytokine profiles.In areas where schistosomiasis is endemic host age, schistosome infection status and PZQ treatment affect the

Proinflammatory Cytokine Responses in Extra-Respiratory Tissues During Severe Influenza

NARCIS (Netherlands)

Short, Kirsty R; Veeris, Rebecca; Leijten, Lonneke M; van den Brand, Judith M; Jong, Victor L; Stittelaar, Koert J; Osterhaus, Ab D M E|info:eu-repo/dai/nl/074960172; Andeweg, Arno C; van Riel, Debby

2017-01-01

Severe influenza is often associated with disease manifestations outside the respiratory tract. While proinflammatory cytokines can be detected in the lungs and blood of infected patients, the role of extra-respiratory organs in the production of proinflammatory cytokines is unknown. Here, we show

Proinflammatory Cytokine Responses in Extra-Respiratory Tissues during Severe Influenza

NARCIS (Netherlands)

Short, Kirsty R.; Veeris, Rebecca; Leijten, Lonneke M.; van den Brand, Judith M A; Jong, Victor L.; Stittelaar, Koert; Osterhaus, Ab D.M.E.; Andeweg, Arno C; Van Riel, Debby

2017-01-01

Severe influenza is often associated with disease manifestations outside the respiratory tract. While proinflammatory cytokines can be detected in the lungs and blood of infected patients, the role of extra-respiratory organs in the production of proinflammatory cytokines is unknown. Here, we show

DNA methylation differentially regulates cytokine secretion in gingival epithelia in response to bacterial challenges.

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Drury, Jeanie L; Chung, Whasun Oh

2015-03-01

Epigenetic modifications are changes in gene expression without altering DNA sequence. We previously reported that bacteria-specific innate immune responses are regulated by epigenetic modifications. Our hypothesis is that DNA methylation affects gingival cytokine secretion in response to bacterial stimulation. Gingival epithelial cells (GECs) were treated with DNMT-1 inhibitors prior to Porphyromonas gingivalis (Pg) or Fusobacterium nucleatum (Fn) exposure. Protein secretion was assessed using ELISA. Gene expression was quantified using qRT-PCR. The ability of bacteria to invade inhibitor pretreated GECs was assessed utilizing flow cytometry. Changes were compared to unstimulated GECs. GEC upregulation of IL-6 and CXCL1 by Pg or Fn stimulation was significantly diminished by inhibitor pretreatment. Pg stimulated IL-1α secretion and inhibitor pretreatment significantly enhanced this upregulation, while Fn alone or with inhibitor pretreatment had no effect on IL-1α expression. GEC upregulation of human beta-definsin-2 in response to Pg and Fn exposure was enhanced following the inhibitor pretreatment. GEC susceptibility to bacterial invasion was unaltered. These results suggest that DNA methylation differentially affects gingival cytokine secretion in response to Pg or Fn. Our data provide basis for better understanding of how epigenetic modifications, brought on by exposure to oral bacteria, will subsequently affect host susceptibility to oral diseases. © FEMS 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Ginger extract inhibits LPS induced macrophage activation and function

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Bruch David

2008-01-01

Full Text Available Abstract Background Macrophages play a dual role in host defence. They act as the first line of defence by mounting an inflammatory response to antigen exposure and also act as antigen presenting cells and initiate the adaptive immune response. They are also the primary infiltrating cells at the site of inflammation. Inhibition of macrophage activation is one of the possible approaches towards modulating inflammation. Both conventional and alternative approaches are being studied in this regard. Ginger, an herbal product with broad anti inflammatory actions, is used as an alternative medicine in a number of inflammatory conditions like rheumatic disorders. In the present study we examined the effect of ginger extract on macrophage activation in the presence of LPS stimulation. Methods Murine peritoneal macrophages were stimulated by LPS in presence or absence of ginger extract and production of proinflammatory cytokines and chemokines were observed. We also studied the effect of ginger extract on the LPS induced expression of MHC II, B7.1, B7.2 and CD40 molecules. We also studied the antigen presenting function of ginger extract treated macrophages by primary mixed lymphocyte reaction. Results We observed that ginger extract inhibited IL-12, TNF-α, IL-1β (pro inflammatory cytokines and RANTES, MCP-1 (pro inflammatory chemokines production in LPS stimulated macrophages. Ginger extract also down regulated the expression of B7.1, B7.2 and MHC class II molecules. In addition ginger extract negatively affected the antigen presenting function of macrophages and we observed a significant reduction in T cell proliferation in response to allostimulation, when ginger extract treated macrophages were used as APCs. A significant decrease in IFN-γ and IL-2 production by T cells in response to allostimulation was also observed. Conclusion In conclusion ginger extract inhibits macrophage activation and APC function and indirectly inhibits T cell activation.

Curcumin ameliorates macrophage infiltration by inhibiting NF-κB activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy

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Suzuki Kenji

2011-06-01

Full Text Available Abstract Background Chronic inflammation plays an important role in the progression of diabetic nephropathy (DN and that the infiltration of macrophages in glomerulus has been implicated in the development of glomerular injury. We hypothesized that the plant polyphenolic compound curcumin, which is known to exert potent anti-inflammatory effect, would ameliorate macrophage infiltration in streptozotocin (STZ-induced diabetic rats. Methods Diabetes was induced with STZ (55 mg/kg by intraperitoneal injection in rats. Three weeks after STZ injection, rats were divided into three groups, namely, control, diabetic, and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 weeks. The rats were sacrificed 11 weeks after induction of diabetes. The excised kidney was used to assess macrophage infiltration and expression of various inflammatory markers. Results At 11 weeks after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, blood urea nitrogen and proteinuria, along with marked reduction in the body weight. All of these abnormalities were significantly reversed by curcumin. Hyperglycemia induced the degradation of IκBα and NF-κB activation and as a result increased infiltration of macrophages (52% as well as increased proinflammatory cytokines: TNF-α and IL-1β. Curcumin treatment significantly reduced macrophage infiltration in the kidneys of diabetic rats, suppressed the expression of above proinflammatory cytokines and degradation of IκBα. In addition, curcumin treatment also markedly decreased ICAM-1, MCP-1 and TGF-β1 protein expression. Moreover, at nuclear level curcumin inhibited the NF-κB activity. Conclusion Our results suggested that curcumin treatment protect against the development of DN in rats by reducing macrophage infiltration through the inhibition of NF-κB activation in STZ-induced diabetic rats.

Regulation of human cytokines by Cordyceps militaris.

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Sun, Yong; Shao, Yani; Zhang, Zhiguo; Wang, Lianfen; Mariga, Alfred M; Pang, Guangchang; Geng, Chaoyu; Ho, Chi-Tang; Hu, Qiuhui; Zhao, Liyan

2014-12-01

Cordyceps (Cordyceps militaris) exhibits many biological activities including antioxidant, inhibition of inflammation, cancer prevention, hypoglycemic, and antiaging properties, etc. However, a majority of studies involving C. militaris have focused only on in vitro and animal models, and there is a lack of direct translation and application of study results to clinical practice (e.g., health benefits). In this study, we investigated the regulatory effects of C. militaris micron powder (3 doses) on the human immune system. The study results showed that administration of C. militaris at various dosages reduced the activity of cytokines such as eotaxin, fibroblast growth factor-2, GRO, and monocyte chemoattractant protein-1. In addition, there was a significant decrease in the activity of various cytokines, including GRO, sCD40L, and tumor necrosis factor-α, and a significant downregulation of interleukin-12(p70), interferon-γ inducible protein 10, and macrophage inflammatory protein-1β activities, indicating that C. militaris at all three dosages downregulated the activity of cytokines, especially inflammatory cytokines and chemokines. Different dosages of C. militaris produced different changes in cytokines. Copyright © 2014. Published by Elsevier B.V.

Cytokine profile of cervical cancer cells

NARCIS (Netherlands)

Hazelbag, S; Fleuren, GJ; Baelde, JJ; Schuuring, E; Kenter, GG; Gorter, A

2001-01-01

Objective. In patients with cervical carcinoma, the presence of cytokines produced by T(H)2 cells, and the presence of an eosinophilic inflammatory infiltrate, has been associated with a less effective immune response and tumor progression. In the present study, we have investigated the cytokine

Cytokine profile of cervical cancer cells

NARCIS (Netherlands)

Hazelbag, S; Fleuren, GJ; Baelde, JJ; Schuuring, E; Kenter, GG; Gorter, A

Objective. In patients with cervical carcinoma, the presence of cytokines produced by T(H)2 cells, and the presence of an eosinophilic inflammatory infiltrate, has been associated with a less effective immune response and tumor progression. In the present study, we have investigated the cytokine

Neural Correlates of Response Inhibition and Conflict Control on Facial Expressions

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Tongran Liu

2018-01-01

Full Text Available Response inhibition and conflict control on affective information can be regarded as two important emotion regulation and cognitive control processes. The emotional Go/Nogo flanker paradigm was adopted and participant’s event-related potentials (ERPs were analyzed to investigate how response inhibition and conflict control interplayed. The behavioral findings revealed that participants showed higher accuracy to identify happy faces in congruent condition relative to that in incongruent condition. The electrophysiological results manifested that response inhibition and conflict control interplayed during the detection/conflict monitoring stage, and Nogo-N2 was more negative in the incongruent trials than the congruent trials. With regard to the inhibitory control/conflict resolution stage, Nogo responses induced greater frontal P3 and parietal P3 responses than Go responses did. The difference waveforms of N2 and parietal P3 showed that response inhibition and conflict control had distinct processes, and the multiple responses requiring both conflict control and response inhibition processes induced stronger monitoring and resolution processes than conflict control. The current study manifested that response inhibition and conflict control on emotional information required separable neural mechanisms during emotion regulation processes.

Noninvasive optical monitoring multiple physiological parameters response to cytokine storm

Science.gov (United States)

Li, Zebin; Li, Ting

2018-02-01

Cancer and other disease originated by immune or genetic problems have become a main cause of death. Gene/cell therapy is a highlighted potential method for the treatment of these diseases. However, during the treatment, it always causes cytokine storm, which probably trigger acute respiratory distress syndrome and multiple organ failure. Here we developed a point-of-care device for noninvasive monitoring cytokine storm induced multiple physiological parameters simultaneously. Oxy-hemoglobin, deoxy-hemoglobin, water concentration and deep-tissue/tumor temperature variations were simultaneously measured by extended near infrared spectroscopy. Detection algorithms of symptoms such as shock, edema, deep-tissue fever and tissue fibrosis were developed and included. Based on these measurements, modeling of patient tolerance and cytokine storm intensity were carried out. This custom device was tested on patients experiencing cytokine storm in intensive care unit. The preliminary data indicated the potential of our device in popular and milestone gene/cell therapy, especially, chimeric antigen receptor T-cell immunotherapy (CAR-T).

Transcutaneous electrical nerve stimulation (TENS) accelerates cutaneous wound healing and inhibits pro-inflammatory cytokines.

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Gürgen, Seren Gülşen; Sayın, Oya; Cetin, Ferihan; Tuç Yücel, Ayşe

2014-06-01

The purpose of this study was to evaluate transcutaneous electrical nerve stimulation (TENS) and other common treatment methods used in the process of wound healing in terms of the expression levels of pro-inflammatory cytokines. In the study, 24 female and 24 male adult Wistar-Albino rats were divided into five groups: (1) the non-wounded group having no incision wounds, (2) the control group having incision wounds, (3) the TENS (2 Hz, 15 min) group, (4) the physiological saline (PS) group and (5) the povidone iodine (PI) group. In the skin sections, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were assessed with enzyme-linked immunosorbent assay and immunohistochemical methods. In the non-wounded group, the expression of IL-1β, IL-6, and TNF-α signaling molecules was weaker in the whole tissue; however, in the control group, significant inflammatory response occurred, and strong cytokine expression was observed in the dermis, granulation tissue, hair follicles, and sebaceous glands (P TENS group, the decrease in TNF-α, IL-1β, and IL-6 immunoreaction in the skin was significant compared to the other forms of treatment (P TENS group suggest that TENS shortened the healing process by inhibating the inflammation phase.

Poxvirus-encoded TNF decoy receptors inhibit the biological activity of transmembrane TNF.

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Pontejo, Sergio M; Alejo, Ali; Alcami, Antonio

2015-10-01

Poxviruses encode up to four different soluble TNF receptors, named cytokine response modifier B (CrmB), CrmC, CrmD and CrmE. These proteins mimic the extracellular domain of the cellular TNF receptors to bind and inhibit the activity of TNF and, in some cases, other TNF superfamily ligands. Most of these ligands are released after the enzymic cleavage of a membrane precursor. However, transmembrane TNF (tmTNF) is not only a precursor of soluble TNF but also exerts specific pro-inflammatory and immunological activities. Here, we report that viral TNF receptors bound and inhibited tmTNF and describe some interesting differences in their activity against the soluble cytokine. Thus, CrmE, which does not inhibit mouse soluble TNF, could block murine tmTNF-induced cytotoxicity. We propose that this anti-tmTNF effect should be taken into consideration when assessing the role of viral TNF decoy receptors in the pathogenesis of poxvirus.

Estradiol and Progesterone Strongly Inhibit the Innate Immune Response of Mononuclear Cells in Newborns ▿

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Giannoni, Eric; Guignard, Laurence; Knaup Reymond, Marlies; Perreau, Matthieu; Roth-Kleiner, Matthias; Calandra, Thierry; Roger, Thierry

2011-01-01

Newborns are particularly susceptible to bacterial infections due to qualitative and quantitative deficiencies of the neonatal innate immune system. However, the mechanisms underlying these deficiencies are poorly understood. Given that fetuses are exposed to high concentrations of estradiol and progesterone during gestation and at time of delivery, we analyzed the effects of these hormones on the response of neonatal innate immune cells to endotoxin, bacterial lipopeptide, and Escherichia coli and group B Streptococcus, the two most common causes of early-onset neonatal sepsis. Here we show that at concentrations present in umbilical cord blood, estradiol and progesterone are as powerful as hydrocortisone for inhibition of cytokine production by cord blood mononuclear cells (CBMCs) and newborn monocytes. Interestingly, CBMCs and newborn monocytes are more sensitive to the effects of estradiol and progesterone than adult peripheral blood mononuclear cells and monocytes. This increased sensitivity is associated with higher expression levels of estrogen and membrane progesterone receptors but is independent of a downregulation of Toll-like receptor 2 (TLR2), TLR4, and myeloid differentiation primary response gene 88 in newborn cells. Estradiol and progesterone mediate their anti-inflammatory activity through inhibition of the NF-κB pathway but not the mitogen-activated protein kinase pathway in CBMCs. Altogether, these results suggest that elevated umbilical cord blood concentrations of estradiol and progesterone acting on mononuclear cells expressing high levels of steroid receptors contribute to impair innate immune responses in newborns. Therefore, intrauterine exposure to estradiol and progesterone may participate in increasing susceptibility to infection during the neonatal period. PMID:21518785

Response to Dengue virus infections altered by cytokine-like substances from mosquito cell cultures

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Laosutthipong Chaowanee

2010-11-01

Full Text Available Abstract Background With both shrimp and commercial insects such as honey bees, it is known that stable, persistent viral infections characterized by absence of disease can sometimes shift to overt disease states as a result of various stress triggers and that this can result in serious economic losses. The main research interest of our group is to understand the dynamics of stable viral infections in shrimp and how they can be destabilized by stress. Since there are no continuous cell lines for crustaceans, we have used a C6/36 mosquito cell line infected with Dengue virus to test hypotheses regarding these interactions. As a result, we accidentally discovered two new cytokine-like substances in 5 kDa extracts from supernatant solutions of acutely and persistently infected mosquito cells. Results Naïve C6/36 cells were exposed for 48 h to 5 kDa membrane filtrates prepared from the supernatant medium of stable C6/36 mosquito cell cultures persistently-infected with Dengue virus. Subsequent challenge of naïve cells with a virulent stock of Dengue virus 2 (DEN-2 and analysis by confocal immunofluorescence microscopy using anti-DEN-2 antibody revealed a dramatic reduction in the percentage of DEN-2 infected cells when compared to control cells. Similar filtrates prepared from C6/36 cells with acute DEN-2 infections were used to treat stable C6/36 mosquito cell cultures persistently-infected with Dengue virus. Confocal immunofluorescence microscopy revealed destabilization in the form of an apoptosis-like response. Proteinase K treatment removed the cell-altering activities indicating that they were caused by small polypeptides similar to those previously reported from insects. Conclusions This is the first report of cytokine-like substances that can alter the responses of mosquito cells to Dengue virus. This simple model system allows detailed molecular studies on insect cytokine production and on cytokine activity in a standard insect cell line.

Myxovirus resistance, osteopontin and suppressor of cytokine signaling 3 polymorphisms predict hepatitis C virus therapy response in an admixed patient population: comparison with IL28B.

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Angelo, Ana Luiza Dias; Cavalcante, Lourianne Nascimento; Abe-Sandes, Kiyoko; Machado, Taísa Bonfim; Lemaire, Denise Carneiro; Malta, Fernanda; Pinho, João Renato; Lyra, Luiz Guilherme Costa; Lyra, Andre Castro

2013-10-01

Suppressor of cytokine signaling 3, myxovirus resistance protein and osteopontin gene polymorphisms may influence the therapeutic response in patients with chronic hepatitis C, and an association with IL28 might increase the power to predict sustained virologic response. Our aims were to evaluate the association between myxovirus resistance protein, osteopontin and suppressor of cytokine signaling 3 gene polymorphisms in combination with IL28B and to assess the therapy response in hepatitis C patients treated with pegylated-interferon plus ribavirin. Myxovirus resistance protein, osteopontin, suppressor of cytokine signaling 3 and IL28B polymorphisms were analyzed by PCR-restriction fragment length polymorphism, direct sequencing and real-time PCR. Ancestry was determined using genetic markers. We analyzed 181 individuals, including 52 who were sustained virologic responders. The protective genotype frequencies among the sustained virologic response group were as follows: the G/G suppressor of cytokine signaling 3 (rs4969170) (62.2%); T/T osteopontin (rs2853744) (60%); T/T osteopontin (rs11730582) (64.3%); and the G/T myxovirus resistance protein (rs2071430) genotype (54%). The patients who had ≥3 of the protective genotypes from the myxovirus resistance protein, the suppressor of cytokine signaling 3 and osteopontin had a greater than 90% probability of achieving a sustained response (pC/C IL28B genotype was present in 58.8% of the subjects in this group. The sustained virological response rates increased to 85.7% and 91.7% by analyzing C/C IL28B with the T/T osteopontin genotype at rs11730582 and the G/G suppressor of cytokine signaling 3 genotype, respectively. Genetic ancestry analysis revealed an admixed population. Hepatitis C genotype 1 patients who were responders to interferon-based therapy had a high frequency of multiple protective polymorphisms in the myxovirus resistance protein, osteopontin and suppressor of cytokine signaling 3 genes. The combined

Tumour tissue microenvironment can inhibit dendritic cell maturation in colorectal cancer.

LENUS (Irish Health Repository)

Michielsen, Adriana J

2011-01-01

Inflammatory mediators in the tumour microenvironment promote tumour growth, vascular development and enable evasion of anti-tumour immune responses, by disabling infiltrating dendritic cells. However, the constituents of the tumour microenvironment that directly influence dendritic cell maturation and function are not well characterised. Our aim was to identify tumour-associated inflammatory mediators which influence the function of dendritic cells. Tumour conditioned media obtained from cultured colorectal tumour explant tissue contained high levels of the chemokines CCL2, CXCL1, CXCL5 in addition to VEGF. Pre-treatment of monocyte derived dendritic cells with this tumour conditioned media inhibited the up-regulation of CD86, CD83, CD54 and HLA-DR in response to LPS, enhancing IL-10 while reducing IL-12p70 secretion. We examined if specific individual components of the tumour conditioned media (CCL2, CXCL1, CXCL5) could modulate dendritic cell maturation or cytokine secretion in response to LPS. VEGF was also assessed as it has a suppressive effect on dendritic cell maturation. Pre-treatment of immature dendritic cells with VEGF inhibited LPS induced upregulation of CD80 and CD54, while CXCL1 inhibited HLA-DR. Interestingly, treatment of dendritic cells with CCL2, CXCL1, CXCL5 or VEGF significantly suppressed their ability to secrete IL-12p70 in response to LPS. In addition, dendritic cells treated with a combination of CXCL1 and VEGF secreted less IL-12p70 in response to LPS compared to pre-treatment with either cytokine alone. In conclusion, tumour conditioned media strongly influences dendritic cell maturation and function.

Associations between cytokines, endocrine stress response, and gastrointestinal symptoms in autism spectrum disorder

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Ferguson, Bradley J.; Marler, Sarah; Altstein, Lily L.; Lee, Evon Batey; Mazurek, Micah O.; McLaughlin, Aaron; Macklin, Eric A.; McDonnell, Erin; Davis, Daniel J.; Belenchia, Anthony M.; Gillespie, Catherine H.; Peterson, Catherine A.; Bauman, Margaret L.; Margolis, Kara Gross; Veenstra-VanderWeele, Jeremy

2016-01-01

Many children and adolescents with autism spectrum disorder (ASD) have significant gastrointestinal (GI) symptoms, but the etiology is currently unknown. Some individuals with ASD show altered reactivity to stress and altered immune markers relative to typically-developing individuals, particularly stress-responsive cytokines including tumor necrosis factor alpha (TNF-?) and interleukin 6 (IL-6). Acute and chronic stress is associated with the onset and exacerbation of GI symptoms in those wi...

Monoethylhexyl Phthalate Elicits an Inflammatory Response in Adipocytes Characterized by Alterations in Lipid and Cytokine Pathways.

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Manteiga, Sara; Lee, Kyongbum

2017-04-01

A growing body of evidence links endocrine-disrupting chemicals (EDCs) with obesity-related metabolic diseases. While it has been shown that EDCs can predispose individuals toward adiposity by affecting developmental processes, little is known about the chemicals' effects on adult adipose tissue. Our aim was to study the effects of low, physiologically relevant doses of EDCs on differentiated murine adipocytes. We combined metabolomics, proteomics, and gene expression analysis to characterize the effects of mono-ethylhexyl phthalate (MEHP) in differentiated adipocytes. Repeated exposure to MEHP over several days led to changes in metabolite and enzyme levels indicating elevated lipogenesis and lipid oxidation. The chemical exposure also increased expression of major inflammatory cytokines, including chemotactic factors. Proteomic and gene expression analysis revealed significant alterations in pathways regulated by peroxisome proliferator activated receptor-γ (PPARγ). Inhibiting the nuclear receptor's activity using a chemical antagonist abrogated not only the alterations in PPARγ-regulated metabolic pathways, but also the increases in cytokine expression. Our results show that MEHP can induce a pro-inflammatory state in differentiated adipocytes. This effect is at least partially mediated PPARγ.

Association of O-Antigen Serotype with the Magnitude of Initial Systemic Cytokine Responses and Persistence in the Urinary Tract

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Horvath, Dennis J.; Patel, Ashay S.; Mohamed, Ahmad; Storm, Douglas W.; Singh, Chandra; Li, Birong; Zhang, Jingwen; Koff, Stephen A.; Jayanthi, Venkata R.; Mason, Kevin M.

2016-01-01

ABSTRACT Urinary tract infection (UTI) is one of the most common ailments requiring both short-term and prophylactic antibiotic therapies. Progression of infection from the bladder to the kidney is associated with more severe clinical symptoms (e.g., fever and vomiting) as well as with dangerous disease sequelae (e.g., renal scaring and sepsis). Host-pathogen interactions that promote bacterial ascent to the kidney are not completely understood. Prior studies indicate that the magnitude of proinflammatory cytokine elicitation in vitro by clinical isolates of uropathogenic Escherichia coli (UPEC) inversely correlates with the severity of clinical disease. Therefore, we hypothesize that the magnitude of initial proinflammatory responses during infection defines the course and severity of disease. Clinical UPEC isolates obtained from patients with a nonfebrile UTI elicited high systemic proinflammatory responses early during experimental UTI in a murine model and were attenuated in bladder and kidney persistence. Conversely, UPEC isolates obtained from patients with febrile UTI elicited low systemic proinflammatory responses early during experimental UTI and exhibited prolonged persistence in the bladder and kidney. Soluble factors in the supernatant from saturated cultures as well as the lipopolysaccharide (LPS) serotype correlated with the magnitude of proinflammatory responses in vitro. Our data suggest that the structure of the O-antigen sugar moiety of the LPS may determine the strength of cytokine induction by epithelial cells. Moreover, the course and severity of disease appear to be the consequence of the magnitude of initial cytokines produced by the bladder epithelium during infection. IMPORTANCE The specific host-pathogen interactions that determine the extent and course of disease are not completely understood. Our studies demonstrate that modest changes in the magnitude of cytokine production observed using in vitro models of infection translate into

Cytokine-producing T cell subsets in human leishmaniasis

DEFF Research Database (Denmark)

Kemp, Kåre

2000-01-01

Leishmania specific Th1/Th2 cells have been identified in humans as well as in mice. There is a correlation between the clinical outcome of the infection and the cytokine response profile. Generally, the production of Th2 cytokines leads to severe infection, whereas the production of Th1 cytokine...

Costunolide inhibits proinflammatory cytokines and iNOS in activated murine BV2 microglia.

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Rayan, Nirmala Arul; Baby, Nimmi; Pitchai, Daisy; Indraswari, Fransisca; Ling, Eng-Ang; Lu, Jia; Dheen, Thameem

2011-06-01

Costunolide, a sesquiterpene lactone present in Costus speciosus root exerts a variety of pharmacological activity but its effects on neuroinflammation have not been studied. Microglia, the resident phagocytic cells in the central nervous system respond to neuroinflammation and their overwhelming response in turn aggravate brain damage during infection, ischemia and neurodegenerative diseases. In this study, we report the effect of Costunolide on the production of proinflammatory mediators and mechanisms involved in BV2 microglial cells stimulated with LPS. Costunolide attenuated the expression of tumour necrosis factor-alpha, interleukin-1,6, inducible nitric oxide synthase, monocyte chemotactic protein 1 and cyclooxygenase 2 in activated microglia. This Costunolide-mediated inhibition was correspondent with the inhibition of NFkappaB activation. It has been further shown that Costunolide suppressed MAPK pathway activation by inducing MKP-1 production. Collectively our results suggest that Costunolide shows an ability to inhibit expression of multiple neuroinflammatory mediators and this is attributable to the compounds inhibition of NFkappaB and MAPK activation. This novel role of Costunolide upon investigation may aid in developing better therapeutic strategies for treatment of neuroinflammatory diseases.

Factor XI Deficiency Alters the Cytokine Response and Activation of Contact Proteases during Polymicrobial Sepsis in Mice.

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Charles E Bane

Full Text Available Sepsis, a systemic inflammatory response to infection, is often accompanied by abnormalities of blood coagulation. Prior work with a mouse model of sepsis induced by cecal ligation and puncture (CLP suggested that the protease factor XIa contributed to disseminated intravascular coagulation (DIC and to the cytokine response during sepsis. We investigated the importance of factor XI to cytokine and coagulation responses during the first 24 hours after CLP. Compared to wild type littermates, factor XI-deficient (FXI-/- mice had a survival advantage after CLP, with smaller increases in plasma levels of TNF-α and IL-10 and delayed IL-1β and IL-6 responses. Plasma levels of serum amyloid P, an acute phase protein, were increased in wild type mice 24 hours post-CLP, but not in FXI-/- mice, supporting the impression of a reduced inflammatory response in the absence of factor XI. Surprisingly, there was little evidence of DIC in mice of either genotype. Plasma levels of the contact factors factor XII and prekallikrein were reduced in WT mice after CLP, consistent with induction of contact activation. However, factor XII and PK levels were not reduced in FXI-/- animals, indicating factor XI deficiency blunted contact activation. Intravenous infusion of polyphosphate into WT mice also induced changes in factor XII, but had much less effect in FXI deficient mice. In vitro analysis revealed that factor XIa activates factor XII, and that this reaction is enhanced by polyanions such polyphosphate and nucleic acids. These data suggest that factor XI deficiency confers a survival advantage in the CLP sepsis model by altering the cytokine response to infection and blunting activation of the contact (kallikrein-kinin system. The findings support the hypothesis that factor XI functions as a bidirectional interface between contact activation and thrombin generation, allowing the two processes to influence each other.

Association of brain injury and neonatal cytokine response during therapeutic hypothermia in newborns with hypoxic-ischemic encephalopathy.

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Orrock, Janet E; Panchapakesan, Karuna; Vezina, Gilbert; Chang, Taeun; Harris, Kari; Wang, Yunfei; Knoblach, Susan; Massaro, An N

2016-05-01

Cytokines have been proposed as mediators of neonatal brain injury via neuroinflammatory pathways triggered by hypoxia-ischemia. Limited data are available on cytokine profiles in larger cohorts of newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Serum cytokines interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, tumor necrosis factor-α, and interferon-γ were measured in newborns with HIE at 24 and 72 h of TH. Differences between infants with favorable (survivors with mild/no magnetic resonance imaging (MRI) injury) vs. adverse outcome (death or moderate/severe MRI injury) were compared using mixed models to adjust for covariates. Data from 36 term newborns with HIE (favorable outcome: n = 20, adverse outcome: n = 16) were evaluated. Cytokines IL-1β, IL-2, IL-6, IL-8, IL-10, and IL-13 were elevated in the adverse relative to favorable outcome group at 24 h. IL-6 remained significantly elevated in the adverse outcome group at 72 h. IL-6 and IL-10 remained significantly associated with outcome group after controlling for covariates. Inflammatory cytokines are elevated in HIE newborns with brain injury by MRI. In particular, IL-6 and IL-10 were associated with adverse outcomes after controlling for baseline characteristics and severity of presentation. These data suggest that cytokine response may identify infants in need of additional neuroprotective interventions.

Cytokines, Chaperones and Neuroinflammatory Responses in Heroin-Related Death: What Can We Learn from Different Patterns of Cellular Expression?

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Vittorio Fineschi

2013-09-01

Full Text Available Heroin (3,6-diacetylmorphine has various effects on the central nervous system with several neuropathological alterations including hypoxic-ischemic brain damage from respiratory depressing effects and neuroinflammatory response. Both of these mechanisms induce the release of cytokines, chemokines and other inflammatory mediators by the activation of many cell types such as leucocytes and endothelial and glial cells, especially microglia, the predominant immunocompetent cell type within the central nervous system. The aim of this study is to clarify the correlation between intravenous heroin administration in heroin related death and the neuroinflammatory response. We selected 45 cases among autopsies executed for heroin-related death (358 total cases; immunohistochemical studies and Western blotting analyses were used to investigate the expression of brain markers such as tumor necrosis factor-α, oxygen-regulated protein 150, (interleukins IL-1β, IL-6, IL-8, IL-10, IL-15, cyclooxygenase-2, heat shock protein 70, and CD68 (MAC387. Findings demonstrated that morphine induces inflammatory response and cytokine release. In particular, oxygen-regulated protein 150, cyclooxygenase-2, heat shock protein 70, IL-6 and IL-15 cytokines were over-expressed with different patterns of cellular expression.

Pre-existing adenovirus immunity modifies a complex mixed Th1 and Th2 cytokine response to an Ad5/HIV-1 vaccine candidate in humans.

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Samuel O Pine

2011-04-01

Full Text Available The results of the recent Step Study highlight a need to clarify the effects of pre-existing natural immunity to a vaccine vector on vaccine-induced T-cell responses. To investigate this interaction, we examined the relationship between pre-existing Ad5 immunity and T-cell cytokine response profiles in healthy, HIV-uninfected recipients of MRKAd5 HIV-1 gag vaccine (HVTN 050, ClinicalTrials.gov #NCT00849732. Participants were grouped by baseline Ad5 neutralizing antibody titer as either Ad5-seronegative (titer ≤18; n = 36 or Ad5-seropositive (titer >200; n = 34. Samples from vaccine recipients were analyzed for immune responses to either HIV-1 Gag peptide pools or Ad5 empty vector using an ex vivo assay that measures thirty cytokines in the absence of long-term culture. The overall profiles of cytokine responses to Gag and Ad5 had similar combinations of induced Th1- and Th2-type cytokines, including IFN-γ, IL-2, TNF-α, IP-10, IL-13, and IL-10, although the Ad5-specific responses were uniformly higher than the Gag-specific responses (p<0.0001 for 9 out of 11 significantly expressed analytes. At the peak response time point, PBMC from Ad5-seronegative vaccinees secreted significantly more IP-10 in response to Gag (p = 0.008, and significantly more IP-10 (p = 0.0009, IL-2 (p = 0.006 and IL-10 (p = 0.05 in response to Ad5 empty vector than PBMC from Ad5-seropositive vaccinees. Additionally, similar responses to the Ad5 vector prior to vaccination were observed in almost all subjects, regardless of Ad5 neutralizing antibody status, and the levels of secreted IFN-γ, IL-10, IL-1Ra and GM-CSF were blunted following vaccination. The cytokine response profile of Gag-specific T cells mirrored the Ad5-specific response present in all subjects before vaccination, and included a number of Th1- and Th2-associated cytokines not routinely assessed in current vaccine trials, such as IP-10, IL-10, IL-13, and GM-CSF. Together, these

Suppressor of cytokine signaling (SOCS genes are silenced by DNA hypermethylation and histone deacetylation and regulate response to radiotherapy in cervical cancer cells.

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Moon-Hong Kim

Full Text Available Suppressor of cytokine signaling (SOCS family is an important negative regulator of cytokine signaling and deregulation of SOCS has been involved in many types of cancer. All cervical cancer cell lines tested showed lower expression of SOCS1, SOCS3, and SOCS5 than normal tissue or cell lines. The immunohistochemistry result for SOCS proteins in human cervical tissue also confirmed that normal tissue expressed higher level of SOCS proteins than neighboring tumor. Similar to the regulation of SOCS in other types of cancer, DNA methylation contributed to SOCS1 downregulation in CaSki, ME-180, and HeLa cells. However, the expression of SOCS3 or SOCS5 was not recovered by the inhibition of DNA methylation. Histone deacetylation may be another regulatory mechanism involved in SOCS1 and SOCS3 expression, however, SOCS5 expression was neither affected by DNA methylation nor histone deacetylation. Ectopic expression of SOCS1 or SOCS3 conferred radioresistance to HeLa cells, which implied SOCS signaling regulates the response to radiation in cervical cancer. In this study, we have shown that SOCS expression repressed by, in part, epigenetically and altered SOCS1 and SOCS3 expression could contribute to the radiosensitive phenotype in cervical cancer.

Addition of exogenous cytokines in mixed lymphocyte culture for selecting related donors for bone marrow transplantation

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Jeane Eliete Laguila Visentainer

Full Text Available CONTEXT: Mixed lymphocyte culturing has led to conflicting opinions regarding the selection of donors for bone marrow transplantation. The association between a positive mixed lymphocyte culture and the development of graft-versus-host disease (GVHD is unclear. The use of exogenous cytokines in mixed lymphocyte cultures could be an alternative for increasing the sensitivity of culture tests. OBJECTIVE: To increase the sensitivity of mixed lymphocyte cultures between donor and recipient human leukocyte antigen (HLA identical siblings, using exogenous cytokines, in order to predict post-transplantation GVHD and/or rejection. TYPE OF STUDY: Prospective study. SETTING: Bone Marrow Transplantation Unit, Universidade Estadual de Campinas. PARTICIPANTS: Seventeen patients with hematological malignancies and their respective donors selected for bone marrow transplantation procedures. PROCEDURES: Standard and modified mixed lymphocyte culturing by cytokine supplementation was carried out using donor and recipient cells typed for HLA. MAIN MEASUREMENTS: Autologous and allogenic responses in mixed lymphocyte cultures after the addition of IL-4 or IL-2. RESULTS: In comparison with the standard method, average responses in the modified mixed lymphocyte cultures increased by a factor of 2.0 using IL-4 (p < 0.001 and 6.4 using IL-2 (p < 0.001, for autologous donor culture responses. For donor-versus-recipient culture responses, the increase was by a factor of 1.9 using IL-4 (p < 0.001 and 4.1 using IL-2 (p < 0.001. For donor-versus-unrelated culture responses, no significant increase was observed using IL-4, and a mean response inhibition of 20% was observed using IL-2 (p < 0.001. Neither of the cytokines produced a significant difference in the unrelated control versus recipient cell responses. CONCLUSION: IL-4 supplementation was the best for increasing the mixed lymphocyte culture sensitivity. However, IL-4 also increased autologous responses, albeit less

Intranuclear interactomic inhibition of NF-κB suppresses LPS-induced severe sepsis

International Nuclear Information System (INIS)

Park, Sung-Dong; Cheon, So Yeong; Park, Tae-Yoon; Shin, Bo-Young; Oh, Hyunju; Ghosh, Sankar; Koo, Bon-Nyeo; Lee, Sang-Kyou

2015-01-01

Suppression of nuclear factor-κB (NF-κB) activation, which is best known as a major regulator of innate and adaptive immune responses, is a potent strategy for the treatment of endotoxic sepsis. To inhibit NF-κB functions, we designed the intra-nuclear transducible form of transcription modulation domain (TMD) of RelA (p65), called nt-p65-TMD, which can be delivered effectively into the nucleus without influencing the cell viability, and work as interactomic inhibitors via disruption of the endogenous p65-mediated transcription complex. nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, or IL-6 from BV2 microglia cells stimulated by lipopolysaccharide (LPS). nt-p65-TMD did not inhibit tyrosine phosphorylation of signaling mediators such as ZAP-70, p38, JNK, or ERK involved in T cell activation, but was capable of suppressing the transcriptional activity of NF-κB without the functional effect on that of NFAT upon T-cell receptor (TCR) stimulation. The transduced nt-p65-TMD in T cell did not affect the expression of CD69, however significantly inhibited the secretion of T cell-specific cytokines such as IL-2, IFN-γ, IL-4, IL-17A, or IL-10. Systemic administration of nt-p65-TMD showed a significant therapeutic effect on LPS-induced sepsis model by inhibiting pro-inflammatory cytokines secretion. Therefore, nt-p65-TMD can be a novel therapeutics for the treatment of various inflammatory diseases, including sepsis, where a transcription factor has a key role in pathogenesis, and further allows us to discover new functions of p65 under normal physiological condition without genetic alteration. - Highlights: • The nt-p65-TMD is intra-nuclear interactomic inhibitor of endogenous p65. • The nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines. • The excellent therapeutic potential of nt-p65-TMD was confirmed in sepsis model

Intranuclear interactomic inhibition of NF-κB suppresses LPS-induced severe sepsis

Energy Technology Data Exchange (ETDEWEB)

Park, Sung-Dong [Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Cheon, So Yeong [Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Park, Tae-Yoon; Shin, Bo-Young [Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Oh, Hyunju; Ghosh, Sankar [Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States); Koo, Bon-Nyeo, E-mail: koobn@yuhs.ac [Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Lee, Sang-Kyou, E-mail: sjrlee@yonsei.ac.kr [Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

2015-08-28

Suppression of nuclear factor-κB (NF-κB) activation, which is best known as a major regulator of innate and adaptive immune responses, is a potent strategy for the treatment of endotoxic sepsis. To inhibit NF-κB functions, we designed the intra-nuclear transducible form of transcription modulation domain (TMD) of RelA (p65), called nt-p65-TMD, which can be delivered effectively into the nucleus without influencing the cell viability, and work as interactomic inhibitors via disruption of the endogenous p65-mediated transcription complex. nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, or IL-6 from BV2 microglia cells stimulated by lipopolysaccharide (LPS). nt-p65-TMD did not inhibit tyrosine phosphorylation of signaling mediators such as ZAP-70, p38, JNK, or ERK involved in T cell activation, but was capable of suppressing the transcriptional activity of NF-κB without the functional effect on that of NFAT upon T-cell receptor (TCR) stimulation. The transduced nt-p65-TMD in T cell did not affect the expression of CD69, however significantly inhibited the secretion of T cell-specific cytokines such as IL-2, IFN-γ, IL-4, IL-17A, or IL-10. Systemic administration of nt-p65-TMD showed a significant therapeutic effect on LPS-induced sepsis model by inhibiting pro-inflammatory cytokines secretion. Therefore, nt-p65-TMD can be a novel therapeutics for the treatment of various inflammatory diseases, including sepsis, where a transcription factor has a key role in pathogenesis, and further allows us to discover new functions of p65 under normal physiological condition without genetic alteration. - Highlights: • The nt-p65-TMD is intra-nuclear interactomic inhibitor of endogenous p65. • The nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines. • The excellent therapeutic potential of nt-p65-TMD was confirmed in sepsis model.

Curcumin alleviates macrophage activation and lung inflammation induced by influenza virus infection through inhibiting the NF-κB signaling pathway.

Science.gov (United States)

Xu, Yiming; Liu, Ling

2017-09-01

Influenza A viruses (IAV) result in severe public health problems with worldwide each year. Overresponse of immune system to IAV infection leads to complications, and ultimately causing morbidity and mortality. Curcumin has been reported to have anti-inflammatory ability. However, its molecular mechanism in immune responses remains unclear. We detected the pro-inflammatory cytokine secretion and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-related protein expression in human macrophages or mice infected by IAV with or without curcumin treatment. We found that the IAV infection caused a dramatic enhancement of pro-inflammatory cytokine productions of human macrophages and mice immune cells. However, curcumin treatment after IAV infection downregulated these cytokines production in a dose-dependent manner. Moreover, the NF-κB has been activated in human macrophages after IAV infection, while administration of curcumin inhibited NF-κB signaling pathway via promoting the expression of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), and inhibiting the translocation of p65 from cytoplasm to nucleus. In summary, IAV infection could result in the inflammatory responses of immune cells, especially macrophages. Curcumin has the therapeutic potentials to relieve these inflammatory responses through inhibiting the NF-κB signaling pathway. © 2017 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

Inhibition of aldose reductase prevents experimental allergic airway inflammation in mice.

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Umesh C S Yadav

2009-08-01

Full Text Available The bronchial asthma, a clinical complication of persistent inflammation of the airway and subsequent airway hyper-responsiveness, is a leading cause of morbidity and mortality in critically ill patients. Several studies have shown that oxidative stress plays a key role in initiation as well as amplification of inflammation in airways. However, still there are no good anti-oxidant strategies available for therapeutic intervention in asthma pathogenesis. Most recent studies suggest that polyol pathway enzyme, aldose reductase (AR, contributes to the pathogenesis of oxidative stress-induced inflammation by affecting the NF-kappaB-dependent expression of cytokines and chemokines and therefore inhibitors of AR could be anti-inflammatory. Since inhibitors of AR have already gone through phase-III clinical studies for diabetic complications and found to be safe, our hypothesis is that AR inhibitors could be novel therapeutic drugs for the prevention and treatment of asthma. Hence, we investigated the efficacy of AR inhibition in the prevention of allergic responses to a common natural airborne allergen, ragweed pollen that leads to airway inflammation and hyper-responsiveness in a murine model of asthma.Primary Human Small Airway Epithelial Cells (SAEC were used to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE-induced cytotoxic and inflammatory signals. Our results indicate that inhibition of AR prevents RWE -induced apoptotic cell death as measured by annexin-v staining, increase in the activation of NF-kappaB and expression of inflammatory markers such as inducible nitric oxide synthase (iNOS, cycloxygenase (COX-2, Prostaglandin (PG E(2, IL-6 and IL-8. Further, BALB/c mice were sensitized with endotoxin-free RWE in the absence and presence of AR inhibitor and followed by evaluation of perivascular and peribronchial inflammation, mucin production, eosinophils infiltration and airway hyperresponsiveness. Our results

Expression of IL-23/Th17-related cytokines in basal cell carcinoma and in the response to medical treatments.

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Cristina Pellegrini

Full Text Available Several immune-related markers have been implicated in basal cell carcinoma (BCC pathogenesis. The BCC inflammatory infiltrate is dominated by Th2 cytokines, suggesting a specific state of immunosuppression. In contrast, regressing BCC are characterized by a Th1 immune response with IFN-γ promoting a tumor suppressive activity. IL-23/Th17-related cytokines, as interleukin (IL-17, IL-23 and IL-22, play a significant role in cutaneous inflammatory diseases, but their involvement in skin carcinogenesis is controversial and is poorly investigated in BCC. In this study we investigated the expression of IFN-γ, IL-17, IL-23 and IL-22 cytokines in BCC at the protein and mRNA level and their modulation during imiquimod (IMQ treatment or photodynamic therapy (PDT. IFN-γ, IL-17, IL-23 and IL-22 levels were evaluated by immunohistochemistry and quantitative Real Time PCR in 41 histopathologically-proven BCCs (28 superficial and 13 nodular from 39 patients. All BCC samples were analyzed at baseline and 19 of 41 also during medical treatment (9 with IMQ 5% cream and 10 with MAL-PDT. Association between cytokines expression and clinico-pathological variables was evaluated. Higher levels of IFN-γ, IL-17, IL-23 and IL-22 were found in BCCs, mainly in the peritumoral infiltrate, compared to normal skin, with the expression being correlated to the severity of the inflammatory infiltrate. IFN-γ production was higher in superficial BCCs compared to nodular BCCs, while IL-17 was increased in nodular BCCs. A significant correlation was found between IFN-γ and IL-17 expression with both cytokines expressed by CD4+ and CD8+ T-cells. An increase of all cytokines occurred during the inflammatory phase induced by IMQ and at the early time point of PDT treatment, with significant evidence for IFN-γ, IL-23, and IL-22. Our results confirm the role of IFN-γ and support the involvement of IL-23/Th17-related cytokines in BCC pathogenesis and in the inflammatory response

Prepotent response inhibition predicts treatment outcome in attention deficit/hyperactivity disorder

NARCIS (Netherlands)

van der Oord, S.; Geurts, H.M.; Prins, P.J.M.; Emmelkamp, P.M.G.; Oosterlaan, J.

2012-01-01

Objective: Inhibition deficits, including deficits in prepotent response inhibition and interference control, are core deficits in ADHD. The predictive value of prepotent response inhibition and interference control was assessed for outcome in a 10-week treatment trial with methylphenidate. Methods:

Illicium verum Extract and Trans-Anethole Attenuate Ovalbumin-Induced Airway Inflammation via Enhancement of Foxp3+ Regulatory T Cells and Inhibition of Th2 Cytokines in Mice

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Yoon-Young Sung

2017-01-01

Full Text Available Illicium verum is used in traditional medicine to treat inflammation. The study investigates the effects of IVE and its component, trans-anethole (AET, on airway inflammation in ovalbumin- (OVA- induced asthmatic mice. Asthma was induced in BALB/c mice by systemic sensitization to OVA, followed by intratracheal, intraperitoneal, and aerosol allergen challenges. IVE and AET were orally administered for four weeks. We investigated the effects of treatment on airway hyperresponsiveness, IgE production, pulmonary eosinophilic infiltration, immune cell phenotypes, Th2 cytokine production in bronchoalveolar lavage, Th1/Th2 cytokine production in splenocytes, forkhead box protein 3 (Foxp3 expression, and lung histology. IVE and AET ameliorated OVA-driven airway hyperresponsiveness (p<0.01, pulmonary eosinophilic infiltration (p<0.05, mucus hypersecretion (p<0.01, and IL-4, IL-5, IL-13, and CCR3 production (p<0.05, as well as IgE levels (p<0.01. IVE and AET increased Foxp3 expression in lungs (p<0.05. IVE and AET reduced IL-4 and increased IFN-γ production in the supernatant of splenocyte cultures (p<0.05. Histological studies showed that IVE and AET inhibited eosinophilia and lymphocyte infiltration in lungs (p<0.01. These results indicate that IVE and AET exert antiasthmatic effects through upregulation of Foxp3+ regulatory T cells and inhibition of Th2 cytokines, suggesting that IVE may be a potential therapeutic agent for allergic lung inflammation.

Tyrosine Phosphorylation of Jak2 in the JH2 Domain Inhibits Cytokine Signaling

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Feener, Edward P.; Rosario, Felicia; Dunn, Sarah L.; Stancheva, Zlatina; Myers, Martin G.

2004-01-01

Jak family tyrosine kinases mediate signaling by cytokine receptors to regulate diverse biological processes. Although Jak2 and other Jak kinase family members are phosphorylated on numerous sites during cytokine signaling, the identity and function of most of these sites remains unknown. Using tandem mass spectroscopic analysis of activated Jak2 protein from intact cells, we identified Tyr221 and Tyr570 as novel sites of Jak2 phosphorylation. Phosphorylation of both sites was stimulated by c...

Inflammatory cytokines and plasma redox status responses in hypertensive subjects after heat exposure

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S.F. Fonseca

2016-03-01

Full Text Available Hypertension is characterized by a pro-inflammatory status, including redox imbalance and increased levels of pro-inflammatory cytokines, which may be exacerbated after heat exposure. However, the effects of heat exposure, specifically in individuals with inflammatory chronic diseases such as hypertension, are complex and not well understood. This study compared the effects of heat exposure on plasma cytokine levels and redox status parameters in 8 hypertensive (H and 8 normotensive (N subjects (age: 46.5±1.3 and 45.6±1.4 years old, body mass index: 25.8±0.8 and 25.6±0.6 kg/m2, mean arterial pressure: 98.0±2.8 and 86.0±2.3 mmHg, respectively. They remained at rest in a sitting position for 10 min in a thermoneutral environment (22°C followed by 30 min in a heated environmental chamber (38°C and 60% relative humidity. Blood samples were collected before and after heat exposure. Plasma cytokine levels were measured using sandwich ELISA kits. Plasma redox status was determined by thiobarbituric acid reactive substances (TBARS levels and ferric reducing ability of plasma (FRAP. Hypertensive subjects showed higher plasma levels of IL-10 at baseline (P<0.05, although levels of this cytokine were similar between groups after heat exposure. Moreover, after heat exposure, hypertensive individuals showed higher plasma levels of soluble TNF receptor (sTNFR1 and lower TBARS (P<0.01 and FRAP (P<0.05 levels. Controlled hypertensive subjects, who use angiotensin-converting-enzyme inhibitor (ACE inhibitors, present an anti-inflammatory status and balanced redox status. Nevertheless, exposure to a heat stress condition seems to cause an imbalance in the redox status and an unregulated inflammatory response.

Concurrent inhibition of kit- and FcepsilonRI-mediated signaling: coordinated suppression of mast cell activation

DEFF Research Database (Denmark)

Jensen, Bettina M; Beaven, Michael A; Iwaki, Shoko

2008-01-01

Although primarily required for the growth, differentiation, and survival of mast cells, Kit ligand (stem cell factor) is also required for optimal antigen-mediated mast cell activation. Therefore, concurrent inhibition of Kit- and FcepsilonRI-mediated signaling would be an attractive approach...... characterized Kit inhibitor imatinib mesylate (imatinib). In contrast to imatinib, however, hypothemycin also effectively inhibited FcepsilonRI-mediated degranulation and cytokine production in addition to the potentiation of these responses via Kit. The effect of hypothemycin on Kit-mediated responses could...... be explained by its inhibition of Kit kinase activity, whereas the inhibitory effects on FcepsilonRI-dependent signaling were at the level of Btk activation. Because hypothemycin also significantly reduced the mouse passive cutaneous anaphylaxis response in vivo, these data provide proof of principle...

Puerarin alleviates neuropathic pain by inhibiting neuroinflammation in spinal cord.

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Liu, Ming; Liao, Kaijun; Yu, Changxi; Li, Xuejun; Liu, Suhuan; Yang, Shuyu

2014-01-01

Neuropathic pain responds poorly to drug treatments, and partial relief is achieved in only about half of the patients. Puerarin, the main constituent of Puerariae Lobatae Radix, has been used extensively in China to treat hypertension and tumor. The current study examined the effects of puerarin on neuropathic pain using two most commonly used animal models: chronic constriction injury (CCI) and diabetic neuropathy. We found that consecutive intrathecal administration of puerarin (4-100 nM) for 7 days inhibited the mechanical and thermal nociceptive response induced by CCI and diabetes without interfering with the normal pain response. Meanwhile, in both models puerarin inhibited the activation of microglia and astroglia in the spinal dorsal horn. Puerarin also reduced the upregulated levels of nuclear factor-κB (NF-κB) and other proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in the spinal cord. In summary, puerarin alleviated CCI- and diabetes-induced neuropathic pain, and its effectiveness might be due to the inhibition of neuroinflammation in the spinal cord. The anti-inflammation effect of puerarin might be related to the suppression of spinal NF-κB activation and/or cytokines upregulation. We conclude that puerarin has a significant effect on alleviating neuropathic pain and thus may serve as a therapeutic approach for neuropathic pain.

Puerarin Alleviates Neuropathic Pain by Inhibiting Neuroinflammation in Spinal Cord

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Ming Liu

2014-01-01

Full Text Available Neuropathic pain responds poorly to drug treatments, and partial relief is achieved in only about half of the patients. Puerarin, the main constituent of Puerariae Lobatae Radix, has been used extensively in China to treat hypertension and tumor. The current study examined the effects of puerarin on neuropathic pain using two most commonly used animal models: chronic constriction injury (CCI and diabetic neuropathy. We found that consecutive intrathecal administration of puerarin (4–100 nM for 7 days inhibited the mechanical and thermal nociceptive response induced by CCI and diabetes without interfering with the normal pain response. Meanwhile, in both models puerarin inhibited the activation of microglia and astroglia in the spinal dorsal horn. Puerarin also reduced the upregulated levels of nuclear factor-κB (NF-κB and other proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in the spinal cord. In summary, puerarin alleviated CCI- and diabetes-induced neuropathic pain, and its effectiveness might be due to the inhibition of neuroinflammation in the spinal cord. The anti-inflammation effect of puerarin might be related to the suppression of spinal NF-κB activation and/or cytokines upregulation. We conclude that puerarin has a significant effect on alleviating neuropathic pain and thus may serve as a therapeutic approach for neuropathic pain.

Susceptibility to Lower Respiratory Infections in Childhood is Associated with Perturbation of the Cytokine Response to Pathogenic Airway Bacteria.

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Vissing, Nadja Hawwa; Larsen, Jeppe Madura; Rasmussen, Morten Arendt; Chawes, Bo Lund Krogsgaard; Thysen, Anna Hammerich; Bønnelykke, Klaus; Brix, Susanne; Bisgaard, Hans

2016-05-01

Neonatal colonization of the airways with respiratory pathogens is associated with increased risk of lower respiratory infections (LRI) in early childhood. Therefore, we hypothesized that children developing LRI have an aberrant immune response to pathogenic bacteria in infancy. The objective was to characterize in vitro the early life systemic immune response to pathogenic bacteria and study the possible association with incidence of LRI during the first 3 years of life. The Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) is a clinical birth cohort study of 411 children born of mothers with asthma. LRI incidence was prospectively captured from 6-monthly planned visits and visits at acute respiratory episodes. The in vitro systemic immune response to Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae was characterized by the production of TNF-α, IFN-γ, IL-2, IL-5, IL-10, IL-13 and IL-17 in peripheral blood mononuclear cells isolated at age 6 months from 291 infants. Data were analyzed by Poisson regression against incidence of LRI in infancy. A multivariable model including all cytokine responses from the 3 different bacterial stimulations significantly identified children at risk of LRI (P = 0.006). The immune response pattern associated with LRI was characterized by perturbed production of several cytokines rather than production of one specific cytokine, and was independent of concurrent asthma. TNF-α and IL-5 were key drivers but did not explain the entire variation in LRI susceptibility. Children at risk of future LRI present a perturbed systemic immune response upon exposure to common airway pathogens in early life.

Prepulse inhibition of auditory change-related cortical responses

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Inui Koji

2012-10-01

Full Text Available Abstract Background Prepulse inhibition (PPI of the startle response is an important tool to investigate the biology of schizophrenia. PPI is usually observed by use of a startle reflex such as blinking following an intense sound. A similar phenomenon has not been reported for cortical responses. Results In 12 healthy subjects, change-related cortical activity in response to an abrupt increase of sound pressure by 5 dB above the background of 65 dB SPL (test stimulus was measured using magnetoencephalography. The test stimulus evoked a clear cortical response peaking at around 130 ms (Change-N1m. In Experiment 1, effects of the intensity of a prepulse (0.5 ~ 5 dB on the test response were examined using a paired stimulation paradigm. In Experiment 2, effects of the interval between the prepulse and test stimulus were examined using interstimulus intervals (ISIs of 50 ~ 350 ms. When the test stimulus was preceded by the prepulse, the Change-N1m was more strongly inhibited by a stronger prepulse (Experiment 1 and a shorter ISI prepulse (Experiment 2. In addition, the amplitude of the test Change-N1m correlated positively with both the amplitude of the prepulse-evoked response and the degree of inhibition, suggesting that subjects who are more sensitive to the auditory change are more strongly inhibited by the prepulse. Conclusions Since Change-N1m is easy to measure and control, it would be a valuable tool to investigate mechanisms of sensory gating or the biology of certain mental diseases such as schizophrenia.

Diclofenac enhances proinflammatory cytokine-induced phagocytosis of cultured microglia via nitric oxide production

International Nuclear Information System (INIS)

Kakita, Hiroki; Aoyama, Mineyoshi; Nagaya, Yoshiaki; Asai, Hayato; Hussein, Mohamed Hamed; Suzuki, Mieko; Kato, Shin; Saitoh, Shinji; Asai, Kiyofumi

2013-01-01

Influenza-associated encephalopathy (IAE) is a central nervous system complication with a high mortality rate, which is increased significantly by the non-steroidal anti-inflammatory drug diclofenac sodium (DCF). In the present study, we investigated the effects of DCF on brain immune cells (i.e. microglia) stimulated with three proinflammatory cytokines, namely tumor necrosis factor-α, interleukin-1β, and interferon-γ. Similar to previous findings in astrocytes, all three cytokines induced the expression of inducible NO synthase (iNOS), as well as NO production, in microglia. The addition of DCF to the culture system augmented iNOS expression and NO production. Immunocytochemical analysis and the phagocytosis assay revealed that cytokine treatment induced morphological changes to and phagocytosis by the microglia. The addition of DCF to the culture system enhanced microglial activation, as well as the phagocytic activity of cytokine-stimulated microglia. Inhibitors of nuclear factor (NF)-κB inhibited iNOS gene expression in cytokine-stimulated microglia with or without DCF, suggesting that the NF-κB pathway is one of the main signaling pathways involved. The iNOS inhibitor N G -monomethyl-L-arginine (L-NMMA) reduced both cytokine-induced phagocytosis and phagocytosis induced by the combination of cytokines plus DCF. Furthermore, the NO donor sodium nitroprusside induced phagocytosis, indicating that NO production is a key regulator of microglial phagocytosis. In conclusion, DCF acts synergistically with proinflammatory cytokines to increase the production of NO in microglia, leading to phagocytic activity of the activated microglia. These findings, together with previous observations regarding astrocytes, may explain the significant increase in mortality of IAE patients treated with DCF. - Highlights: ► Influenza-associated encephalopathy (IAE) is associated with a high mortality rate. ► Hyperimmunization in the brain is believed to be responsible for IAE

Diclofenac enhances proinflammatory cytokine-induced phagocytosis of cultured microglia via nitric oxide production

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Kakita, Hiroki [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Aoyama, Mineyoshi, E-mail: ao.mine@med.nagoya-cu.ac.jp [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Nagaya, Yoshiaki; Asai, Hayato [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Hussein, Mohamed Hamed [Neonatal Intensive Care Unit, Pediatric Hospital, Cairo University, Cairo 11559 (Egypt); Maternal and Child Health Department, VACSERA, 51 Wizaret El-Zeraa-Agouza, Giza 22311 (Egypt); Suzuki, Mieko [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Kato, Shin [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Saitoh, Shinji [Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan); Asai, Kiyofumi [Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 (Japan)

2013-04-15

Influenza-associated encephalopathy (IAE) is a central nervous system complication with a high mortality rate, which is increased significantly by the non-steroidal anti-inflammatory drug diclofenac sodium (DCF). In the present study, we investigated the effects of DCF on brain immune cells (i.e. microglia) stimulated with three proinflammatory cytokines, namely tumor necrosis factor-α, interleukin-1β, and interferon-γ. Similar to previous findings in astrocytes, all three cytokines induced the expression of inducible NO synthase (iNOS), as well as NO production, in microglia. The addition of DCF to the culture system augmented iNOS expression and NO production. Immunocytochemical analysis and the phagocytosis assay revealed that cytokine treatment induced morphological changes to and phagocytosis by the microglia. The addition of DCF to the culture system enhanced microglial activation, as well as the phagocytic activity of cytokine-stimulated microglia. Inhibitors of nuclear factor (NF)-κB inhibited iNOS gene expression in cytokine-stimulated microglia with or without DCF, suggesting that the NF-κB pathway is one of the main signaling pathways involved. The iNOS inhibitor N{sup G}-monomethyl-L-arginine (L-NMMA) reduced both cytokine-induced phagocytosis and phagocytosis induced by the combination of cytokines plus DCF. Furthermore, the NO donor sodium nitroprusside induced phagocytosis, indicating that NO production is a key regulator of microglial phagocytosis. In conclusion, DCF acts synergistically with proinflammatory cytokines to increase the production of NO in microglia, leading to phagocytic activity of the activated microglia. These findings, together with previous observations regarding astrocytes, may explain the significant increase in mortality of IAE patients treated with DCF. - Highlights: ► Influenza-associated encephalopathy (IAE) is associated with a high mortality rate. ► Hyperimmunization in the brain is believed to be responsible for

Thiol dependent NF-κB suppression and inhibition of T-cell mediated adaptive immune responses by a naturally occurring steroidal lactone Withaferin A

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Gambhir, Lokesh; Checker, Rahul; Sharma, Deepak; Thoh, M. [Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai (India); Patil, Anand [Advanced Centre for Treatment Research and Education in Cancer, Kharghar, Navi Mumbai (India); Degani, M. [Institute of Chemical Technology, Matunga, Mumbai (India); Gota, Vikram [Advanced Centre for Treatment Research and Education in Cancer, Kharghar, Navi Mumbai (India); Sandur, Santosh K., E-mail: sskumar@barc.gov.in [Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai (India)

2015-12-01

Withaferin A (WA), a steroidal lactone isolated from ayurvedic medicinal plant Withania somnifera, was shown to inhibit tumor growth by inducing oxidative stress and suppressing NF-κB pathway. However, its effect on T-cell mediated adaptive immune responses and the underlying mechanism has not been investigated. Since both T-cell responses and NF-κB pathway are known to be redox sensitive, the present study was undertaken to elucidate the effect of WA on adaptive immune responses in vitro and in vivo. WA inhibited mitogen induced T-cell and B-cell proliferation in vitro without inducing any cell death. It inhibited upregulation of T-cell (CD25, CD69, CD71 and CD54) and B-cell (CD80, CD86 and MHC-II) activation markers and secretion of Th1 and Th2 cytokines. WA induced oxidative stress by increasing the basal ROS levels and the immunosuppressive effects of WA were abrogated only by thiol anti-oxidants. The redox modulatory effects of WA in T-cells were attributed to its ability to directly interact with free thiols. WA inhibited NF-κB nuclear translocation in lymphocytes and prevented the direct binding of nuclear NF-κB to its consensus sequence. MALDI-TOF analysis using a synthetic NF-κB-p50 peptide containing Cys-62 residue suggested that WA can modify the cysteine residue of NF-κB. The pharmacokinetic studies for WA were also carried out and in vivo efficacy of WA was studied using mouse model of Graft-versus-host disease. In conclusion, WA is a potent inhibitor of T-cell responses and acts via a novel thiol dependent mechanism and inhibition of NF-κB pathway. - Highlights:: • Withaferin A (WA) inhibited T-cell and B-cell mediated immune responses. • WA increased basal ROS levels in lymphocytes. • WA directly interacted with GSH as studied using spectrophotometry and HPLC. • WA inhibited NF-κB nuclear translocation and binding of nuclear NF-κB to DNA. • WA inhibited induction of the graft-versus-host disease in mice.

Oral Administration of p-Hydroxycinnamic Acid Attenuates Atopic Dermatitis by Downregulating Th1 and Th2 Cytokine Production and Keratinocyte Activation.

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Hyun-Su Lee

Full Text Available Atopic dermatitis (AD is a complex disease that is caused by various factors, including environmental change, genetic defects, and immune imbalance. We previously showed that p-hydroxycinnamic acid (HCA isolated from the roots of Curcuma longa inhibits T-cell activation without inducing cell death. Here, we demonstrated that oral administration of HCA in a mouse model of ear AD attenuates the following local and systemic AD manifestations: ear thickening, immune-cell infiltration, production of AD-promoting immunoregulatory cytokines in ear tissues, increased spleen and draining lymph node size and weight, increased pro-inflammatory cytokine production by draining lymph nodes, and elevated serum immunoglobulin production. HCA treatment of CD4+ T cells in vitro suppressed their proliferation and differentiation into Th1 or Th2 and their Th1 and Th2 cytokine production. HCA treatment of keratinocytes lowered their production of the pro-inflammatory cytokines that drive either Th1 or Th2 responses in AD. Thus, HCA may be of therapeutic potential for AD as it acts by suppressing keratinocyte activation and downregulating T-cell differentiation and cytokine production.

Xylitol, an anticaries agent, exhibits potent inhibition of inflammatory responses in human THP-1-derived macrophages infected with Porphyromonas gingivalis.

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Park, Eunjoo; Na, Hee Sam; Kim, Sheon Min; Wallet, Shannon; Cha, Seunghee; Chung, Jin

2014-06-01

Xylitol is a well-known anticaries agent and has been used for the prevention and treatment of dental caries. In this study, the anti-inflammatory effects of xylitol are evaluated for possible use in the prevention and treatment of periodontal infections. Cytokine expression was stimulated in THP-1 (human monocyte cell line)-derived macrophages by live Porphyromonas gingivalis, and enzyme-linked immunosorbent assay and a commercial multiplex assay kit were used to determine the effects of xylitol on live P. gingivalis-induced production of cytokine. The effects of xylitol on phagocytosis and the production of nitric oxide were determined using phagocytosis assay, viable cell count, and Griess reagent. The effects of xylitol on P. gingivalis adhesion were determined by immunostaining, and costimulatory molecule expression was examined by flow cytometry. Live P. gingivalis infection increased the production of representative proinflammatory cytokines, such as tumor necrosis factor-α and interleukin (IL)-1β, in a multiplicity of infection- and time-dependent manner. Live P. gingivalis also enhanced the release of cytokines and chemokines, such as IL-12 p40, eotaxin, interferon γ-induced protein 10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1. The pretreatment of xylitol significantly inhibited the P. gingivalis-induced cytokines production and nitric oxide production. In addition, xylitol inhibited the attachment of live P. gingivalis on THP-1-derived macrophages. Furthermore, xylitol exerted antiphagocytic activity against both Escherichia coli and P. gingivalis. These findings suggest that xylitol acts as an anti-inflammatory agent in THP-1-derived macrophages infected with live P. gingivalis, which supports its use in periodontitis.

Atomoxetine restores the response inhibition network in Parkinson's disease.

Science.gov (United States)

Rae, Charlotte L; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E; Jones, P Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

2016-08-01

Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction

Association of O-Antigen Serotype with the Magnitude of Initial Systemic Cytokine Responses and Persistence in the Urinary Tract.

Science.gov (United States)

Horvath, Dennis J; Patel, Ashay S; Mohamed, Ahmad; Storm, Douglas W; Singh, Chandra; Li, Birong; Zhang, Jingwen; Koff, Stephen A; Jayanthi, Venkata R; Mason, Kevin M; Justice, Sheryl S

2016-01-11

Urinary tract infection (UTI) is one of the most common ailments requiring both short-term and prophylactic antibiotic therapies. Progression of infection from the bladder to the kidney is associated with more severe clinical symptoms (e.g., fever and vomiting) as well as with dangerous disease sequelae (e.g., renal scaring and sepsis). Host-pathogen interactions that promote bacterial ascent to the kidney are not completely understood. Prior studies indicate that the magnitude of proinflammatory cytokine elicitation in vitro by clinical isolates of uropathogenic Escherichia coli (UPEC) inversely correlates with the severity of clinical disease. Therefore, we hypothesize that the magnitude of initial proinflammatory responses during infection defines the course and severity of disease. Clinical UPEC isolates obtained from patients with a nonfebrile UTI elicited high systemic proinflammatory responses early during experimental UTI in a murine model and were attenuated in bladder and kidney persistence. Conversely, UPEC isolates obtained from patients with febrile UTI elicited low systemic proinflammatory responses early during experimental UTI and exhibited prolonged persistence in the bladder and kidney. Soluble factors in the supernatant from saturated cultures as well as the lipopolysaccharide (LPS) serotype correlated with the magnitude of proinflammatory responses in vitro. Our data suggest that the structure of the O-antigen sugar moiety of the LPS may determine the strength of cytokine induction by epithelial cells. Moreover, the course and severity of disease appear to be the consequence of the magnitude of initial cytokines produced by the bladder epithelium during infection. The specific host-pathogen interactions that determine the extent and course of disease are not completely understood. Our studies demonstrate that modest changes in the magnitude of cytokine production observed using in vitro models of infection translate into significant

Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans

DEFF Research Database (Denmark)

Rask-Madsen, Christian; Domínguez, Helena; Ihlemann, Nikolaj

2003-01-01

BACKGROUND: Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin....../or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220+/-44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow....... Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (Palpha...

Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

International Nuclear Information System (INIS)

Levina, Vera; Marrangoni, Adele M.; DeMarco, Richard; Gorelik, Elieser; Lokshin, Anna E.

2008-01-01

TRAIL is a death ligand that induces apoptosis in malignant but not normal cells. Recently the ability of TRAIL to induce proliferation in apoptosis-resistant normal and malignant cells was reported. In this study, we analyzed TRAIL effects in apoptosis sensitive MCF7, OVCAR3 and H460 human tumor cell lines. TRAIL at low concentrations preferentially induced cell proliferation. At 100 ng/ml, apoptotic death was readily observed, however surviving cells acquired higher proliferative capacity. TRAIL-stimulated production of several cytokines, IL-8, RANTES, MCP-1 and bFGF, and activation of caspases 1 and 8 was essential for this effect. Antibodies to IL-8, RANTES, and bFGF blocked TRAIL-induced cell proliferation and further stimulated apoptosis. For the first time, we report that high TRAIL concentrations induced cell senescence as determined by the altered morphology and expression of several senescence markers: SA-β-gal, p21 Waf1/Cip1 , p16 INK4a , and HMGA. Caspase 9 inhibition protected TRAIL-treated cells from senescence, whereas inhibition of caspases 1 and 8 increased the yield of SLP cells. In conclusion, in cultured human carcinoma cells, TRAIL therapy results in three functional outcomes, apoptosis, proliferation and senescence. TRAIL-induced proapoptotic and prosurvival responses correlate with the strength of signaling. TRAIL-induced cytokine production is responsible for its proliferative and prosurvival effects

The immunological response and post-treatment survival of DC-vaccinated melanoma patients are associated with increased Th1/Th17 and reduced Th3 cytokine responses.

Science.gov (United States)

Durán-Aniotz, Claudia; Segal, Gabriela; Salazar, Lorena; Pereda, Cristián; Falcón, Cristián; Tempio, Fabián; Aguilera, Raquel; González, Rodrigo; Pérez, Claudio; Tittarelli, Andrés; Catalán, Diego; Nervi, Bruno; Larrondo, Milton; Salazar-Onfray, Flavio; López, Mercedes N

2013-04-01

Immunization with autologous dendritic cells (DCs) loaded with a heat shock-conditioned allogeneic melanoma cell lysate caused lysate-specific delayed type hypersensitivity (DTH) reactions in a number of patients. These responses correlated with a threefold prolonged long-term survival of DTH(+) with respect to DTH(-) unresponsive patients. Herein, we investigated whether the immunological reactions associated with prolonged survival were related to dissimilar cellular and cytokine responses in blood. Healthy donors and melanoma patient's lymphocytes obtained from blood before and after vaccinations and from DTH biopsies were analyzed for T cell population distribution and cytokine release. Peripheral blood lymphocytes from melanoma patients have an increased proportion of Th3 (CD4(+) TGF-β(+)) regulatory T lymphocytes compared with healthy donors. Notably, DTH(+) patients showed a threefold reduction of Th3 cells compared with DTH(-) patients after DCs vaccine treatment. Furthermore, DCs vaccination resulted in a threefold augment of the proportion of IFN-γ releasing Th1 cells and in a twofold increase of the IL-17-producing Th17 population in DTH(+) with respect to DTH(-) patients. Increased Th1 and Th17 cell populations in both blood and DTH-derived tissues suggest that these profiles may be related to a more effective anti-melanoma response. Our results indicate that increased proinflammatory cytokine profiles are related to detectable immunological responses in vivo (DTH) and to prolonged patient survival. Our study contributes to the understanding of immunological responses produced by DCs vaccines and to the identification of follow-up markers for patient outcome that may allow a closer individual monitoring of patients.

Dysregulation of cytokine response in Canadian First Nations communities: is there an association with persistent organic pollutant levels?

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Pascal Imbeault

Full Text Available In vitro and animal studies report that some persistent organic pollutants (POPs trigger the secretion of proinflammatory cytokines. Whether POP exposure is associated with a dysregulation of cytokine response remains to be investigated in humans. We studied the strength of association between plasma POP levels and circulating cytokines as immune activation markers. Plasma levels of fourteen POPs and thirteen cytokines were measured in 39 Caucasians from a comparator sample in Québec City (Canada and 72 First Nations individuals from two northern communities of Ontario (Canada. Caucasians showed significantly higher levels of organochlorine insecticides (β-HCH, p,p'-DDE and HCB compared to First Nations. Conversely, First Nations showed higher levels of Mirex, Aroclor 1260, PCB 153, PCB 170, PCB 180 and PCB 187 compared to Caucasians. While there was no difference in cytokine levels of IL-4, IL-6, IL-10 and IL-22 between groups, First Nations had significantly greater average levels of IFNγ, IL-1β, IL-2, IL-5, IL-8, IL-12p70, IL-17A, TNFα and TNFβ levels compared to Caucasians. Among candidate predictor variables (age, body mass index, insulin resistance and POP levels, high levels of PCBs were the only predictor accounting for a small but significant effect of observed variance (∼7% in cytokine levels. Overall, a weak but significant association is detected between persistent organochlorine pollutant exposure and elevated cytokine levels. This finding augments the already existing information that environmental pollution is related to inflammation, a common feature of several metabolic disorders that are known to be especially prevalent in Canada's remote First Nations communities.

Response inhibition under alcohol: effects of cognitive and motivational conflict.

Science.gov (United States)

Fillmore, M T; Vogel-Sprott, M

2000-03-01

This experiment tested the effect of cognitive and motivational conflict on response inhibition under alcohol. Fifty-six male social drinkers were randomly assigned to one of eight groups (n = 8). Four pairs of groups received 0.62 g/kg of alcohol, or a placebo, and each pair performed a go/stop choice reaction time task under one of four conflict conditions. One condition (C) produced cognitive conflict by presenting "go" and "stop" signals in the task. Another condition (IR) added motivational conflict by administering an equal monetary reward for inhibiting responses to stop-signals, and for responding to go-signals. The remaining two conditions resolved the motivational conflict by administering the monetary reward only for inhibitions (I), or only for responses (R). Compared with placebo, alcohol reduced inhibitions (i.e., impaired inhibitory control) under cognitive conflict (C; p = .041) and under motivational conflict (IR; p = .012). No significant effect of alcohol on inhibitions was observed in conditions where conflict was resolved (i.e., I and R). The study shows that alcohol can reduce the ability to inhibit a response. However, impaired inhibitory control is not an inevitable outcome of the drug action, because it can be counteracted by the consequences of behavior in the situation.

Male Seminal Relaxin Contributes to Induction of the Post-mating Cytokine Response in the Female Mouse Uterus

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Danielle J. Glynn

2017-06-01

Full Text Available The hormone relaxin is important in female reproduction for embryo implantation, cardiovascular function, and during labor and lactation. Relaxin is also synthesized in males by organs of the male tract. We hypothesized that relaxin might be one component of seminal plasma responsible for eliciting the female cytokine response induced in the uterus at mating. When recombinant relaxin was injected into the uterus of wild-type (Rln+/+ mice at estrus, it evoked the production of Cxcl1 mRNA and its secreted protein product CXCL1 in four of eight animals. Mating experiments were then conducted using mice with a null mutation in the relaxin gene (Rln−/− mice. qRT-PCR analysis of mRNA expression in wild-type females showed diminished uterine expression of several cytokine and chemokine genes in the absence of male relaxin. Similar differences were also noted comparing Rln−/− and Rln+/+ females mated to wild-type males. Quantification of uterine luminal fluid cytokine content confirmed that male relaxin provokes the production of CXCL10 and CSF3 in Rln+/+ females. Differences were also seen comparing Rln−/− and Rln+/+ females mated with Rln−/− males for CXCL1, CSF3, and CCL5, implying that endogenous relaxin in females might prime the uterus to respond appropriately to seminal fluid at coitus. Finally, pan-leukocyte CD45 mRNA was increased in wild-type matings compared to other combinations, implying that male and female relaxin may trigger leukocyte expansion in the uterus. We conclude that male and/or female relaxin may be important in activating the uterine cytokine/chemokine network required to initiate maternal immune adaptation to pregnancy.

PAMs ameliorates the imiquimod-induced psoriasis-like skin disease in mice by inhibition of translocation of NF-κB and production of inflammatory cytokines.

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Rongkun Dou

Full Text Available Psoriasis is a chronic and persistent inflammatory skin disease seriously affecting the quality of human life. In this study, we reported an ancient formula of Chinese folk medicine, the natural plant antimicrobial solution (PAMs for its anti-inflammatory effects and proposed the primary mechanisms on inhibiting the inflammatory response in TNF-α/IFN-γ-induced HaCaT cells and imiquimod-induced psoriasis-like skin disease mouse model. Two main functional components of hydroxysafflor Yellow A and allantoin in PAMs were quantified by HPLC to be 94.2±2.2 and 262.9±12.5 μg/mL respectively. PAMs could significantly reduce the gene expression and inflammatory cytokines production of Macrophage-Derived Chemokine (MDC, IL-8 and IL-6 in TNF-α/IFN-γ-induced HaCaT cells. PAMs also significantly ameliorates the psoriatic-like symptoms in a mouse model with the evaluation scores for both the single (scales, thickness, erythema and cumulative features were in the order of blank control < Dexamethasone < PAMs < 50% ethanol < model groups. The results were further confirmed by hematoxylin-eosin staining, RT-qPCR and immunohistochemistry. The down-regulated gene expression of IL-8, TNF-α, ICAM-1 and IL-23 in mouse tissues was consistent with the results from those of the HaCaT cells. The inhibition of psoriasis-like skin inflammation by PAMs was correlated with the inactivation of the translocation of P65 protein into cellular nucleus, indicating the inhibition of the inflammatory NF-κB signaling pathway. Taken together, these findings suggest that PAMs may be a promising drug candidate for the treatment of inflammatory skin disorders, such as psoriasis.

Improving response inhibition in Parkinson's disease with atomoxetine.

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Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

2015-04-15

Dopaminergic drugs remain the mainstay of Parkinson's disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Patients with Parkinson's disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson's disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson's disease. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Cytokines in the host response to Candida vaginitis: Identifying a role for non-classical immune mediators, S100 alarmins

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Yano, Junko; Noverr, Mairi C.; Fidel, Paul L.

2011-01-01

Vulvovaginal candidiasis (VVC), caused by Candida albicans, affects a significant number of women during their reproductive years. More than two decades of research have been focused on the mechanisms associated with susceptibility or resistance to symptomatic infection. Adaptive immunity by Th1-type CD4+ T cells and downstream cytokine responses are considered the predominant host defense mechanisms against mucosal Candida infections. However, numerous clinical and animal studies have indicated no or limited protective role of cells and cytokines of the Th1 or Th2 lineage against vaginal infection. The role for Th17 is only now begun to be investigated in-depth for VVC with results already showing significant controversy. On the other hand, a clinical live-challenge study and an established animal model have shown that a symptomatic condition is intimately associated with the vaginal infiltration of polymorphonuclear leukocytes (PMNs) but with no effect on vaginal fungal burden. Subsequent studies identified S100A8 and S100A9 Alarmins as key chemotactic mediators of the acute PMN response. These chemotactic danger signals appear to be secreted by vaginal epithelial cells upon interaction and early adherence of Candida. Thus, instead of a putative immunodeficiency against Candida involving classical immune cells and cytokines of the adaptive response, the pathological inflammation in VVC is now considered a consequence of a non-productive innate response initiated by non-classical immune mediators. PMID:22182685

Anti-cytokine therapies in T1D

DEFF Research Database (Denmark)

Nepom, Gerald T; Ehlers, Mario; Mandrup-Poulsen, Thomas

2013-01-01

Therapeutic targeting of proinflammatory cytokines is clinically beneficial in several autoimmune disorders. Several of these cytokines are directly implicated in the pathogenesis of type 1 diabetes, suggesting opportunities for design of clinical trials in type 1 diabetes that incorporate select...... suitable for modulating the immune response in T1D....

Aeromonas caviae strain induces Th1 cytokine response in mouse intestinal tract

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Hayes, S L; Lye, D J; McKinstry, Craig A.; Vesper, Sephen J.

2010-01-01

Aeromonas caviae has been associated with human gastrointestinal disease. Strains of this species typically lack virulence factors (VFs) such as enterotoxins and hemolysins that are produced by other human pathogens of the Aeromonas genus. Microarray profiling of murine small intestinal extracts, 24 hours after oral infection with an A. caviae strain, provides evidence of a Th1 type immune response. A large number of gamma-interferon (γ-IFN) induced genes are up-regulated as well as several tumor necrosis factor-alpha (TNF-α) transcripts. A. caviae has always been considered as opportunistic pathogen because it lacks obvious virulence factors. This current effort suggests that an A. caviae strain can colonize the murine intestinal tract and cause what has been described by others as a dysregulatory cytokine response. This response could explain why a number of diarrheal waterborne disease cases have been attributed to A. caviae even though it lacks obvious enteropathogenic properties.

Elaeocarpusin Inhibits Mast Cell-Mediated Allergic Inflammation

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Min-Jong Kim

2018-06-01

Full Text Available Mast cells are major effector cells for allergic responses that act by releasing inflammatory mediators, such as histamine and pro-inflammatory cytokines. Accordingly, different strategies have been pursued to develop anti-allergic and anti-inflammatory candidates by regulating the function of mast cells. The purpose of this study was to determine the effectiveness of elaeocarpusin (EL on mast cell-mediated allergic inflammation. We isolated EL from Elaeocarpus sylvestris L. (Elaeocarpaceae, which is known to possess anti-inflammatory properties. For this study, various sources of mast cells and mouse anaphylaxis models were used. EL suppressed the induction of markers for mast cell degranulation, such as histamine and β-hexosaminidase, by reducing intracellular calcium levels. Expression of pro-inflammatory cytokines, such as tumor necrosis factor-α and IL-4, was significantly decreased in activated mast cells by EL. This inhibitory effect was related to inhibition of the phosphorylation of Fyn, Lyn, Syk, and Akt, and the nuclear translocation of nuclear factor-κB. To confirm the effect of EL in vivo, immunoglobulin E-mediated passive cutaneous anaphylaxis (PCA and ovalbumin-induced active systemic anaphylaxis (ASA models were induced. EL reduced the PCA reaction in a dose dependent manner. In addition, EL attenuated ASA reactions such as hypothemia, histamine release, and IgE production. Our results suggest that EL is a potential therapeutic candidate for allergic inflammatory diseases that acts via the inhibition of mast cell degranulation and expression of proinflammatory cytokines.

Inhibition of the immune response to experimental fresh osteoarticular allografts

International Nuclear Information System (INIS)

Rodrigo, J.J.; Schnaser, A.M.; Reynolds, H.M. Jr.; Biggart, J.M. III; Leathers, M.W.; Chism, S.E.; Thorson, E.; Grotz, T.; Yang, Q.M.

1989-01-01

The immune response to osteoarticular allografts is capable of destroying the cartilage--a tissue that has antigens on its cells identical to those on the bone and marrow cells. Osteoarticular allografts of the distal femur were performed in rats using various methods to attempt to temporarily inhibit the antibody response. The temporary systemic immunosuppressant regimens investigated were cyclophosphamide, azathioprine and prednisolone, cyclosporine A, and total lymphoid irradiation. The most successful appeared to be cyclosporine A, but significant side effects were observed. To specifically inhibit the immune response in the allograft antigens without systemically inhibiting the entire immune system, passive enhancement and preadministration of donor blood were tried. Neither was as effective as coating the donor bone with biodegradable cements, a method previously found to be successful. Cyclosporine A was investigated in dogs in a preliminary study of medial compartmental knee allografts and was found to be successful in inhibiting the antibody response and in producing a more successful graft; however, some significant side effects were similarly observed

Sex differences in emotional contexts modulation on response inhibition.

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Ramos-Loyo, Julieta; Angulo-Chavira, Armando; Llamas-Alonso, Luis A; González-Garrido, Andrés A

2016-10-01

The aim of the present study was to explore sex differences in the effects that emotional contexts exert on the temporal course of response inhibition using event-related potentials (ERP). Participants performed a Go-NoGo response inhibition task under 3 context conditions: with 1) neutral background stimuli, and 2) pleasant, and 3) unpleasant emotional contexts. No sex differences were found in relation to accuracy. Women showed higher N2NoGo amplitudes than men in both emotional contexts; whereas during inhibition men tended to show higher P3NoGo amplitudes than women in the unpleasant context. Both groups experienced a relevant effect of the presence of the unpleasant context during inhibition processing, as shown by the enhancement of the N2NoGo amplitudes in frontal regions compared to results from the neutral and pleasant conditions. In addition, women showed differences between the pleasant and unpleasant contexts, with the latter inducing higher amplitude values. Only in men did inhibition accuracy correlate with higher N2NoGo and lower P3NoGo amplitudes in the emotional context conditions. These findings suggest that when an inhibition task is performed in an emotionally-neutral background context no sex differences are observed in either accuracy or ERP components. However, when the emotional context was introduced -especially the unpleasant one- some gender differences did become evident. The higher N2NoGo amplitude at the presence of the unpleasant context may reflect an effect on attention and conflict monitoring. In addition, results suggest that during earlier processing stages, women invested more resources to process inhibition than men. Furthermore, men who invested more neural resources during earlier stages showed better response inhibition than those who did it during later processing stages, more closely-related to cognitive and motor inhibition processes. Copyright © 2016 Elsevier Ltd. All rights reserved.

PORCINE CYTOKINE RESPONSES TO PAMP-STRUCTURES IN VITRO

DEFF Research Database (Denmark)

Sørensen, Nanna Skall; Skovgaard, Kerstin; Vorsholt, Henriette

Pathogen-associated molecular patterns (PAMPs) are conserved microbial structures recognized by pattern-recognition receptors (PRRs) of the innate immune system. Binding of PAMPs by certain PRRs on dendritic cells induces these to express costimulatory molecules and cytokines, enabling an inducti...

Aspergillus fumigatus conidial melanin modulates host cytokine response.

NARCIS (Netherlands)

Chai, L.; Netea, M.G.; Sugui, J.; Vonk, A.G.; Sande, W.W. van de; Warris, A.; Kwon-Chung, K.J.; Kullberg, B.J.

2010-01-01

Melanin biopigments have been linked to fungal virulence. Aspergillus fumigatus conidia are melanised and are weakly immunogenic. We show that melanin pigments on the surface of resting Aspergillus fumigatus conidia may serve to mask pathogen-associated molecular patterns (PAMPs)-induced cytokine

Markers of liver function and inflammatory cytokines modulation by ...

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Conclusion: Aerobic exercise training modulates inflammatory cytokine levels and markers of liver function in patients with nonalcoholic ... and is associated with over nutrition and under activity, ... of these subjects with leptin reduced liver fat and liver enzyme ... tissue, muscle-released interleukin-6 inhibition of tumor.

Response inhibition signals and miscoding of direction in dorsomedial striatum

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Daniel W Bryden

2012-09-01

Full Text Available The ability to inhibit action is critical for everyday behavior and is affected by a variety of disorders. Behavioral control and response inhibition is thought to depend on a neural circuit that includes the dorsal striatum, yet the neural signals that lead to response inhibition and its failure are unclear. To address this issue, we recorded from neurons in rat dorsomedial striatum (mDS in a novel task in which rats responded to a spatial cue that signaled that reward would be delivered either to the left or to the right. On 80% of trials rats were instructed to respond in the direction cued by the light (GO. On 20% of trials a second light illuminated instructing the rat to refrain from making the cued movement and move in the opposite direction (STOP. Many neurons in mDS encoded direction, firing more or less strongly for GO movements made ipsilateral or contralateral to the recording electrode. Neurons that fired more strongly for contralateral GO responses were more active when rats were faster, showed reduced activity on STOP trials, and miscoded direction on errors, suggesting that when these neurons were overly active, response inhibition failed. Neurons that decreased firing for contralateral movement were excited during trials in which the rat was required to stop the ipsilateral movement. For these neurons activity was reduced when errors were made and was negatively correlated with movement time suggesting that when these neurons were less active on STOP trials, response inhibition failed. Finally, the activity of a significant number of neurons represented a global inhibitory signal, firing more strongly during response inhibition regardless of response direction. Breakdown by cell type suggests that putative medium spiny neurons tended to fire more strongly under STOP trials, whereas putative interneurons exhibited both activity patterns. 

Atomoxetine restores the response inhibition network in Parkinson’s disease

Science.gov (United States)

Rae, Charlotte L.; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E.; Jones, P. Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

2016-01-01

Abstract Parkinson’s disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson’s disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson’s disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson’s disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson’s disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced

Virulent Type A Francisella tularensis actively suppresses cytokine responses in human monocytes

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Devyn D Gilette

2014-04-01

Full Text Available Francisella tularensis is a Gram-negative facultative bacterium that can cause the disease tularemia, even upon exposure to low numbers of bacteria. One critical characteristic of Francisella is its ability to dampen or subvert the host immune response. Previous work has shown that monocytes infected with highly virulent F. tularensis subsp. tularensis strain Schu S4 responded with a general pattern of quantitatively reduced pro-inflammatory signaling pathway genes and cytokine production in comparison to those infected with the less virulent related F. novicida. However, it has been unclear whether the virulent Schu S4 was merely evading or actively suppressing monocyte responses. By using mixed infection assays with F. tularensis and F. novicida, we show that F. tularensis actively suppresses monocyte pro-inflammatory responses. Additional experiments show that this suppression occurs in a dose-dependent manner and is dependent upon the viability of F. tularensis. Importantly, F. tularensis was able to suppress pro-inflammatory responses to earlier infections with F. novicida. These results lend support that F. tularensis actively dampens human monocyte responses and this likely contributes to its enhanced pathogenicity.

TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTCL.

Science.gov (United States)

Kremer, Kimberly N; Dinkel, Brittney A; Sterner, Rosalie M; Osborne, Douglas G; Jevremovic, Dragan; Hedin, Karen E

2017-08-24

As with many immunopathologically driven diseases, the malignant T cells of cutaneous T-cell lymphomas (CTCLs), such as Sézary syndrome, display aberrant cytokine secretion patterns that contribute to pathology and disease progression. Targeting this disordered release of cytokines is complicated by the changing cytokine milieu that drives the phenotypic changes of CTCLs. Here, we characterize a novel signaling pathway that can be targeted to inhibit the secretion of cytokines by modulating either CXCR4 or CXCR4-mediated signaling. We demonstrate that upon ligation of the T-cell antigen receptor (TCR), the TCR associates with and transactivates CXCR4 via phosphorylation of S339-CXCR4 in order to activate a PREX1-Rac1-signaling pathway that stabilizes interleukin-2 (IL-2) , IL-4 , and IL-10 messenger RNA (mRNA) transcripts. Pharmacologic inhibition of either TCR-CXCR4 complex formation or PREX1-Rac1 signaling in primary human T cells decreased mRNA stability and inhibited secretion of IL-2, IL-4, and IL-10. Applying this knowledge to Sézary syndrome, we demonstrate that targeting various aspects of this signaling pathway blocks both TCR-dependent and TCR-independent cytokine secretion from a Sézary syndrome-derived cell line and patient isolates. Together, these results identify multiple aspects of a novel TCR-CXCR4-signaling pathway that could be targeted to inhibit the aberrant cytokine secretion that drives the immunopathogenesis of Sézary syndrome and other immunopathological diseases. © 2017 by The American Society of Hematology.

Celastrol Alleviates Airway Hyperresponsiveness and Inhibits Th17 Responses in Obese Asthmatic Mice

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Zeyu Zeng

2018-01-01

Full Text Available Severe airway hyperresponsiveness (AHR is a clinical feature of asthma, which has been associated with obesity and has shown a poor response to standard asthma treatments such as glucocorticoids. Numerous studies have shown that Interleukin (IL-17 producing CD4+T cells (Th17 cells, which could be inhibited by celastrol, is essential in mediating steroid-resistant AHR. The following study investigates the impact of celastrol and its mechanism on the regulation of AHR in murine model of obesity and asthma. C57BL/6 mice were sensitized by intraperitoneal injection of ovalbumin (OVA on day 1 and 13 starting from 12th week, which was followed by aerosol OVA challenge that lasted for 30 min per daily for 7 consecutive days starting from 16th week. Diet-induced obesity (DIO mice were fed a high fat diet (HFD for 16 weeks. Celastrol was administrated orally for 7 consecutive days, 30 min before every challenge in DIO-OVA-induced mice. Lung functions were analyzed by measuring the airway resistance (Rn and methacholine (MCh AHR, while H&E staining was used to examine histological changes in the lungs. Immunohistochemistry was used to observe IL-17A protein in lung tissues; flow cytometry to detect the proportion of Th17 cells in CD4+T cells. The concentration of cytokines IL-17A in serum was assessed by standardized sandwich ELISA, while the expression of IL-17A mRNA in lung was examined by quantitative real-time RT-PCR. Briefly, our data indicated that celastrol reduced body mass in DIO-OVA-induced obesity and asthma. Both baseline Rn and MCh AHR were significantly lower in celastrol group. Moreover, celastrol treatment decreased the frequency of Th17 cell expansion and reduced the production of IL-17A in both lung and serum. To sum up, our findings indicated that Th17 and its cytokine measured in the spleen and lung were closely associated with AHR. In addition, celastrol has shown the ability to suppress AHR through Th17 inhibition in obese asthmatic

INVESTIGATION OF CYTOKINE PROFILE IN PATIENTS WITH REACTIVE ARTHRITIS

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T. V. Gaponova

2008-01-01

Full Text Available Abstract. Pathogenesis of reactive arthritis (ReA is not clear yet. Several trials suggest that increased production of proinflammatory cytokines is responsible for development of arthritis in ReA, while other studies report that Th1 cytokine response in ReA is impaired in favor of Th2 response. The aim of our study was to investigate serum levels of cytokines IL-1β, IL-4, IL-6, TNFα, IFNγ and IL-1Ra in the patients with ReA of different etiology, as compared with infection-related arthritis. The results of our study had demonstrated that serum levels of IL-1β and TNFα in the patients with ReA were significantly higher, whereas IL-1Ra, IL-4, IL-6 proved to be significantly lower than in healthy controls. Serum levels of IL-6 were significantly higher in patients with chronic ReA, as compared to the cases of acute and recurrent ReA. No significant differences in cytokine profiles were found between the patients with ReA, and the persons with infection-related arthritis. The data obtained are, generally, suggestive for proinflammatory Th1 cytokine profile in ReA patients studied, this confirming the mostly assumed pathogenetic hypothesis for reactive arthritis where an underlying cytokine imbalance is suggested. (Med. Immunol., 2008, vol. 10, N 2-3, pp 167-172.

Placental-mediated increased cytokine response to lipopolysaccharides: a potential mechanism for enhanced inflammation susceptibility of the preterm fetus

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Ross MG

2012-07-01

Full Text Available Julie L Boles,1 Michael G Ross,1 Ron Beloosesky,2 Mina Desai,1 Louiza Belkacemi11Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Torrance, CA, USA; 2Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, IsraelBackground: Cerebral palsy is a nonprogressive motor impairment syndrome that has no effective cure. The etiology of most cases of cerebral palsy remains unknown; however, recent epidemiologic data have demonstrated an association between fetal neurologic injury and infection/inflammation. Maternal infection/inflammation may be associated with the induction of placental cytokines that could result in increased fetal proinflammatory cytokine exposure, and development of neonatal neurologic injury. Therefore, we sought to explore the mechanism by which maternal infection may produce a placental inflammatory response. We specifically examined rat placental cytokine production and activation of the Toll-like receptor 4 (TLR4 pathway in response to lipopolysaccharide exposure at preterm and near-term gestational ages.Methods: Preterm (e16 or near-term (e20 placental explants from pregnant rats were treated with 0, 1, or 10 µg/mL lipopolysaccharide. Explant integrity was assessed by lactate dehydrogenase assay. Interleukin-6 and tumor necrosis alpha levels were determined using enzyme-linked immunosorbent assay kits. TLR4 and phosphorylated nuclear factor kappa light chain enhancer of activated B cells (NFκB protein expression levels were determined by Western blot analysis.Results: At both e16 and e20, lactate dehydrogenase levels were unchanged by treatment with lipopolysaccharide. After exposure to lipopolysaccharide, the release of interleukin-6 and tumor necrosis alpha from e16 placental explants increased by 4-fold and 8–9-fold, respectively (P < 0.05 versus

Crosstalk between monocytes and myometrial smooth muscle in culture generates synergistic pro-inflammatory cytokine production and enhances myocyte contraction, with effects opposed by progesterone.

Science.gov (United States)

Rajagopal, S P; Hutchinson, J L; Dorward, D A; Rossi, A G; Norman, J E

2015-08-01

Both term and preterm parturition are characterized by an influx of macrophages and neutrophils into the myometrium and cervix, with co-incident increased peripheral blood monocyte activation. Infection and inflammation are strongly implicated in the pathology of preterm labour (PTL), with progesterone considered a promising candidate for its prevention or treatment. In this study, we investigated the effect of monocytes on myometrial smooth muscle cell inflammatory cytokine production both alone and in response to LPS, a TLR4 agonist used to trigger PTL in vivo. We also investigated the effect of monocytes on myocyte contraction. Monocytes, isolated from peripheral blood samples from term pregnant women, were cultured alone, or co-cultured with PHM1-41 myometrial smooth muscle cells, for 24 h. In a third set of experiments, PHM1-41 myocytes were cultured for 24 h in isolation. Cytokine secretion was determined by ELISA or multiplex assays. Co-culture of monocytes and myocytes led to synergistic secretion of pro-inflammatory cytokines and chemokines including IL-6, IL-8 and MCP-1, with the secretion being further enhanced by LPS (100 ng/ml). The synergistic secretion of IL-6 and IL-8 from co-cultures was mediated in part by direct cell-cell contact, and by TNF. Conditioned media from co-cultures stimulated contraction of PHM1-41 myocytes, and the effect was inhibited by progesterone. Both progesterone and IL-10 inhibited LPS-stimulated IL-6 and IL-8 secretion from co-cultures, while progesterone also inhibited chemokine secretion. These data suggest that monocytes infiltrating the myometrium at labour participate in crosstalk that potentiates pro-inflammatory cytokine secretion, an effect that is enhanced by LPS, and can augment myocyte contraction. These effects are all partially inhibited by progesterone. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Cytokine inhibition in chronic fatigue syndrome patients: study protocol for a randomized controlled trial.

Science.gov (United States)

Roerink, Megan E; Knoop, Hans; Bredie, Sebastian J H; Heijnen, Michael; Joosten, Leo A B; Netea, Mihai G; Dinarello, Charles A; van der Meer, Jos W M

2015-10-05

Chronic fatigue syndrome (CFS) is a medically unexplained syndrome for which no somatic or pharmacological treatment has been proven effective. Dysfunction of the cytokine network has been suspected to play a role in the pathophysiology of CFS. The disturbances of the cytokine network detected in CFS patients are highly variable, in part due to the lack of adequate controls in many studies. Furthermore, all studies have been performed on peripheral venous blood of patients. As cytokines mainly act in tissues, for example, the brain, the information that can be derived from peripheral blood cells is limited. The information regarding the possible role of cytokines in the pathophysiology could come from intervention studies in which the activities of relevant cytokines are reduced, for example, reducing interleukin-1, interleukin-6 or tumor necrosis factor. In this study, the clinical usefulness of anakinra, an IL-1 antagonist, will be assessed in patients with CFS. A randomized placebo-controlled, double-blind trial will be conducted. Fifty adult female patients meeting the Centers for Disease Control (CDC) criteria for CFS and without psychiatric co-morbidity will be included. After inclusion, patients will be randomized between treatment with anakinra (recombinant human interleukin-1 receptor antagonist) or placebo. Each group will be treated for 4 weeks. Outcome measures will be assessed at baseline, after 4 weeks of intervention, and 6 months after baseline assessment. The primary outcome measure will be fatigue severity at 4 weeks, measured with the validated Checklist of Individual Strength (CIS). Secondary outcome measures are functional impairment, physical and social functioning, psychological distress, pain severity, presence of accompanying symptoms, and cytokine and cortisol concentrations. This is the first randomized placebo-controlled trial that will evaluate the effect of interference with IL-1 on the experience of fatigue in patients with CFS. The

Cardiorespiratory control and cytokine profile in response to heat stress, hypoxia, and lipopolysaccharide (LPS) exposure during early neonatal period.

Science.gov (United States)

McDonald, Fiona B; Chandrasekharan, Kumaran; Wilson, Richard J A; Hasan, Shabih U

2016-02-01

Sudden infant death syndrome (SIDS) is one of the most common causes of postneonatal infant mortality in the developed world. An insufficient cardiorespiratory response to multiple environmental stressors (such as prone sleeping positioning, overwrapping, and infection), during a critical period of development in a vulnerable infant, may result in SIDS. However, the effect of multiple risk factors on cardiorespiratory responses has rarely been tested experimentally. Therefore, this study aimed to quantify the independent and possible interactive effects of infection, hyperthermia, and hypoxia on cardiorespiratory control in rats during the neonatal period. We hypothesized that lipopolysaccharide (LPS) administration will negatively impact cardiorespiratory responses to increased ambient temperature and hypoxia in neonatal rats. Sprague-Dawley neonatal rat pups were studied at postnatal day 6-8. Rats were examined at an ambient temperature of 33°C or 38°C. Within each group, rats were allocated to control, saline, or LPS (200 μg/kg) treatments. Cardiorespiratory and thermal responses were recorded and analyzed before, during, and after a hypoxic exposure (10% O2). Serum samples were taken at the end of each experiment to measure cytokine concentrations. LPS significantly increased cytokine concentrations (such as TNFα, IL-1β, MCP-1, and IL-10) compared to control. Our results do not support a three-way interaction between experimental factors on cardiorespiratory control. However, independently, heat stress decreased minute ventilation during normoxia and increased the hypoxic ventilatory response. Furthermore, LPS decreased hypoxia-induced tachycardia. Herein, we provide an extensive serum cytokine profile under various experimental conditions and new evidence that neonatal cardiorespiratory responses are adversely affected by dual interactions of environmental stress factors. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on

Immunotoxicity of aflatoxin B1: Impairment of the cell-mediated response to vaccine antigen and modulation of cytokine expression

International Nuclear Information System (INIS)

Meissonnier, Guylaine M.; Pinton, Philippe; Laffitte, Joelle; Cossalter, Anne-Marie; Gong, Yun Yun; Wild, Christopher P.; Bertin, Gerard; Galtier, Pierre; Oswald, Isabelle P.

2008-01-01

Aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus flavus or A. parasiticus, is a frequent contaminant of food and feed. This toxin is hepatotoxic and immunotoxic. The present study analyzed in pigs the influence of AFB1 on humoral and cellular responses, and investigated whether the immunomodulation observed is produced through interference with cytokine expression. For 28 days, pigs were fed a control diet or a diet contaminated with 385, 867 or 1807 μg pure AFB1/kg feed. At days 4 and 15, pigs were vaccinated with ovalbumin. AFB1 exposure, confirmed by an observed dose-response in blood aflatoxin-albumin adduct, had no major effect on humoral immunity as measured by plasma concentrations of total IgA, IgG and IgM and of anti-ovalbumin IgG. Toxin exposure did not impair the mitogenic response of lymphocytes but delayed and decreased their specific proliferation in response to the vaccine antigen, suggesting impaired lymphocyte activation in pigs exposed to AFB1. The expression level of pro-inflammatory (TNF-α, IL-1β, IL-6, IFN-γ) and regulatory (IL-10) cytokines was assessed by real-time PCR in spleen. A significant up-regulation of all 5 cytokines was observed in spleen from pigs exposed to the highest dose of AFB1. In pigs exposed to the medium dose, IL-6 expression was increased and a trend towards increased IFN-γ and IL-10 was observed. In addition we demonstrate that IL-6 impaired in vitro the antigenic- but not the mitogenic-induced proliferation of lymphocytes from control pigs vaccinated with ovalbumin. These results indicate that AFB1 dietary exposure decreases cell-mediated immunity while inducing an inflammatory response. These impairments in the immune response could participate in failure of vaccination protocols and increased susceptibility to infections described in pigs exposed to AFB1

Cytokines and Pancreatic β-Cell Apoptosis

DEFF Research Database (Denmark)

Berchtold, L A; Prause, M; Størling, J

2016-01-01

The discovery 30 years ago that inflammatory cytokines cause a concentration, activity, and time-dependent bimodal response in pancreatic β-cell function and viability has been a game-changer in the fields of research directed at understanding inflammatory regulation of β-cell function and survival...... and the causes of β-cell failure and destruction in diabetes. Having until then been confined to the use of pathophysiologically irrelevant β-cell toxic chemicals as a model of β-cell death, researchers could now mimic endocrine and paracrine effects of the cytokine response in vitro by titrating concentrations...... of local, chronic islet inflammation. Since then, numerous studies have clarified how these bimodal responses depend on discrete signaling pathways. Most interest has been devoted to the proapoptotic response dependent upon mainly nuclear factor κ B and mitogen-activated protein kinase activation, leading...

Amino acid substitutions in the melanoma antigen recognized by T cell 1 peptide modulate cytokine responses in melanoma-specific T cells

DEFF Research Database (Denmark)

Nielsen, M B; Kirkin, A F; Loftus, D

2000-01-01

enhances the production of mRNA for interleukin (IL)-5, IL-10, IL-13, IL-15, and interferon-gamma and significantly enhances release of IL-13 and IL-10 from anti-MART-1 cytotoxic T cells. Another heteroclitic peptide, 1L, with an A to L substitution in MART-1(27-35), also enhances the tyrosine...... phosphorylation response in anti-MART-1 cytotoxic CD8+ T cells. Yet, 1L does not enhance the production of T helper cell type 2-like cytokines (IL-10 and IL-13). Together these data show that minor amino acid modifications of immunodominant melanoma peptides profoundly influence the cytokine response in melanoma...

T cell cytokine responses to stimulation with Ureaplasma parvum in pregnancy.

Science.gov (United States)

Friedland, Yael D; Lee-Pullen, Tracey F; Nathan, Elizabeth A; Watts, Rory; Keelan, Jeffrey A; Payne, Matthew S; Ireland, Demelza J

2016-08-01

Ureaplasma spp. are a common vaginal microorganism causally linked to inflammation-driven preterm birth (PTB). The nature of the immune response to Ureaplasma spp. may influence PTB risk. This study sought to define maternal T cell cytokine responses to in vitro stimulation with Ureaplasma parvum serovar 3 (UpSV3) in vaginally colonised (UP+) and non-colonised (UP-) pregnant women. Whole blood flow cytometry demonstrated an increase (p=0.027) in the baseline frequency of IFNγ-positive CD3(+)CD4(-)(CD8(+)) T cells in UP+ women. UpSV3 stimulation resulted in a significant and specific increase (p=0.001) in the frequency of IFNγ-positive CD3(+)CD4(-)(CD8(+)) T cells, regardless of vaginal colonisation status. UpSV3 stimulation also increased the frequency of IFNγ-positive CD3(+)CD4(+) T cells, particularly in the UP+ group (p=0.003). This is the first published study to examine T cell responses to Ureaplasma spp. Future appropriately-powered studies are needed to assess whether insufficient priming or a loss of tolerance to Ureaplasma spp. is occurring in UP+ women at risk of PTB. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Changes in cerebro-cerebellar interaction during response inhibition after performance improvement.

Science.gov (United States)

Hirose, Satoshi; Jimura, Koji; Kunimatsu, Akira; Abe, Osamu; Ohtomo, Kuni; Miyashita, Yasushi; Konishi, Seiki

2014-10-01

It has been demonstrated that motor learning is supported by the cerebellum and the cerebro-cerebellar interaction. Response inhibition involves motor responses and the higher-order inhibition that controls the motor responses. In this functional MRI study, we measured the cerebro-cerebellar interaction during response inhibition in two separate days of task performance, and detected the changes in the interaction following performance improvement. Behaviorally, performance improved in the second day, compared to the first day. The psycho-physiological interaction (PPI) analysis revealed the interaction decrease from the right inferior frontal cortex (rIFC) to the cerebellum (lobule VII or VI). It was also revealed that the interaction increased from the same cerebellar region to the primary motor area. These results suggest the involvement of the cerebellum in response inhibition, and raise the possibility that the performance improvement was supported by the changes in the cerebro-cerebellar interaction. Copyright © 2014 Elsevier Inc. All rights reserved.

Viral Pseudo Enzymes Activate RIG-I via Deamidation to Evade Cytokine Production

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He, Shanping; Zhao, Jun; Song, Shanshan; He, Xiaojing; Minassian, Arlet; Zhou, Yu; Zhang, Junjie; Brulois, Kevin; Wang, Yuqi; Cabo, Jackson; Zandi, Ebrahim; Liang, Chengyu; Jung, Jae U; Zhang, Xuewu; Feng, Pinghui

2015-01-01

SUMMARY RIG-I is a pattern recognition receptor that senses viral RNA and is crucial for host innate immune defense. Here we describe a mechanism of RIG-I activation through amidotransferase-mediated deamidation. We show that viral homologues of phosphoribosylformyglycinamide synthase (PFAS), although lacking intrinsic enzyme activity, recruit cellular PFAS to deamidate and activate RIG-I. Accordingly, depletion and biochemical inhibition of PFAS impair RIG-I deamidation and concomitant activation. Purified PFAS and viral homologue thereof deamidate RIG-I in vitro. Ultimately, herpesvirus hijacks activated RIG-I to avoid antiviral cytokine production; loss of RIG-I or inhibition of RIG-I deamidation results in elevated cytokine production. Together, these findings demonstrate a surprising mechanism of RIG-I activation that is mediated by an enzyme. PMID:25752576

Cytokines as biomarkers of nanoparticle immunotoxicity.

Science.gov (United States)

Elsabahy, Mahmoud; Wooley, Karen L

2013-06-21

Nanoscale objects, whether of biologic origin or synthetically created, are being developed into devices for a variety of bionanotechnology diagnostic and pharmaceutical applications. However, the potential immunotoxicity of these nanomaterials and mechanisms by which they may induce adverse reactions have not received sufficient attention. Nanomaterials, depending on their characteristics and compositions, can interact with the immune system in several ways and either enhance or suppress immune system function. Cytokines perform pleiotropic functions to mediate and regulate the immune response and are generally recognized as biomarkers of immunotoxicity. While the specificity and validity of certain cytokines as markers of adverse immune response has been established for chemicals, small and macromolecular drugs, research on their applicability for predicting and monitoring the immunotoxicity of engineered nanomaterials is still ongoing. The goal of this review is to provide guidelines as to important cytokines that can be utilized for evaluating the immunotoxicity of nanomaterials and to highlight the role of those cytokines in mediating adverse reactions, which is of particular importance for the clinical development of nanopharmaceuticals and other nanotechnology-based products. Importantly, the rational design of nanomaterials of low immunotoxicity will be discussed, focusing on synthetic nanodevices, with emphasis on both the nanoparticle-forming materials and the embedded cargoes.

Instruction of hematopoietic lineage choice by cytokine signaling

Energy Technology Data Exchange (ETDEWEB)

Endele, Max; Etzrodt, Martin; Schroeder, Timm, E-mail: timm.schroeder@bsse.ethz.ch

2014-12-10

Hematopoiesis is the cumulative consequence of finely tuned signaling pathways activated through extrinsic factors, such as local niche signals and systemic hematopoietic cytokines. Whether extrinsic factors actively instruct the lineage choice of hematopoietic stem and progenitor cells or are only selectively allowing survival and proliferation of already intrinsically lineage-committed cells has been debated over decades. Recent results demonstrated that cytokines can instruct lineage choice. However, the precise function of individual cytokine-triggered signaling molecules in inducing cellular events like proliferation, lineage choice, and differentiation remains largely elusive. Signal transduction pathways activated by different cytokine receptors are highly overlapping, but support the production of distinct hematopoietic lineages. Cellular context, signaling dynamics, and the crosstalk of different signaling pathways determine the cellular response of a given extrinsic signal. New tools to manipulate and continuously quantify signaling events at the single cell level are therefore required to thoroughly interrogate how dynamic signaling networks yield a specific cellular response. - Highlights: • Recent studies provided definite proof for lineage-instructive action of cytokines. • Signaling pathways involved in hematopoietic lineage instruction remain elusive. • New tools are emerging to quantitatively study dynamic signaling networks over time.

Neutrophil-Derived Proteases Escalate Inflammation through Activation of IL-36 Family Cytokines

Directory of Open Access Journals (Sweden)

Conor M. Henry

2016-02-01

Full Text Available Recent evidence has strongly implicated the IL-1 family cytokines IL-36α, IL-36β, and IL-36γ as key initiators of skin inflammation. Similar to the other members of the IL-1 family, IL-36 cytokines are expressed as inactive precursors and require proteolytic processing for activation; however, the responsible proteases are unknown. Here, we show that IL-36α, IL-36β, and IL-36γ are activated differentially by the neutrophil granule-derived proteases cathepsin G, elastase, and proteinase-3, increasing their biological activity ∼500-fold. Active IL-36 promoted a strong pro-inflammatory signature in primary keratinocytes and was sufficient to perturb skin differentiation in a reconstituted 3D human skin model, producing features resembling psoriasis. Furthermore, skin eluates from psoriasis patients displayed significantly elevated cathepsin G-like activity that was sufficient to activate IL-36β. These data identify neutrophil granule proteases as potent IL-36-activating enzymes, adding to our understanding of how neutrophils escalate inflammatory reactions. Inhibition of neutrophil-derived proteases may therefore have therapeutic benefits in psoriasis.

The Effectiveness of Reward and Punishment Contingencies on Response Inhibition

Science.gov (United States)

Costantini, Arthur F.; Hoving, Kenneth L.

1973-01-01

The relative effectiveness of reward and punishment on the development of response inhibition was evaluated developmentally with kindergarteners and second graders. Removal of positive reinforcers was apparently more effective than reward in producing inhibiting at both age levels. Transfer of inhibition training was also evaluated. (DP)

Differential Role of Cathepsins S and B In Hepatic APC-Mediated NKT Cell Activation and Cytokine Secretion.

Science.gov (United States)

de Mingo Pulido, Álvaro; de Gregorio, Estefanía; Chandra, Shilpi; Colell, Anna; Morales, Albert; Kronenberg, Mitchell; Marí, Montserrat

2018-01-01

Natural killer T (NKT) cells exhibit a specific tissue distribution, displaying the liver the highest NKT/conventional T cell ratio. Upon antigen stimulation, NKT cells secrete Th1 cytokines, including interferon γ (IFNγ), and Th2 cytokines, including IL-4 that recruit and activate other innate immune cells to exacerbate inflammatory responses in the liver. Cysteine cathepsins control hepatic inflammation by regulating κB-dependent gene expression. However, the contribution of cysteine cathepsins other than Cathepsin S to NKT cell activation has remained largely unexplored. Here we report that cysteine cathepsins, cathepsin B (CTSB) and cathepsin S (CTSS), regulate different aspects of NKT cell activation. Inhibition of CTSB or CTSS reduced hepatic NKT cell expansion in a mouse model after LPS challenge. By contrast, only CTSS inhibition reduced IFNγ and IL-4 secretion after in vivo α-GalCer administration. Accordingly, in vitro studies reveal that only CTSS was able to control α-GalCer-dependent loading in antigen-presenting cells (APCs), probably due to altered endolysosomal protein degradation. In summary, our study discloses the participation of cysteine cathepsins, CTSB and CTSS, in the activation of NKT cells in vivo and in vitro .

Differential Role of Cathepsins S and B In Hepatic APC-Mediated NKT Cell Activation and Cytokine Secretion

Directory of Open Access Journals (Sweden)

Álvaro de Mingo Pulido

2018-02-01

Full Text Available Natural killer T (NKT cells exhibit a specific tissue distribution, displaying the liver the highest NKT/conventional T cell ratio. Upon antigen stimulation, NKT cells secrete Th1 cytokines, including interferon γ (IFNγ, and Th2 cytokines, including IL-4 that recruit and activate other innate immune cells to exacerbate inflammatory responses in the liver. Cysteine cathepsins control hepatic inflammation by regulating κB-dependent gene expression. However, the contribution of cysteine cathepsins other than Cathepsin S to NKT cell activation has remained largely unexplored. Here we report that cysteine cathepsins, cathepsin B (CTSB and cathepsin S (CTSS, regulate different aspects of NKT cell activation. Inhibition of CTSB or CTSS reduced hepatic NKT cell expansion in a mouse model after LPS challenge. By contrast, only CTSS inhibition reduced IFNγ and IL-4 secretion after in vivo α-GalCer administration. Accordingly, in vitro studies reveal that only CTSS was able to control α-GalCer-dependent loading in antigen-presenting cells (APCs, probably due to altered endolysosomal protein degradation. In summary, our study discloses the participation of cysteine cathepsins, CTSB and CTSS, in the activation of NKT cells in vivo and in vitro.

Invariant NKT cells regulate experimental autoimmune uveitis through inhibition of Th17 differentiation.

Science.gov (United States)

Oh, Keunhee; Byoun, Ok-Jin; Ham, Don-Il; Kim, Yon Su; Lee, Dong-Sup

2011-02-01

Although NKT cells have been implicated in diverse immunomodulatory responses, the effector mechanisms underlying the NKT cell-mediated regulation of pathogenic T helper cells are not well understood. Here, we show that invariant NKT cells inhibited the differentiation of CD4(+) T cells into Th17 cells both in vitro and in vivo. The number of IL-17-producing CD4(+) T cells was reduced following co-culture with purified NK1.1(+) TCR(+) cells from WT, but not from CD1d(-/-) or Jα18(-/-) , mice. Co-cultured NKT cells from either cytokine-deficient (IL-4(-/-) , IL-10(-/-) , or IFN-γ(-/-) ) or WT mice efficiently inhibited Th17 differentiation. The contact-dependent mechanisms of NKT cell-mediated regulation of Th17 differentiation were confirmed using transwell co-culture experiments. On the contrary, the suppression of Th1 differentiation was dependent on IL-4 derived from the NKT cells. The in vivo regulatory capacity of NKT cells on Th17 cells was confirmed using an experimental autoimmune uveitis model induced with human IRBP(1-20) (IRBP, interphotoreceptor retinoid-binding protein) peptide. NKT cell-deficient mice (CD1d(-/-) or Jα18(-/-) ) demonstrated an increased disease severity, which was reversed by the transfer of WT or cytokine-deficient (IL-4(-/-) , IL-10(-/-) , or IFN-γ(-/-) ) NKT cells. Our results indicate that invariant NKT cells inhibited autoimmune uveitis predominantly through the cytokine-independent inhibition of Th17 differentiation. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ghrelin’s Effects on Proinflammatory Cytokine Mediated Apoptosis and Their Impact on β-Cell Functionality

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Antonia Diaz-Ganete

2015-01-01

Full Text Available Ghrelin is a peptidic hormone, which stimulates cell proliferation and inhibits apoptosis in several tissues, including pancreas. In preclinical stage of type 1 diabetes, proinflammatory cytokines generate a destructive environment for β-cells known as insulitis, which results in loss of β-cell mass and impaired insulin secretion, leading to diabetes. Our aim was to demonstrate that ghrelin could preserve β-cell viability, turnover rate, and insulin secretion acting as a counter balance of cytokines. In the present work we reproduced proinflammatory milieu found in insulitis stage by treating murine cell line INS-1E and rat islets with a cytokine cocktail including IL-1β, IFNγ, and TNFα and/or ghrelin. Several proteins involved in survival pathways (ERK 1/2 and Akt/PKB and apoptosis (caspases and Bcl-2 protein family and endoplasmic reticulum stress markers as well as insulin secretion were analyzed. Our results show that ghrelin alone has no remarkable effects on β-cells in basal conditions, but interestingly it activates cell survival pathways, downregulates apoptotic mediators and endoplasmic reticulum stress, and restores insulin secretion in response to glucose when beta-cells are cytokine-exposed. These data suggest a potential role of ghrelin in preventing or slowing down the transition from a preclinical to clinically established diabetes by ameliorating the effects of insulitis on β-cells.

Response Inhibition and Internet Gaming Disorder: A Meta-analysis.

Science.gov (United States)

Argyriou, Evangelia; Davison, Christopher B; Lee, Tayla T C

2017-08-01

Previous research has demonstrated that Internet Gaming Disorder (IGD) has multiple negative effects in psychological functioning and health. This makes the identification of its underpinnings, such as response inhibition, essential for the development of relevant interventions that target these core features of the disorder resulting in more effective treatment. Several empirical studies have evaluated the relationship between response inhibition deficits and IGD using neurocognitive tasks, but provided mixed results. In this study, we conducted a meta-analysis of studies using three neurocognitive tasks, the Go/No Go, the Stroop, and the Stop-Signal tasks, to integrate existing research and estimate the magnitude of this relationship. We found a medium overall effect size (d=0.56, 95% CI [0.32, 0.80]) indicating that compared with healthy individuals, individuals with IGD are more likely to exhibit impaired response inhibition. This finding is in alignment with literature on inhibition and addictive and impulsive behaviors, as well as with neuroimaging research. Theoretical implications regarding the conceptualization of IGD as a clinical disorder, shared commonalities with externalizing psychopathology, and clinical implications for treatment are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Oral administration of Saccharomyces boulardii alters duodenal morphology, enzymatic activity and cytokine production response in broiler chickens.

Science.gov (United States)

Sun, Yajing; Rajput, Imran Rashid; Arain, Muhammad Asif; Li, Yanfei; Baloch, Dost Muhammad

2017-08-01

The present study evaluated the effects of Saccharomyces boulardii on duodenal digestive enzymes, morphology and cytokine induction response in broiler chicken. A total of 200 birds were allotted into two groups (n = 100) and each group divided into five replications (n = 20). The control group was fed basal diet in addition to antibiotic (virginiamycin 20 mg/kg), and treatment group received (1 × 10 8  colony-forming units/kg feed) S. boulardii in addition to basal diet lasting for 72 days. The results compared to control group revealed that adenosine triphosphatase, gamma glutamyl transpeptidase, lipase and trypsin activities were higher, while, no significant improvement was observed in amylase activities in the duodenum of the treatment group. Moreover, morphological findings showed that villus height, width and number of goblet cells markedly increased. Additionally, transmission electron microscopy visualized that villus height, width and structural condensation significantly increased in the treatment group. The immunohistological observations showed increased numbers of immunoglobulin A (IgA)-positive cells in the duodenum of the treatment group. Meanwhile, cytokine production levels of tumor necrosis factor-α, interleukin (IL)-10, transforming growth factor-β and secretory IgA markedly increased, and IL-6 statistically remained unchanged as compared to the control group. These findings illustrated that initial contact of S. boulardii to the duodenum has significant impact in improving enzymatic activity, intestinal morphology and cytokine response in broiler chicken. © 2016 Japanese Society of Animal Science.

A Newly Emergent Turkey Arthritis Reovirus Shows Dominant Enteric Tropism and Induces Significantly Elevated Innate Antiviral and T Helper-1 Cytokine Responses.

Directory of Open Access Journals (Sweden)

Tamer A Sharafeldin

Full Text Available Newly emergent turkey arthritis reoviruses (TARV were isolated from tendons of lame 15-week-old tom turkeys that occasionally had ruptured leg tendons. Experimentally, these TARVs induced remarkable tenosynovitis in gastrocnemius tendons of turkey poults. The current study aimed to characterize the location and the extent of virus replication as well as the cytokine response induced by TARV during the first two weeks of infection. One-week-old male turkeys were inoculated orally with TARV (O'Neil strain. Copy numbers of viral genes were estimated in intestines, internal organs and tendons at ½, 1, 2, 3, 4, 7, 14 days Post inoculation (dpi. Cytokine profile was measured in intestines, spleen and leg tendons at 0, 4, 7 and 14 dpi. Viral copy number peaked in jejunum, cecum and bursa of Fabricius at 4 dpi. Copy numbers increased dramatically in leg tendons at 7 and 14 dpi while minimal copies were detected in internal organs and blood during the same period. Virus was detected in cloacal swabs at 1-2 dpi, and peaked at 14 dpi indicating enterotropism of the virus and its early shedding in feces. Elevation of IFN-α and IFN-β was observed in intestines at 7 dpi as well as a prominent T helper-1 response (IFN-γ at 7 and 14 dpi. IFN-γ and IL-6 were elevated in gastrocnemius tendons at 14 dpi. Elevation of antiviral cytokines in intestines occurred at 7dpi when a significant decline of viral replication in intestines was observed. T helper-1 response in intestines and leg tendons was the dominant T-helper response. These results suggest the possible correlation between viral replication and cytokine response in early infection of TARV in turkeys. Our findings provide novel insights which help elucidate viral pathogenesis in turkey tendons infected with TARV.

Regulation and function of interleukin-36 cytokines.

Science.gov (United States)

Bassoy, Esen Yonca; Towne, Jennifer E; Gabay, Cem

2018-01-01

The interleukin (IL)-36 cytokines include 3 agonists, IL-36α, IL-36β, and IL-36γ that bind to a common receptor composed of IL-36R and IL-1RAcP to stimulate inflammatory responses. IL-36Ra is a natural antagonist that binds to IL-36R, but does not recruit the co-receptor IL-1RAcP and does not stimulate any intracellular responses. The IL-36 cytokines are expressed predominantly by epithelial cells and act on a number of cells including immune cells, epithelial cells, and fibroblasts. Processing of the N-terminus is required for full agonist or antagonist activity for all IL-36 members. The role of IL-36 has been extensively demonstrated in the skin where it can act on keratinocytes and immune cells to induce a robust inflammatory response that has been implicated in psoriatic disorders. Emerging data also suggest a role for this cytokine family in pulmonary and intestinal physiology and pathology. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Reinforcement and stimulant medication ameliorate deficient response inhibition in children with Attention-Deficit/Hyperactivity Disorder

Science.gov (United States)

Rosch, Keri S.; Fosco, Whitney D.; Pelham, William E.; Waxmonsky, James G.; Bubnik, Michelle G.; Hawk, Larry W.

2015-01-01

This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n=111, 25 girls) and typically-developing (TD) controls (n=33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions. PMID:25985978

Notch and presenilin regulate cellular expansion and cytokine secretion but cannot instruct Th1/Th2 fate acquisition.

Directory of Open Access Journals (Sweden)

Chin-Tong Ong

2008-07-01

Full Text Available Recent reports suggested that Delta1, 4 and Jagged1, 2 possessed the ability to instruct CD4(+ T cell into selection of Th1 or Th2 fates, respectively, although the underlying mechanism endowing the cleaved Notch receptor with memory of ligand involved in its activation remains elusive. To examine this, we prepared artificial antigen-presenting cells expressing either DLL1 or Jag1. Although both ligands were efficient in inducing Notch2 cleavage and activation in CD4(+ T or reporter cells, the presence of Lunatic Fringe in CD4(+ T cells inhibited Jag1 activation of Notch1 receptor. Neither ligand could induce Th1 or Th2 fate choice independently of cytokines or redirect cytokine-driven Th1 or Th2 development. Instead, we find that Notch ligands only augment cytokine production during T cell differentiation in the presence of polarizing IL-12 and IL-4. Moreover, the differentiation choices of naïve CD4(+ T cells lacking gamma-secretase, RBP-J, or both in response to polarizing cytokines revealed that neither presenilin proteins nor RBP-J were required for cytokine-induced Th1/Th2 fate selection. However, presenilins facilitate cellular proliferation and cytokine secretion in an RBP-J (and thus, Notch independent manner. The controversies surrounding the role of Notch and presenilins in Th1/Th2 polarization may reflect their role as genetic modifiers of T-helper cells differentiation.

Chemioxyexcitation (delta pO2/ROS)-dependent release of IL-1 beta, IL-6 and TNF-alpha: evidence of cytokines as oxygen-sensitive mediators in the alveolar epithelium.

Science.gov (United States)

Haddad, J J; Safieh-Garabedian, B; Saadé, N E; Kanaan, S A; Land, S C

2001-02-07

The signalling mechanisms in oxidative stress mediated by cytokines in the perinatal alveolar epithelium are not well known. In an in vitro model of fetal alveolar type II epithelial cells, we investigated the profile of cytokines in response to ascending Deltap O(2)regimen (oxyexcitation). The peak of TNF-alpha (4 h) preceded IL-1beta and IL-6 (6-9 h), indicating a positive feedback autocrine loop confirmed by exogenous rmTNF-alpha. Reactive oxygen species (ROS) induced a dose-dependent release of cytokines, an effect specifically obliterated by selective antioxidants of the hydroxyl radical (*OH) and superoxide anion (O(2)-). Actinomycin and cycloheximide blocked the induced production of cytokines, implicating transcriptional and translational control. Whilst the dismutating enzymes superoxide dismutase (SOD) and catalase were ineffective in reducing ROS-induced cytokines, MnP, a cell-permeating SOD mimetic, abrogated xanthine/xanthine oxidase-dependent cytokine release. Desferrioxamine mesylate, which inhibits the iron-catalysed generation of *OH via the Fenton reaction, exhibited a mild effect on the release of cytokines. Dynamic variation in alveolar p O(2)constitutes a potential signalling mechanism within the perinatal lung allowing upregulation of cytokines in an ROS-dependent manner. Copyright 2001 Academic Press.

Perillyl alcohol suppresses antigen-induced immune responses in the lung

International Nuclear Information System (INIS)

Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide; Nakagome, Kazuyuki; Harada, Hiroaki; Kawahata, Kimito; Tanaka, Ryoichi; Yamamoto, Kazuhiko; Dohi, Makoto

2014-01-01

Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4 + T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4 + T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects

Cytokines and cytokine networks target neurons to modulate long-term potentiation.

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Prieto, G Aleph; Cotman, Carl W

2017-04-01

Cytokines play crucial roles in the communication between brain cells including neurons and glia, as well as in the brain-periphery interactions. In the brain, cytokines modulate long-term potentiation (LTP), a cellular correlate of memory. Whether cytokines regulate LTP by direct effects on neurons or by indirect mechanisms mediated by non-neuronal cells is poorly understood. Elucidating neuron-specific effects of cytokines has been challenging because most brain cells express cytokine receptors. Moreover, cytokines commonly increase the expression of multiple cytokines in their target cells, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Here, we review evidence on both direct and indirect-mediated modulation of LTP by cytokines. We also describe novel approaches based on neuron- and synaptosome-enriched systems to identify cytokines able to directly modulate LTP, by targeting neurons and synapses. These approaches can test multiple samples in parallel, thus allowing the study of multiple cytokines simultaneously. Hence, a cytokine networks perspective coupled with neuron-specific analysis may contribute to delineation of maps of the modulation of LTP by cytokines. Copyright © 2017 Elsevier Ltd. All rights reserved.

Th-17 regulatory cytokines IL-21, IL-23, and IL-6 enhance neutrophil production of IL-17 cytokines during asthma.

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Halwani, Rabih; Sultana, Asma; Vazquez-Tello, Alejandro; Jamhawi, Amer; Al-Masri, Abeer A; Al-Muhsen, Saleh

2017-11-01

In a subset of severe asthma patients, chronic airway inflammation is associated with infiltration of neutrophils, Th-17 cells and elevated expression of Th-17-derived cytokines (e.g., interleukin [IL]-17, IL-21, IL-22). Peripheral neutrophils from allergic asthmatics are known to express higher IL-17 cytokine levels than those from healthy subjects, but the regulatory mechanisms involved are not well understood. We hypothesize that Th-17 regulatory cytokines could modulate IL-17 expression in neutrophils. Peripheral blood neutrophils isolated from asthmatics were stimulated with IL-21, IL-23, and IL-6 cytokines and their ability to produce IL-17A and IL-17F was determined relative to healthy controls. Signal transducer and activator of transcription 3 (STAT3) phosphorylation levels were measured in stimulated neutrophil using flow cytometry. The requirement for STAT3 phosphorylation was determined by blocking its activation using a specific chemical inhibitor. Stimulating asthmatic neutrophils with IL-21, 23, and 6 enhanced the production of IL-17A and IL-17F at significantly higher levels comparatively to healthy controls. Stimulating neutrophils with IL-21, IL-23, and IL-6 cytokines enhanced STAT3 phosphorylation, in all cases. Interestingly, inhibiting STAT3 phosphorylation using a specific chemical inhibitor dramatically blocked the ability of neutrophils to produce IL-17, demonstrating that STAT3 activation is the major factor mediating IL-17 gene expression. These findings suggest that neutrophil infiltration in lungs of severe asthmatics may represent an important source of pro-inflammatory IL-17A and -F cytokines, a production enhanced by Th-17 regulatory cytokines, and thus providing a feedback mechanism that sustains inflammation. Our results suggest that STAT3 pathway could be a potential target for regulating neutrophilic inflammation during severe asthma.

Resisting distraction and response inhibition trigger similar enhancements of future performance.

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Bissett, Patrick G; Grant, Lauren D; Weissman, Daniel H

2017-10-01

Resisting distraction and response inhibition are crucial aspects of cognitive control. Interestingly, each of these abilities transiently improves just after it is utilized. Competing views differ, however, as to whether utilizing either of these abilities (e.g., resisting distraction) enhances future performance involving the other ability (e.g., response inhibition). To distinguish between these views, we combined a Stroop-like task that requires resisting distraction with a restraint variant of the stop-signal task that requires response inhibition. We observed similar sequential-trial effects (i.e., performance enhancements) following trials in which participants (a) resisted distraction (i.e., incongruent go trials) and (b) inhibited a response (i.e., congruent stop trials). First, the congruency effect in go trials, which indexes overall distractibility, was smaller after both incongruent go trials and congruent stop trials than it was after congruent go trials. Second, stop failures were less frequent after both incongruent go trials and congruent stop trials than after congruent go trials. A control experiment ruled out the possibility that perceptual conflict or surprise engendered by occasional stop signals triggers sequential-trial effects independent of stopping. Thus, our findings support a novel, integrated view in which resisting distraction and response inhibition trigger similar sequential enhancements of future performance. Copyright © 2017 Elsevier B.V. All rights reserved.

T-helper cell-mediated proliferation and cytokine responses against recombinant Merkel cell polyomavirus-like particles.

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Arun Kumar

Full Text Available The newly discovered Merkel Cell Polyomavirus (MCPyV resides in approximately 80% of Merkel cell carcinomas (MCC. Causal role of MCPyV for this rare and aggressive skin cancer is suggested by monoclonal integration and truncation of large T (LT viral antigen in MCC cells. The mutated MCPyV has recently been found in highly purified leukemic cells from patients with chronic lymphocytic leukemia (CLL, suggesting a pathogenic role also in CLL. About 50-80% of adults display MCPyV-specific antibodies. The humoral immunity does not protect against the development of MCC, as neutralizing MCPyV antibodies occur in higher levels among MCC patients than healthy controls. Impaired T-cell immunity has been linked with aggressive MCC behavior. Therefore, cellular immunity appears to be important in MCPyV infection surveillance. In order to elucidate the role of MCPyV-specific Th-cell immunity, peripheral blood mononuclear cells (PBMC of healthy adults were stimulated with MCPyV VP1 virus-like particles (VLPs, using human bocavirus (HBoV VLPs and Candida albicans antigen as positive controls. Proliferation, IFN-γ, IL-13 and IL-10 responses were examined in 15 MCPyV-seropositive and 15 seronegative volunteers. With the MCPyV antigen, significantly stronger Th-cell responses were found in MCPyV-seropositive than MCPyV-seronegative subjects, whereas with the control antigens, the responses were statistically similar. The most readily detectable cytokine was IFN-γ. The MCPyV antigen tended to induce stronger IFN-γ responses than HBoV VLP antigen. Taken together, MCPyV-specific Th-cells elicit vigorous IFN-γ responses. IFN-γ being a cytokine with major antiviral and tumor suppressing functions, Th-cells are suggested to be important mediators of MCPyV-specific immune surveillance.

Maturation of cognitive control: delineating response inhibition and interference suppression.

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Christopher R Brydges

Full Text Available Cognitive control is integral to the ability to attend to a relevant task whilst suppressing distracting information or inhibiting prepotent responses. The current study examined the development of these two subprocesses by examining electrophysiological indices elicited during each process. Thirteen 18 year-old adults and thirteen children aged 8-11 years (mean=9.77 years completed a hybrid Go/Nogo flanker task while continuous EEG data were recorded. The N2 topography for both response inhibition and interference suppression changed with increasing age. The neural activation associated with response inhibition became increasingly frontally distributed with age, and showed decreases of both amplitude and peak latency from childhood to adulthood, possibly due to reduced cognitive demands and myelination respectively occurring during this period. Interestingly, a significant N2 effect was apparent in adults, but not observed in children during trials requiring interference suppression. This could be due to more diffuse activation in children, which would require smaller levels of activation over a larger region of the brain than is reported in adults. Overall, these results provide evidence of distinct maturational processes occurring throughout late childhood and adolescence, highlighting the separability of response inhibition and interference suppression.

The neural markers of an imminent failure of response inhibition.

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Bengson, Jesse J; Mangun, George R; Mazaheri, Ali

2012-01-16

In his novel Ulysses, James Joyce wrote that mistakes are the "…portals of discovery". The present study investigated the pre-stimulus oscillatory EEG signatures of selective attention and motor preparation that predicted failures of overt response inhibition. We employed a trial-by-trial spatial cueing task using a go/no-go response paradigm with bilateral target stimuli. Subjects were required to covertly attend to the spatial location cued on each trial and respond to most of the number targets (go trials) at that location while withholding responses for one designated number (no-go trials). We analyzed the post-cue/pre-target spectral patterns comparing no-go trials in which a response occurred in error (False Alarms, FA) with trials in which participants correctly withheld a response (Correct Rejections, CR). We found that cue-induced occipital alpha (8-12 Hz) lateralization and inter-frequency anti-correlations between the motor beta (18-24 Hz) and pre-frontal theta (3-5 Hz) bands each independently predicted subsequent failures of response inhibition. Based on these findings, we infer that independent perceptual and motor mechanisms operate in parallel to contribute to failures of response inhibition. Copyright © 2011 Elsevier Inc. All rights reserved.

Invasion of human aortic endothelial cells by oral viridans group streptococci and induction of inflammatory cytokine production.

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Nagata, E; de Toledo, A; Oho, T

2011-02-01

Oral viridans group streptococci are the major commensal bacteria of the supragingival oral biofilm and have been detected in human atheromatous plaque. Atherosclerosis involves an ongoing inflammatory response, reportedly involving chronic infection caused by multiple pathogens. The aim of this study was to examine the invasion of human aortic endothelial cells (HAECs) by oral viridans group streptococci and the subsequent cytokine production by viable invaded HAECs. The invasion of HAECs by bacteria was examined using antibiotic protection assays and was visualized by confocal scanning laser microscopy. The inhibitory effects of catalase and cytochalasin D on the invasion of HAECs were also examined. The production of cytokines by invaded or infected HAECs was determined using enzyme-linked immunosorbent assays, and a real-time polymerase chain reaction method was used to evaluate the expression of cytokine messenger RNA. The oral streptococci tested were capable of invading HAECs. The number of invasive bacteria increased with the length of the co-culture period. After a certain co-culture period, some organisms were cytotoxic to the HAECs. Catalase and cytochalasin D inhibited the invasion of HAECs by the organism. HAECs invaded by Streptococcus mutans Xc, Streptococcus gordonii DL1 (Challis), Streptococcus gordonii ATCC 10558 and Streptococcus salivarius ATCC 13419 produced more cytokine(s) (interleukin-6, interleukin-8, monocyte chemoattractant protein-1) than non-invaded HAECs. The HAECs invaded by S. mutans Xc produced the largest amounts of cytokines, and the messenger RNA expression of cytokines by invaded HAECs increased markedly compared with that by non-invaded HAECs. These results suggest that oral streptococci may participate in the pathogenesis of atherosclerosis. © 2010 John Wiley & Sons A/S.

Improving Response Inhibition in Parkinson’s Disease with Atomoxetine

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Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R.; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L.; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.; Rowe, James B.

2015-01-01

Background Dopaminergic drugs remain the mainstay of Parkinson’s disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. Methods This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Results Patients with Parkinson’s disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. Conclusions This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinson’s disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson’s disease. PMID:24655598

The inflammatory cytokines: molecular biomarkers for major depressive disorder?

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Martin, Charlotte; Tansey, Katherine E; Schalkwyk, Leonard C; Powell, Timothy R

2015-01-01

Cytokines are pleotropic cell signaling proteins that, in addition to their role as inflammatory mediators, also affect neurotransmitter systems, brain functionality and mood. Here we explore the potential utility of cytokine biomarkers for major depressive disorder. Specifically, we explore how genetic, transcriptomic and proteomic information relating to the cytokines might act as biomarkers, aiding clinical diagnosis and treatment selection processes. We advise future studies to investigate whether cytokine biomarkers might differentiate major depressive disorder patients from other patient groups with overlapping clinical characteristics. Furthermore, we invite future pharmacogenetic studies to investigate whether early antidepressant-induced changes to cytokine mRNA or protein levels precede behavioral changes and act as longer-term predictors of clinical antidepressant response.

Resisting temptation: decreasing alcohol-related affect and drinking behavior by training response inhibition

NARCIS (Netherlands)

Houben, K.; Nederkoorn, C.; Wiers, R.W.; Jansen, A.

2011-01-01

According to dual-process models, excessive alcohol use emerges when response inhibition ability is insufficient to inhibit automatic impulses to drink alcohol. This study examined whether strengthening response inhibition for alcohol-related cues decreases alcohol intake. Fifty-two heavy drinking

Distinctive in vitro effects of T-cell growth cytokines on cytomegalovirus-stimulated T-cell responses of HIV-infected HAART recipients

International Nuclear Information System (INIS)

Patterson, Julie; Jesser, Renee; Weinberg, Adriana

2008-01-01

Functional immune reconstitution is limited after HAART, maintaining the interest in adjunctive immune-modulators. We compared in vitro the effects of the γ-chain T-cell growth cytokines IL-2, IL-4, IL-7 and IL-15 on cytomegalovirus-stimulated cell-mediated immunity. IL-2 and IL-15 increased cytomegalovirus-specific lymphocyte proliferation in HAART recipients, whereas IL-4 and IL-7 did not. The boosting effect of IL-2 and IL-15 on proliferation correlated with their ability to prevent late apoptosis. However, IL-2 increased the frequency of cells in early apoptosis, whereas IL-15 increased the frequency of fully viable cells. Both IL-2 and IL-15 increased cytomegalovirus-induced CD4 + and CD8 + T-cell proliferation and the synthesis of Th1 and pro-inflammatory cytokines and chemokines. However, only IL-2 increased the frequency of regulatory T cells and Th2 cytokine production, both of which have the potential to attenuate antiviral immune responses. Overall, compared to other γ-chain cytokines, IL-15 had the most favorable profile for boosting antiviral cell-mediated immunity

Differential effect of conditioning regimens on cytokine responses during allogeneic stem cell transplantation

DEFF Research Database (Denmark)

Andersen, J; Heilmann, C; Jacobsen, N

2006-01-01

The purpose of this study was to characterize cytokine responses during conditioning in patients undergoing allogeneic stem cell transplantation (SCT) with the aim to identify which markers that may reliably reflect inflammatory activity during conditioning. We investigated inflammatory and anti.......002), followed by VP-16 (184%, P=0.03), cyclophosphamide (129%, P=0.03) and total body irradiation (148%, P=0.0005). Administration of i.v. busulfan (Busilvex; BU) was not associated with significant changes in sTNFRI levels. At day 0 (the day of stem cell infusion) the sTNFRI levels were not only elevated...

Impaired right inferior frontal gyrus response to contextual cues in male veterans with PTSD during response inhibition.

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van Rooij, Sanne J H; Rademaker, Arthur R; Kennis, Mitzy; Vink, Matthijs; Kahn, René S; Geuze, Elbert

2014-09-01

Posttraumatic stress disorder (PTSD) is often associated with impaired fear inhibition and decreased safety cue processing; however, studies capturing the cognitive aspect of inhibition and contextual cue processing are limited. In this fMRI study, the role of contextual cues in response inhibition was investigated. Male medication-naive war veterans with PTSD, male control veterans (combat controls) and healthy nonmilitary men (healthy controls) underwent fMRI while performing the stop-signal anticipation task (SSAT). The SSAT evokes 2 forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipation of stopping based on contextual cues). We enrolled 28 veterans with PTSD, 26 combat controls and 25 healthy controls in our study. Reduced reactive inhibition was observed in all veterans, both with and without PTSD, but not in nonmilitary controls, whereas decreased inhibition of the left pre/postcentral gyrus appeared to be specifically associated with PTSD. Impaired behavioural proactive inhibition was also specific to PTSD. Furthermore, the PTSD group showed a reduced right inferior frontal gyrus response during proactive inhibition compared with the combat control group. Most patients with PTSD had comorbid psychiatric disorders, but such comorbidity is common in patients with PTSD. Also, the education level (estimate of intelligence) of participants, but not of their parents, differed among the groups. Our findings of reduced proactive inhibition imply that patients with PTSD show reduced contextual cue processing. These results complement previous findings on fear inhibition and demonstrate that contextual cue processing in patients with PTSD is also reduced during cognitive processes, indicating a more general deficit.

Relationship of cytokines and cytokine signaling to immunodeficiency disorders in the mouse

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Morawetz R.A.

1998-01-01

Full Text Available The contributions of cytokines to the development and progression of disease in a mouse model of retrovirus-induced immunodeficiency (MAIDS are controversial. Some studies have indicated an etiologic role for type 2 cytokines, while others have emphasized the importance of type 1 cytokines. We have used mice deficient in expression of IL-4, IL-10, IL-4 and IL-10, IFN-g, or ICSBP - a transcriptional protein involved in IFN signaling - to examine their contributions to this disorder. Our results demonstrate that expression of type 2 cytokines is an epiphenomenon of infection and that IFN-g is a driving force in disease progression. In addition, exogenously administered IL-12 prevents many manifestations of disease while blocking retrovirus expression. Interruption of the IFN signaling pathways in ICSBP-/- mice blocks induction of MAIDS. Predictably, ICSBP-deficient mice exhibit impaired responses to challenge with several other viruses. This immunodeficiency is associated with impaired production of IFN-g and IL-12. Unexpectedly, however, the ICSBP-/- mice also develop a syndrome with many similarities to chronic myelogenous leukemia in humans. The chronic phase of this disease is followed by a fatal blast crisis characterized by clonal expansions of undifferentiated cells. ICSBP is thus an important determinant of hematopoietic growth and differentiation as well as a prominent signaling molecule for IFNs

Plasma cytokines do not reflect expression of pro- and anti-inflammatory cytokine mRNA at organ level after cardiopulmonary bypass in neonatal pigs

DEFF Research Database (Denmark)

Brix-Christensen, V.; Vestergaard, C.; Chew, M.

2003-01-01

Background: Plasma concentrations of inflammatory markers are increased in response to the trauma of cardiac surgery and cardiopulmonary bypass (CPB). It is, however, unknown whether the plasma cytokine levels and cytokine mRNA expression at organ level reflect each other. Methods: Twenty...

Differential responsiveness of obese (fa/fa) and lean (Fa/Fa) Zucker rats to cytokine-induced anorexia.

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Plata-Salamán, C R; Vasselli, J R; Sonti, G

1997-01-01

Pathophysiological and pharmacological concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in the cerebrospinal fluid (CSF) induce anorexia in normal rats. Obesity in humans and rodents is associated with increased TNF-alpha messenger RNA and protein levels in various cell types. This suggests that obese individuals may have differential regulation of cytokine production and dissimilar responsiveness to cytokines. In the present study, we investigated the effects of the intracerebroventricular (ICV) microinfusion of TNF-alpha (50, 100, and 500 ng/rat), IL-1 beta (1.0, 4.0, and 8.0 ng), and TNF-alpha (100 ng) plus IL-1 beta (1.0 ng) on obese (fa/fa) and lean (Fa/Fa) Zucker rats. The results show that: TNF-alpha and IL-1 beta, and the concomitant administration of TNF-alpha and IL-1 beta decreased the short-term (4 hours), nighttime (12 hours), and total daily food intakes in obese and lean rats; IL-1 beta was more potent relative to TNF-alpha; obese rats showed greater responsiveness to IL-1 beta: 8.0 ng IL-1 beta, for example, decreased the 12-hour food intake by 52% in obese and 22% in lean rats. On the other hand, obese and lean rats did not exhibit a significantly different responsiveness to the anorexia induced by 50, 100, or 500 ng TNF-alpha at the 4-hour period; and the concomitant ICV administration of TNF-alpha and IL-1 beta induced anorexia with additive (4-hour period) or synergistic (12-hour and 24-hour periods) effects in obese rats. The effect of TNF-alpha plus IL-1 beta in lean rats was greater than additive for the 12-hour and 24-hour periods. The difference in suppression of total daily food intake by TNF-alpha plus IL-1 beta in obese (-43%) versus lean (-23%) rats was significantly different (p < 0.01). The results show that obese (fa/fa) and lean (Fa/Fa) Zucker rats have differential responsiveness to the ICV microinfusion of two different classes of cytokines.

Single cell analysis of innate cytokine responses to pattern recognition receptor stimulation in children across four continents

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Smolen, Kinga K; Cai, Bing; Fortuno, Edgardo S; Gelinas, Laura; Larsen, Martin; Speert, David P; Chamekh, Mustapha; Kollmann, Tobias R

2014-01-01

Innate immunity instructs adaptive immunity, and suppression of innate immunity is associated with increased risk for infection. We had previously shown that whole blood cellular components from a cohort of South African children secreted significantly lower levels of most cytokines following stimulation of pattern recognition receptors (PRR) as compared to whole blood from cohorts of Ecuadorian, Belgian, or Canadian children. To begin dissecting the responsible molecular mechanisms, we now set out to identify the relevant cellular source of these differences. Across the four cohorts represented in our study, we identified significant variation in the cellular composition of whole blood; however, significant reduction of the intracellular cytokine production on the single cell level was only detected in South African childrens’ monocytes, cDC, and pDC. We also uncovered a marked reduction in polyfunctionality for each of these cellular compartments in South African children as compared to children from other continents. Together our data identify differences in cell composition as well as profoundly lower functional responses of innate cells in our cohort of South African children. A possible link between altered innate immunity and increased risk for infection or lower response to vaccines in South African infants needs to be explored. PMID:25135829

Pro-inflammatory Cytokines Are Involved in Fluoride-Induced Cytotoxic Potential in HeLa Cells.

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Wang, Hong-Wei; Zhou, Bian-Hua; Cao, Jian-Wen; Zhao, Jing; Zhao, Wen-Peng; Tan, Pan-Pan

2017-01-01

This study was designed to investigate the pro-inflammatory cytokines and their involvement in the cytotoxic potential of fluoride (F) in HeLa cells. HeLa cells were cultured with varying F concentrations (1-50 mg/L) for 48 h, and treatment effects were analyzed. The viability of HeLa cells was determined with a colorimetric method. The concentrations of IL-1β, IL-2, IL-6, and TNF-a in culture supernatant were measured through enzyme linked immunosorbent assay (ELISA). The mRNA expression levels of IL-1β, IL-2, IL-6 and TNF-a were subjected to transcript analysis and quantified through reverse transcription real-time PCR. Results showed that 10, 20 and 50 mg/L F significantly decreased the viability of HeLa cells incubated for 24 and 48 h. With their cytotoxic effect, the concentrations of IL-1β, IL-2, IL-6, and TNF-a decreased significantly in response to F, especially at 20 and 50 mg/L for 48 h. The mRNA expression levels of IL-1β, IL-2, IL-6, and TNF-a were downregulated at 50 mg/L F for 48 h. Therefore, F inhibited HeLa cell growth; as such, F could be used to alleviate the inhibition of pro-inflammatory cytokine expression.

A novel immune-to-CNS communication pathway: cells of the meninges surrounding the spinal cord CSF space produce proinflammatory cytokines in response to an inflammatory stimulus.

Science.gov (United States)

Wieseler-Frank, Julie; Jekich, Brian M; Mahoney, John H; Bland, Sondra T; Maier, Steven F; Watkins, Linda R

2007-07-01

Pain is enhanced in response to elevations of proinflammatory cytokines in spinal cerebrospinal fluid (CSF), following either intrathecal injection of these cytokines or intrathecal immune challenge with HIV-1 gp120 that induces cytokine release. Spinal cord glia have been assumed to be the source of endogenous proinflammatory cytokines that enhance pain. However, assuming that spinal cord glia are the sole source of CSF cytokines may be an underestimate, as the cellular composition of the meninges surrounding the spinal cord CSF space includes several cell types known to produce proinflammatory cytokines. The present experiments provide the first investigation of the immunocompetent nature of the spinal cord meninges. Here, we explore whether rat meninges are responsive to intrathecal gp120. These studies demonstrate that: (a) intrathecal gp120 upregulates meningeal gene expression of proinflammatory signals, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin 6 (IL-6), and inducible nitric oxide synthase (iNOS), and (b) intrathecal gp120 induces meningeal release of TNF-alpha, IL-1beta, and IL-6. In addition, stimulation of isolated meninges in vitro with gp120 induced the release of TNF-alpha and IL-1beta, indicating that the resident cells of the meninges are able to respond without immune cell recruitment. Taken together, these data document that the meninges are responsive to immunogenic stimuli in the CSF and that the meninges may be a source of immune products detected in CSF. The ability of the meninges to release to proinflammatory signals suggests a potential role in the modulation of pain.

In vitro cytokine responses to periodontal pathogens: generalized aggressive periodontitis is associated with increased IL-6 response to Porphyromonas gingivalis

DEFF Research Database (Denmark)

Borch, T S; Holmstrup, Palle; Bendtzen, K

2010-01-01

with GAgP and 10 controls stimulated with periodontal pathogens or a control antigen, tetanus toxoid (TT) in the presence of autologous serum. The pathogens used were Porphyromonas gingivalis, Prevotella intermedia and Fusobacterium nucleatum, either as type strains or bacteria isolated from...... the participants' inherent oral flora. The P. gingivalis -induced production of IL-6 was approximately 2.5-fold higher in patients with GAgP than in healthy controls (P gingivalis, as all cytokine...... responses induced by Pr. intermedia, F. nucleatum and TT was similar in the two groups. A reduced IL-12p70 response to Pr. intermedia and F. nucleatum was observed in smokers compared to non-smoking patients (P gingivalis, MNC...

Genetic influences on phase synchrony of brain oscillations supporting response inhibition.

Science.gov (United States)

Müller, Viktor; Anokhin, Andrey P; Lindenberger, Ulman

2017-05-01

Phase synchronization of neuronal oscillations is a fundamental mechanism underlying cognitive processing and behavior, including context-dependent response production and inhibition. Abnormalities in neural synchrony can lead to abnormal information processing and contribute to cognitive and behavioral deficits in neuropsychiatric disorders. However, little is known about genetic and environmental contributions to individual differences in cortical oscillatory dynamics underlying response inhibition. This study examined heritability of event-related phase synchronization of brain oscillations in 302 young female twins including 94 MZ and 57 DZ pairs performing a cued Go/No-Go version of the Continuous Performance Test (CPT). We used the Phase Locking Index (PLI) to assess inter-trial phase clustering (synchrony) in several frequency bands in two time intervals after stimulus onset (0-300 and 301-600ms). Response inhibition (i.e., successful response suppression in No-Go trials) was characterized by a transient increase in phase synchronization of delta- and theta-band oscillations in the fronto-central midline region. Genetic analysis showed significant heritability of the phase locking measures related to response inhibition, with 30 to 49% of inter-individual variability being accounted for by genetic factors. This is the first study providing evidence for heritability of task-related neural synchrony. The present results suggest that PLI can serve as an indicator of genetically transmitted individual differences in neural substrates of response inhibition. Copyright © 2016 Elsevier B.V. All rights reserved.

Regulation of cytokines by small RNAs during skin inflammation

Directory of Open Access Journals (Sweden)

Mikkelsen Jacob G

2010-07-01

Full Text Available Abstract Intercellular signaling by cytokines is a vital feature of the innate immune system. In skin, an inflammatory response is mediated by cytokines and an entwined network of cellular communication between T-cells and epidermal keratinocytes. Dysregulated cytokine production, orchestrated by activated T-cells homing to the skin, is believed to be the main cause of psoriasis, a common inflammatory skin disorder. Cytokines are heavily regulated at the transcriptional level, but emerging evidence suggests that regulatory mechanisms that operate after transcription play a key role in balancing the production of cytokines. Herein, we review the nature of cytokine signaling in psoriasis with particular emphasis on regulation by mRNA destabilizing elements and the potential targeting of cytokine-encoding mRNAs by miRNAs. The proposed linkage between mRNA decay mediated by AU-rich elements and miRNA association is described and discussed as a possible general feature of cytokine regulation in skin. Moreover, we describe the latest attempts to therapeutically target cytokines at the RNA level in psoriasis by exploiting the cellular RNA interference machinery. The applicability of cytokine-encoding mRNAs as future clinical drug targets is evaluated, and advances and obstacles related to topical administration of RNA-based drugs targeting the cytokine circuit in psoriasis are described.

A novel synthetic derivative of melatonin, 5-hydroxy-2’-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation

International Nuclear Information System (INIS)

Shim, Do-Wan; Shin, Hee Jae; Han, Ji-Won; Ji, Young-Eun; Jang, Cheol-Hun; Koppula, Sushruta; Kang, Tae-Bong; Lee, Kwang-Ho

2015-01-01

Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2′-isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models. Lipopolysaccharide was used to induce in vitro inflammatory responses in RAW 264.7 macrophages. LPS-primed macrophages were pulsed with biologically unrelated toxic molecules to evaluate the role of HIS on inflammasome activation. In vivo verifications were carried out using acute lung injury (ALI) and Escherichia coli-induced septic shock mouse models. HIS inhibited the production of proinflammatory mediators and cytokines such as nitric oxide, cyclooxygenase 2, IL-1β, IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophages. HIS suppressed the infiltration of immune cells into the lung and the production of pro-inflammatory cytokines such as IL-6 and TNF-α in broncho-alveolar lavage fluid in the ALI mouse model. Mechanistic studies revealed that the inhibitory effects of HIS were mediated through the regulation of the TIR domain-containing, adaptor-inducing, interferon-β (TRIF)-dependent signaling pathway from toll-like receptors. Further, HIS attenuated IL-1β secretion via the inhibition of NLRP3 inflammasome activation independent of mitochondrial ROS production. Furthermore, HIS suppressed IL-1β, IL-6 and interferon-β production in peritoneal lavage in the Escherichia coli-induced sepsis mouse model. In conclusion, HIS exerted potent anti-inflammatory effects via the regulation of TRIF-dependent signaling and inflammasome activation. Notably, the superior anti-inflammatory properties of this derivative compared with its parent compound could be a promising lead for treating various inflammatory-mediated diseases. - Highlights: • Νovel compound, 5-hydroxy-2′-isobutyl-streptochlorin (HIS) was

A novel synthetic derivative of melatonin, 5-hydroxy-2’-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation

Energy Technology Data Exchange (ETDEWEB)

Shim, Do-Wan [Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju (Korea, Republic of); Shin, Hee Jae [Marine Natural Products Chemistry Laboratory, Korea Institute of Ocean Science & Technology, Ansan (Korea, Republic of); Han, Ji-Won; Ji, Young-Eun; Jang, Cheol-Hun; Koppula, Sushruta; Kang, Tae-Bong [Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju (Korea, Republic of); Lee, Kwang-Ho, E-mail: kwangho@kku.ac.kr [Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju (Korea, Republic of)

2015-04-15

Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2′-isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models. Lipopolysaccharide was used to induce in vitro inflammatory responses in RAW 264.7 macrophages. LPS-primed macrophages were pulsed with biologically unrelated toxic molecules to evaluate the role of HIS on inflammasome activation. In vivo verifications were carried out using acute lung injury (ALI) and Escherichia coli-induced septic shock mouse models. HIS inhibited the production of proinflammatory mediators and cytokines such as nitric oxide, cyclooxygenase 2, IL-1β, IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophages. HIS suppressed the infiltration of immune cells into the lung and the production of pro-inflammatory cytokines such as IL-6 and TNF-α in broncho-alveolar lavage fluid in the ALI mouse model. Mechanistic studies revealed that the inhibitory effects of HIS were mediated through the regulation of the TIR domain-containing, adaptor-inducing, interferon-β (TRIF)-dependent signaling pathway from toll-like receptors. Further, HIS attenuated IL-1β secretion via the inhibition of NLRP3 inflammasome activation independent of mitochondrial ROS production. Furthermore, HIS suppressed IL-1β, IL-6 and interferon-β production in peritoneal lavage in the Escherichia coli-induced sepsis mouse model. In conclusion, HIS exerted potent anti-inflammatory effects via the regulation of TRIF-dependent signaling and inflammasome activation. Notably, the superior anti-inflammatory properties of this derivative compared with its parent compound could be a promising lead for treating various inflammatory-mediated diseases. - Highlights: • Νovel compound, 5-hydroxy-2′-isobutyl-streptochlorin (HIS) was

PEP-1-SIRT2 inhibits inflammatory response and oxidative stress-induced cell death via expression of antioxidant enzymes in murine macrophages.

Science.gov (United States)

Kim, Mi Jin; Kim, Dae Won; Park, Jung Hwan; Kim, Sang Jin; Lee, Chi Hern; Yong, Ji In; Ryu, Eun Ji; Cho, Su Bin; Yeo, Hyeon Ji; Hyeon, Jiye; Cho, Sung-Woo; Kim, Duk-Soo; Son, Ora; Park, Jinseu; Han, Kyu Hyung; Cho, Yoon Shin; Eum, Won Sik; Choi, Soo Young

2013-10-01

Sirtuin 2 (SIRT2), a member of the sirtuin family of proteins, plays an important role in cell survival. However, the biological function of SIRT2 protein is unclear with respect to inflammation and oxidative stress. In this study, we examined the protective effects of SIRT2 on inflammation and oxidative stress-induced cell damage using a cell permeative PEP-1-SIRT2 protein. Purified PEP-1-SIRT2 was transduced into RAW 264.7 cells in a time- and dose-dependent manner and protected against lipopolysaccharide- and hydrogen peroxide (H₂O₂)-induced cell death and cytotoxicity. Also, transduced PEP-1-SIRT2 significantly inhibited the expression of cytokines as well as the activation of NF-κB and mitogen-activated protein kinases (MAPKs). In addition, PEP-1-SIRT2 decreased cellular levels of reactive oxygen species (ROS) and of cleaved caspase-3, whereas it elevated the expression of antioxidant enzymes such as MnSOD, catalase, and glutathione peroxidase. Furthermore, topical application of PEP-1-SIRT2 to 12-O-tetradecanoylphorbol 13-acetate-treated mouse ears markedly inhibited expression levels of COX-2 and proinflammatory cytokines as well as the activation of NF-κB and MAPKs. These results demonstrate that PEP-1-SIRT2 inhibits inflammation and oxidative stress by reducing the levels of expression of cytokines and ROS, suggesting that PEP-1-SIRT2 may be a potential therapeutic agent for various disorders related to ROS, including skin inflammation. Copyright © 2013 Elsevier Inc. All rights reserved.

Topoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses

OpenAIRE

Pépin, Geneviève; Nejad, Charlotte; Ferrand, Jonathan; Thomas, Belinda J.; Stunden, H. James; Sanij, Elaine; Foo, Chwan-Hong; Stewart, Cameron R.; Cain, Jason E.; Bardin, Philip G.; Williams, Bryan R. G.; Gantier, Michael P.

2017-01-01

ABSTRACT Inflammatory responses, while essential for pathogen clearance, can also be deleterious to the host. Chemical inhibition of topoisomerase 1 (Top1) by low-dose camptothecin (CPT) can suppress transcriptional induction of antiviral and inflammatory genes and protect animals from excessive and damaging inflammatory responses. We describe the unexpected finding that minor DNA damage from topoisomerase 1 inhibition with low-dose CPT can trigger a strong antiviral immune response through c...

Acute LSD effects on response inhibition neural networks.

Science.gov (United States)

Schmidt, A; Müller, F; Lenz, C; Dolder, P C; Schmid, Y; Zanchi, D; Lang, U E; Liechti, M E; Borgwardt, S

2017-10-02

Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations. In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire. Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery. Our findings show that 5-HT2AR activation by LSD leads to a hippocampal-prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.

Expression of membrane anchored cytokines and B7-1 alters tumor microenvironment and induces protective antitumor immunity in a murine breast cancer model.

Science.gov (United States)

Bozeman, Erica N; Cimino-Mathews, Ashley; Machiah, Deepa K; Patel, Jaina M; Krishnamoorthy, Arun; Tien, Linda; Shashidharamurthy, Rangaiah; Selvaraj, Periasamy

2013-05-07

Many studies have shown that the systemic administration of cytokines or vaccination with cytokine-secreting tumors augments an antitumor immune response that can result in eradication of tumors. However, these approaches are hampered by the risk of systemic toxicity induced by soluble cytokines. In this study, we have evaluated the efficacy of 4TO7, a highly tumorigenic murine mammary tumor cell line, expressing glycosyl phosphatidylinositol (GPI)-anchored form of cytokine molecules alone or in combination with the costimulatory molecule B7-1 as a model for potential cell or membrane-based breast cancer vaccines. We observed that the GPI-anchored cytokines expressed on the surface of tumor cells greatly reduced the overall tumorigenicity of the 4TO7 tumor cells following direct live cell challenge as evidenced by transient tumor growth and complete regression within 30 days post challenge. Tumors co-expressing B7-1 and GPI-IL-12 grew the least and for the shortest duration, suggesting that this combination of immunostimulatory molecules is most potent. Protective immune responses were also observed following secondary tumor challenge. Further, the 4TO7-B7-1/GPI-IL-2 and 4TO7-B7-1/GPI-IL-12 transfectants were capable of inducing regression of a wild-type tumor growing at a distant site in a concomitant tumor challenge model, suggesting the tumor immunity elicited by the transfectants can act systemically and inhibit the tumor growth at a distant site. Additionally, when used as irradiated whole cell vaccines, 4TO7-B7-1/GPI-IL-12 led to a significant inhibition in tumor growth of day 7 established tumors. Lastly, we observed a significant decrease in the prevalence of myeloid-derived suppressor cells and regulatory T-cells in the tumor microenvironment on day 7 post challenge with 4TO7-B7-1/GPI-IL-12 cells, which provides mechanistic insight into antitumor efficacy of the tumor-cell membrane expressed IL-12. These studies have implications in designing membrane

Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation.

Science.gov (United States)

Fridman, Jordan S; Scherle, Peggy A; Collins, Robert; Burn, Timothy; Neilan, Claire L; Hertel, Denise; Contel, Nancy; Haley, Patrick; Thomas, Beth; Shi, Jack; Collier, Paul; Rodgers, James D; Shepard, Stacey; Metcalf, Brian; Hollis, Gregory; Newton, Robert C; Yeleswaram, Swamy; Friedman, Steven M; Vaddi, Kris

2011-09-01

JAKs are required for signaling initiated by several cytokines (e.g., IL-4, IL-12, IL-23, thymic stromal lymphopoietin (TSLP), and IFNγ) implicated in the pathogenesis of inflammatory skin diseases such as psoriasis and atopic dermatitis (AD). Direct antagonism of cytokines, such as IL-12 and IL-23 using ustekinumab, has proven effective in randomized studies in psoriasis patients. We hypothesized that local inhibition of cytokine signaling using topical administration of INCB018424, a small molecule inhibitor of JAK1 and JAK2, would provide benefit similar to systemic cytokine neutralization. In cellular assays, INCB018424 inhibits cytokine-induced JAK/signal transducers and activators of transcription (STAT) signaling and the resultant production of inflammatory proteins (e.g., IL-17, monocyte chemotactic protein-1, and IL-22) in lymphocytes and monocytes, with half-maximal inhibitory concentration values keratinocyte proliferation in a murine contact hypersensitivity model and inhibited tissue inflammation induced by either intradermal IL-23 or TSLP. Topical INCB018424 was also well tolerated in a 28-day safety study in Gottingen minipigs. These results suggest that localized JAK1/JAK2 inhibition may be therapeutic in a range of inflammatory skin disorders such as psoriasis and AD. Clinical evaluation of topical INCB018424 is ongoing.

Inhibition by TNF-alpha and IL-4 of cationic lipid mediated gene transfer in cystic fibrosis tracheal gland cells.

Science.gov (United States)

Bastonero, Sonia; Gargouri, Myriem; Ortiou, Sandrine; Guéant, Jean-Louis; Merten, Marc D

2005-11-01

In vivo, tracheal gland serous cells highly express the cystic fibrosis transmembrane conductance regulator (cftr) gene. This gene is mutated in the lethal monogenic disease cystic fibrosis (CF). Clinical trials in which the human CFTR cDNA was delivered to the respiratory epithelia of CF patients have resulted in weak and transient gene expression. As CF is characterized by mucus inspissation, airway infection, and severe inflammation, we tested the hypothesis that inflammation and especially two cytokines involved in the Th1/Th2 inflammatory response, interleukin 4 (IL-4) and TNFalpha, could inhibit gene transfer efficiency using a model of human CF tracheal gland cells (CF-KM4) and Lipofectamine reagent as a transfection reagent. The specific secretory defects of CF-KM4 cells were corrected by Lipofectamine-mediated human CFTR gene transfer. However, this was altered when cells were pre-treated with IL-4 and TNFalpha. Inhibition of luciferase reporter gene expression by IL-4 and TNFalpha pre-treated CF-KM4 cells was measured by activity and real-time RT-PCR. Both cytokines induced similar and synergistic inhibition of transgene expression and activity. This cytokine-mediated inhibition could be prevented by anti-inflammatory agents such as glucocorticoids but not by non-steroidal (NSAI) agents. This data suggests that an inflammatory context generated by IL-4 and TNFalpha can inhibit human CFTR gene transfer in CF tracheal gland cells and that glucocorticoids may have a protecting action. Copyright (c) 2005 John Wiley & Sons, Ltd.

Tissue specific distribution of iNKT cells impacts their cytokine response

OpenAIRE

Lee, You Jeong; Wang, Haiguang; Starrett, Gabriel J.; Phuong, Vanessa; Jameson, Stephen C.; Hogquist, Kristin A.

2015-01-01

Three subsets of invariant natural killer T (iNKT) cells have been identified, NKT1, NKT2 and NKT17, which produce distinct cytokines when stimulated, but little is known about their localization. Here, we have defined the anatomic localization and systemic distribution of these subsets and measured their cytokine production. Thymic NKT2 cells that produced interleukin-4 (IL-4) at steady state were located in the medulla and conditioned medullary thymocytes. NKT2 cells were abundant in the me...

Neuropathic pain and cytokines: current perspectives

Directory of Open Access Journals (Sweden)

Clark AK

2013-11-01

Full Text Available Anna K Clark, Elizabeth A Old, Marzia Malcangio Wolfson Centre for Age Related Diseases, King's College London, London, UK Abstract: Neuropathic pain represents a major problem in clinical medicine because it causes debilitating suffering and is largely resistant to currently available analgesics. A characteristic of neuropathic pain is abnormal response to somatic sensory stimulation. Thus, patients suffering peripheral neuropathies may experience pain caused by stimuli which are normally nonpainful, such as simple touching of the skin or by changes in temperature, as well as exaggerated responses to noxious stimuli. Convincing evidence suggests that this hypersensitivity is the result of pain remaining centralized. In particular, at the first pain synapse in the dorsal horn of the spinal cord, the gain of neurons is increased and neurons begin to be activated by innocuous inputs. In recent years, it has become appreciated that a remote damage in the peripheral nervous system results in neuronal plasticity and changes in microglial and astrocyte activity, as well as infiltration of macrophages and T cells, which all contribute to central sensitization. Specifically, the release of pronociceptive factors such as cytokines and chemokines from neurons and non-neuronal cells can sensitize neurons of the first pain synapse. In this article we review the current evidence for the role of cytokines in mediating spinal neuron–non-neuronal cell communication in neuropathic pain mechanisms following peripheral nerve injury. Specific and selective control of cytokine-mediated neuronal–glia interactions results in attenuation of the hypersensitivity to both noxious and innocuous stimuli observed in neuropathic pain models, and may represent an avenue for future therapeutic intervention. Keywords: anti-inflammatory cytokines, proinflammatory cytokines, microglia, astrocytes, first pain synapse

Suppressor of cytokine signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR signaling.

Science.gov (United States)

Kedzierski, Lukasz; Tate, Michelle D; Hsu, Alan C; Kolesnik, Tatiana B; Linossi, Edmond M; Dagley, Laura; Dong, Zhaoguang; Freeman, Sarah; Infusini, Giuseppe; Starkey, Malcolm R; Bird, Nicola L; Chatfield, Simon M; Babon, Jeffrey J; Huntington, Nicholas; Belz, Gabrielle; Webb, Andrew; Wark, Peter Ab; Nicola, Nicos A; Xu, Jianqing; Kedzierska, Katherine; Hansbro, Philip M; Nicholson, Sandra E

2017-02-14

Influenza virus infections have a significant impact on global human health. Individuals with suppressed immunity, or suffering from chronic inflammatory conditions such as COPD, are particularly susceptible to influenza. Here we show that suppressor of cytokine signaling (SOCS) five has a pivotal role in restricting influenza A virus in the airway epithelium, through the regulation of epidermal growth factor receptor (EGFR). Socs5 -deficient mice exhibit heightened disease severity, with increased viral titres and weight loss. Socs5 levels were differentially regulated in response to distinct influenza viruses (H1N1, H3N2, H5N1 and H11N9) and were reduced in primary epithelial cells from COPD patients, again correlating with increased susceptibility to influenza. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza.

Embryotoxic cytokines-Potential roles in embryo loss and fetal programming.

Science.gov (United States)

Robertson, Sarah A; Chin, Peck-Yin; Femia, Joseph G; Brown, Hannah M

2018-02-01

Cytokines in the reproductive tract environment at conception mediate a dialogue between the embryo and maternal tissues to profoundly influence embryo development and implantation success. Through effects on gene expression and the cell stress response, cytokines elicit an epigenetic impact with consequences for placental development and fetal growth, which in turn affect metabolic phenotype and long-term health of offspring. There is substantial evidence demonstrating that pro-survival cytokines, such as GM-CSF, CSF1, LIF, HB-EGF and IGFII, support embryos to develop optimally. Less attention has been paid to cytokines that adversely impact embryo development, including the pro-inflammatory cytokines TNF, TRAIL and IFNG. These agents elicit cell stress, impair cell survival and retard blastocyst development, and at sufficiently high concentrations, can cause embryo demise. Experiments in mice suggest these so-called 'embryotoxic' cytokines can harm embryos through pro-apoptotic and adverse programming effects, as well as indirectly suppressing uterine receptivity through the maternal immune response. Embryotrophic factors may mitigate against and protect from these adverse effects. Thus, the balance between embryotrophic and embryotoxic cytokines can impart effects on embryo development and implantation, and has the potential to contribute to endometrial 'biosensor' function to mediate embryo selection. Embryotoxic cytokines can be elevated in plasma and reproductive tract tissues in inflammatory conditions including infection, diabetes, obesity, PCOS and endometriosis. Studies are therefore warranted to investigate whether excessive embryotoxic cytokines contribute to infertility and recurrent implantation failure in women, and compromised reproductive performance in livestock animals. Copyright © 2018 Elsevier B.V. All rights reserved.

No effects of bilateral tDCS over inferior frontal gyrus on response inhibition and aggression

NARCIS (Netherlands)

Dambacher, F.; Schuhmann, T.; Lobbestael, J.; Arntz, A.; Brugman, S.; Sack, A.T.

2015-01-01

Response inhibition is defined as the capacity to adequately withdraw pre-planned responses. It has been shown that individuals with deficits in inhibiting pre-planned responses tend to display more aggressive behaviour. The prefrontal cortex is involved in both, response inhibition and aggression.

Role of HLA, KIR, MICA, and Cytokines Genes in Leprosy

Science.gov (United States)

Jarduli, Luciana Ribeiro; Sell, Ana Maria; Reis, Pâmela Guimarães; Ayo, Christiane Maria; Mazini, Priscila Saamara; Alves, Hugo Vicentin; Teixeira, Jorge Juarez Vieira; Visentainer, Jeane Eliete Laguila

2013-01-01

Many genes including HLA, KIR, and MICA genes, as well as polymorphisms in cytokines have been investigated for their role in infectious disease. HLA alleles may influence not only susceptibility or resistance to leprosy, but also the course of the disease. Some combinations of HLA and KIR may result in negative as well as positive interactions between NK cells and infected host cells with M. leprae, resulting in activation or inhibition of NK cells and, consequently, in death of bacillus. In addition, studies have demonstrated the influence of MICA genes in the pathogenesis of leprosy. Specifically, they may play a role in the interaction between NK cells and infected cells. Finally, pro- and anti-inflammatory cytokines have been influencing the clinical course of leprosy. Data from a wide variety of sources support the existence of genetic factors influencing the leprosy pathogenesis. These sources include twin studies, segregation analyses, family-based linkage and association studies, candidate gene association studies, and, most recently, genome-wide association studies (GWAS). The purpose of this brief review was to highlight the importance of some immune response genes and their correlation with the clinical forms of leprosy, as well as their implications for disease resistance and susceptibility. PMID:23936864

Inhibition of TNF-α in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats

Energy Technology Data Exchange (ETDEWEB)

Song, Xin-Ai; Jia, Lin-Lin [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Cui, Wei [Department of Endocrinology and Metabolism, First Affiliated Hospital of Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhang, Meng [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Chen, Wensheng [Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Yuan, Zu-Yi [Department of Cardiovascular Medicine, First Affiliated Hospital of Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Guo, Jing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Li, Hui-Hua [Key Laboratory of Remodeling-related Cardiovascular Diseases, Department of Pathology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Liu, Hao, E-mail: haoliu75@163.com [Department of Neurosurgery, First Affiliated Hospital of Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China)

2014-11-15

We hypothesized that chronic inhibition of tumor necrosis factor-alpha (TNF-α) in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), decreasing nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase activities, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle for 4 weeks. SHR rats showed higher mean arterial pressure and cardiac hypertrophy compared with WKY rats, as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC) mRNA expressions. Compared with WKY rats, SHR rats had higher PVN levels of tyrosine hydroxylase, PICs, the chemokine monocyte chemoattractant protein-1 (MCP-1), NF-κB p65 activity, mRNA expressions of NOX-2 and NOX-4, and lower PVN levels of IL-10 and 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma norepinephrine. PVN infusion of pentoxifylline or etanercept attenuated all these changes in SHR rats. These findings suggest that SHR rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN; and chronic inhibition of TNF-α in the PVN delays the progression of hypertension by restoring the balances of neurotransmitters and cytokines in the PVN, and attenuating PVN NF-κB p65 activity and oxidative stress, thereby attenuating hypertension-induced sympathetic hyperactivity and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of

Optimal Method to Stimulate Cytokine Production and Its Use in Immunotoxicity Assessment

Directory of Open Access Journals (Sweden)

Huiming Chen

2013-08-01

Full Text Available Activation of lymphocytes can effectively produce a large amount of cytokines. The types of cytokines produced may depend on stimulating reagents and treatments. To find an optimal method to stimulate cytokine production and evaluate its effect on immunotoxicity assessments, the authors analyzed production of IL-2, IL-4, IL-6, IL-10, IL-13, IFN-γ, TNF-α, GM-CSF, RANTES and TGF-β in undiluted rat whole blood culture (incubation for 0, 2, 4, 6, 8 or 10 h with different concentrations of PMA/ionomycin, PHA, Con A, LPS and PWM. We also evaluated the effects of cyclosporin A and azathioprine on cytokine production. The results revealed a rapid increase of IL-2, IFN-γ, TNF-α, RANTES and TGF-β secretion within 6 h after stimulation with 25 ng/mL PMA and 1 μg/mL ionomycin. The inhibition of these cytokine profiles reflected the effects of immunosuppressants on the immune system. Therefore, the results of this is study recommend the detection of cytokine profiles in undiluted whole blood stimulated 6 h with 25 ng/mL PMA and 1 μg/mL ionomycin as a powerful immunotoxicity assessment method.

Cytokines and the neurodevelopmental basis of mental illness

Directory of Open Access Journals (Sweden)

Udani eRatnayake

2013-10-01

Full Text Available Epidemiological studies suggest that prenatal exposure to different types of viral or bacterial infections may be associated with similar outcomes; i.e., an increased risk of mental illness disorders in the offspring. Infections arising from various causes have similar debilitating effects in later life, suggesting that the exact pathogen may not be the critical factor in determining the neurological and cognitive outcome in the offspring. Instead, it is thought that response of the innate immune system, specifically the increased production of inflammatory cytokines, may be the critical mediator in altering fetal brain development pre-disposing the offspring to mental illness disorders later in life. Inflammatory cytokines are essential for normal brain development. Factors such as the site of cytokine production, a change in balance between anti- and pro- inflammatory cytokines, placental transfer of cytokines, the effects of cytokines on glial cells, and the effects of glucocorticoids are important when evaluating the impact of maternal infection on fetal brain development. Although it is clear that cytokines are altered in the fetal brain following maternal infection, further evidence is required to determine if cytokines are the critical factor that alters the trajectory of brain development, subsequently leading to postnatal behavioural and neurological abnormalities.

High dose of plasmid IL-15 inhibits immune responses in an influenza non-human primates immunogenicity model

International Nuclear Information System (INIS)

Yin Jiangmei; Dai Anlan; Laddy, Dominick J.; Yan Jian; Arango, Tatiana; Khan, Amir S.; Lewis, Mark G.; Andersen, Hanne; Kutzler, Michele A.; Draghia-Akli, Ruxandra; Weiner, David B.; Boyer, Jean D.

2009-01-01

Interleukin (IL)-15, is a cytokine that is important for the maintenance of long-lasting, high-avidity T cell response to invading pathogens and has, therefore, been used in vaccine and therapeutic platforms as an adjuvant. In addition to pure protein delivery, plasmids encoding the IL-15 gene have been utilized. However, it is critical to determine the appropriate dose to maximize the adjuvanting effects. We immunized rhesus macaques with different doses of IL-15 expressing plasmid in an influenza non-human primate immunogenicity model. We found that co-immunization of rhesus macaques with a Flu DNA-based vaccine and low doses of plasmid encoding macaque IL-15 enhanced the production of IFN-γ (0.5 mg) and the proliferation of CD4 + and CD8 + T cells, as well as T CM levels in proliferating CD8 + T cells (0.25 mg). Whereas, high doses of IL-15 (4 mg) decrease the production of IFN-γ and the proliferation of CD4 + and CD8 + T cells and T CM levels in the proliferating CD4 + and CD8 + T cells. In addition, the data of hemagglutination inhibition (HI) antibody titer suggest that although not significantly different, there appears to be a slight increase in antibodies at lower doses of IL-15. Importantly, however, the higher doses of IL-15 decrease the antibody levels significantly. This study demonstrates the importance of optimizing DNA-based cytokine adjuvants.

Depletion of H2S during obesity enhances store-operated Ca2+ entry in adipose tissue macrophages to increase cytokine production.

Science.gov (United States)

Velmurugan, Gopal V; Huang, Huiya; Sun, Hongbin; Candela, Joseph; Jaiswal, Mukesh K; Beaman, Kenneth D; Yamashita, Megumi; Prakriya, Murali; White, Carl

2015-12-15

The increased production of proinflammatory cytokines by adipose tissue macrophages (ATMs) contributes to chronic, low-level inflammation during obesity. We found that obesity in mice reduced the bioavailability of the gaseous signaling molecule hydrogen sulfide (H2S). Steady-state, intracellular concentrations of H2S were lower in ATMs isolated from mice with diet-induced obesity than in ATMs from lean mice. In addition, the intracellular concentration of H2S in the macrophage cell line RAW264.7 was reduced during an acute inflammatory response evoked by the microbial product lipopolysaccharide (LPS). Reduced intracellular concentrations of H2S led to increased Ca(2+) influx through the store-operated Ca(2+) entry (SOCE) pathway, which was prevented by the exogenous H2S donor GYY4137. Furthermore, GYY4137 inhibited the Orai3 channel, a key component of the SOCE machinery. The enhanced production of proinflammatory cytokines by RAW264.7 cells and ATMs from obese mice was reduced by exogenous H2S or by inhibition of SOCE. Together, these data suggest that the depletion of macrophage H2S that occurs during acute (LPS-induced) or chronic (obesity) inflammation increases SOCE through disinhibition of Orai3 and promotes the production of proinflammatory cytokines. Copyright © 2015, American Association for the Advancement of Science.

The Effect of C. burnetii Infection on the Cytokine Response of PBMCs from Pregnant Goats

Science.gov (United States)

Ammerdorffer, Anne; Roest, Hendrik-I J.; Dinkla, Annemieke; Post, Jacob; Schoffelen, Teske; van Deuren, Marcel; Sprong, Tom; Rebel, Johanna M.

2014-01-01

In humans, infection with Coxiella burnetii, the causative agent of Q fever, leads to acute or chronic infection, both associated with specific clinical symptoms. In contrast, no symptoms are observed in goats during C. burnetii infection, although infection of the placenta eventually leads to premature delivery, stillbirth and abortion. It is unknown whether these differences in clinical outcome are due to the early immune responses of the goats. Therefore, peripheral blood mononuclear cells (PBMCs) were isolated from pregnant goats. In total, 17 goats were included in the study. Six goats remained naive, while eleven goats were infected with C. burnetii. Toll-like receptor (TLR) and cytokine mRNA expression were measured after in vitro stimulation with heat-killed C. burnetii at different time points (prior infection, day 7, 35 and 56 after infection). In naive goats an increased expression of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-10 and interferon (IFN)-γ mRNA upon C. burnetii stimulation was detected. In addition, TLR2 expression was strongly up-regulated. In goats infected with C. burnetii, PBMCs re-stimulated in vitro with C. burnetii, expressed significantly more TNF-α mRNA and IFN-γ mRNA compared to naive goats. In contrast, IL-10 mRNA production capacity was down-regulated during C. burnetii infection. Interestingly, at day 7 after inoculation a decreased IFN-γ protein level was observed in stimulated leukocytes in whole blood from infected goats, whereas at other time-points increased production of IFN-γ protein was seen. Our study shows that goats initiate a robust pro-inflammatory immune response against C. burnetii in vitro. Furthermore, PBMCs from C. burnetii infected goats show augmented pro-inflammatory cytokine responses compared to PBMCs from non-infected goats. However, despite this pro-inflammatory response, goats are not capable of clearing the C. burnetii infection. PMID:25279829

Examination of epithelial tissue cytokine response to natural peste des petits ruminants virus (PPRV) infection in sheep and goats by immunohistochemistry.

Science.gov (United States)

Atmaca, H T; Kul, O

2012-01-01

In this study, we aimed to evaluate expression of IL-4, IL-10, TNF-α, IFN-γ and iNOS in lingual, buccal mucosa and lung epithelial tissue using immunoperoxidase technique and to compare with the tissues of control animals. The tissues used in the study were collected from 17 PPRV-affected and 5 healthy sheep and goats. In PPRV positive animals, the lungs, lingual and buccal mucosa had significantly higher iNOS, IFN-γ and TNF-α expressions compared to control group animals. There was no significant difference between PPRV positive and control groups for IL-4 and IL-10 expressions of epithelial tissues. In conclusion, the epithelial tissues infected by PPRV showed significant iNOS, IFN-γ and TNF-α expressions and they might play an important role in the initiation and regulation of cytokine response, as they take place in the first host barrier to be in contact with PPRV. It is suggested that the more epithelial damage produced by PPRV the more cytokine response may result in the infected epithelial cells. The first demonstration of iNOS expression and epithelial cytokine response to PPRV in natural cases is important because it may contribute to an early initiation of systemic immunity against PPRV infection, in addition to direct elimination of the virus during the initial epithelial phase of the infection.

Study on cytokine modulation in mast cell-induced allergic reactions by using gamma-irradiated natural herbal extracts

International Nuclear Information System (INIS)

Gwon, Hui Jeong; Lim, Youn Mook; Kim, Yong Soo; Nho, Young Chang; Kim Hae Kyoung

2009-01-01

We previously described that some natural herbal extracts such as Houttuynia cordata (H), Centella asiatica (C), Plantago asiatica (P), Morus alba L. (M), and Ulmus davidiana (U), differentially suppress an atopic dermatitis like skin lesions. The objective of this study was to evaluate the pro-inflammatory cytokine modulation of the water extract of the H, C, P, M, U, and those mixtures (M) and their mechanism in a phorbol myristate acetate (PMA) plus calcium inopore A23187 treated human mast cell line (HMC-1). The H, C, P, M, U, and M inhibited the inflammatory cytokines such as TNF-α, IL-6 and IL-8 stimulated by PMA plus A23187 from HMC-1 cells. In addition, the M did not significantly affect the cell viability and had no toxicity on the HMC-1 cells. Based on these results, M can be used for the treatment of an allergic inflammation response

Study on cytokine modulation in mast cell-induced allergic reactions by using gamma-irradiated natural herbal extracts

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Gwon, Hui Jeong; Lim, Youn Mook; Kim, Yong Soo; Nho, Young Chang [Korea Atomic Energy Research Institute, Jeongeup (Korea, Republic of); Kim Hae Kyoung [Chonbuk National University, Jeonju (Korea, Republic of)

2009-12-15

We previously described that some natural herbal extracts such as Houttuynia cordata (H), Centella asiatica (C), Plantago asiatica (P), Morus alba L. (M), and Ulmus davidiana (U), differentially suppress an atopic dermatitis like skin lesions. The objective of this study was to evaluate the pro-inflammatory cytokine modulation of the water extract of the H, C, P, M, U, and those mixtures (M) and their mechanism in a phorbol myristate acetate (PMA) plus calcium inopore A23187 treated human mast cell line (HMC-1). The H, C, P, M, U, and M inhibited the inflammatory cytokines such as TNF-{alpha}, IL-6 and IL-8 stimulated by PMA plus A23187 from HMC-1 cells. In addition, the M did not significantly affect the cell viability and had no toxicity on the HMC-1 cells. Based on these results, M can be used for the treatment of an allergic inflammation response.

Emotion potentiates response activation and inhibition in masked priming.

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Bocanegra, Bruno R; Zeelenberg, René

2012-01-01

Previous studies have shown that emotion can have 2-fold effects on perception. At the object-level, emotional stimuli benefit from a stimulus-specific boost in visual attention at the relative expense of competing stimuli. At the visual feature-level, recent findings indicate that emotion may inhibit the processing of small visual details and facilitate the processing of coarse visual features. In the present study, we investigated whether emotion can boost the activation and inhibition of automatic motor responses that are generated prior to overt perception. To investigate this, we tested whether an emotional cue affects covert motor responses in a masked priming task. We used a masked priming paradigm in which participants responded to target arrows that were preceded by invisible congruent or incongruent prime arrows. In the standard paradigm, participants react faster, and commit fewer errors responding to the directionality of target arrows, when they are preceded by congruent vs. incongruent masked prime arrows (positive congruency effect, PCE). However, as prime-target SOAs increase, this effect reverses (negative congruency effect, NCE). These findings have been explained as evidence for an initial activation and a subsequent inhibition of a partial response elicited by the masked prime arrow. Our results show that the presentation of fearful face cues, compared to neutral face cues, increased the size of both the PCE and NCE, despite the fact that the primes were invisible. This is the first demonstration that emotion prepares an individual's visuomotor system for automatic activation and inhibition of motor responses in the absence of visual awareness.

Cytokine modulation by stress hormones and antagonist specific hormonal inhibition in rainbow trout (Oncorhynchus mykiss) and gilthead sea bream (Sparus aurata) head kidney primary cell culture.

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Khansari, Ali Reza; Parra, David; Reyes-López, Felipe E; Tort, Lluís

2017-09-01

A tight interaction between endocrine and immune systems takes place mainly due to the key role of head kidney in both hormone and cytokine secretion, particularly under stress situations in which the physiological response promotes the synthesis and release of stress hormones which may lead into immunomodulation as side effect. Although such interaction has been previously investigated, this study evaluated for the first time the effect of stress-associated hormones together with their receptor antagonists on the expression of cytokine genes in head kidney primary cell culture (HKPCC) of the freshwater rainbow trout (Oncorhynchus mykiss) and the seawater gilthead sea bream (Sparus aurata). The results showed a striking difference when comparing the response obtained in trout and seabream. Cortisol and adrenocorticotropic hormone (ACTH) decreased the expression of immune-related genes in sea bream but not in rainbow trout and this cortisol effect was reverted by the antagonist mifepristone but not spironolactone. On the other hand, while adrenaline reduced the expression of pro-inflammatory cytokines (IL-1β, IL-6) in rainbow trout, the opposite effect was observed in sea bream showing an increased expression (IL-1β, IL-6). Interestingly, this effect was reverted by antagonist propranolol but not phentolamine. Overall, our results confirm the regional interaction between endocrine and cytokine messengers and a clear difference in the sensitivity to the hormonal stimuli between the two species. Copyright © 2017 Elsevier Inc. All rights reserved.

High-dose alcohol intoxication differentially modulates cognitive subprocesses involved in response inhibition.

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Stock, Ann-Kathrin; Schulz, Tom; Lenhardt, Martin; Blaszkewicz, Meinolf; Beste, Christian

2016-01-01

Aside from well-known physiological effects, high-dose alcohol intoxication (a.k.a. binge drinking) can lead to aversive social and legal consequences because response inhibition is usually compromised under the influence of alcohol. Although the behavioral aspects of this phenomenon were reported on extensively, the underlying neurophysiological mechanisms mediating this disinhibition are unclear. To close this gap, we used both behavioral and neurophysiological measures (event-related potentials, ERPs) to investigate which subprocesses of response inhibition are altered under the influence of high-dose alcohol intoxication. Using a within-subject design, we asked young healthy participants (n = 27) to complete a GO/NOGO task once sober and once intoxicated (approximately 1.2‰). During intoxication, high-dose alcohol effects were highest in a condition where the participants could not rely on automated stimulus-response mapping processes during response inhibition. In this context, the NOGO-P3 (ERP), that likely depends on dopaminergic signaling within mesocorticolimbic pathways and is thought to reflect motor inhibition and/or the evaluation of inhibitory processes, was altered in the intoxicated state. In contrast to this, the N2 component, which largely depends on nigrostriatal dopamine pathways and is thought to reflect inhibition on a pre-motor level, was not altered. Based on these results, we demonstrate that alcohol-induced changes of dopaminergic neurotransmission do not exert a global effect on response inhibition. Instead, changes are highly subprocess-specific and seem to mainly target mesocorticolimbic pathways that contribute to motor inhibition and the evaluation of such. © 2014 Society for the Study of Addiction.

Perillyl alcohol suppresses antigen-induced immune responses in the lung

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Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide; Nakagome, Kazuyuki; Harada, Hiroaki; Kawahata, Kimito; Tanaka, Ryoichi; Yamamoto, Kazuhiko [Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Dohi, Makoto, E-mail: mdohi-tky@umin.ac.jp [Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Institute of Respiratory Immunology, Shibuya Clinic for Respiratory Diseases and Allergology, Tokyo (Japan)

2014-01-03

Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4{sup +} T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4{sup +} T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.

1,5-Anhydro-D-fructose attenuates lipopolysaccharide-induced cytokine release via suppression of NF-κB p65 phosphorylation

International Nuclear Information System (INIS)

Meng Xiaojie; Kawahara, Ko-ichi; Nawa, Yuko; Miura, Naoki; Shrestha, Binita; Tancharoen, Salunya; Sameshima, Hisayo; Hashiguchi, Teruto; Maruyama, Ikuro

2009-01-01

Lipopolysaccharide (LPS) stimulates macrophages by activating NF-κB, which contributes to the release of tumor necrosis factor (TNF)-α and interleukin (IL)-6. 1,5-anhydro-D-fructose (1,5-AF), a monosaccharide formed from starch and glycogen, exhibits anti-oxidant activity and enhances insulin secretion. This study examined the effects of 1,5-AF on LPS-induced inflammatory reactions and elucidated its molecular mechanisms. Before LPS challenge, mice were pretreated with 1,5-AF (38.5 mg/kg). We found that 1,5-AF pretreatment attenuated cytokine release into the serum, including TNF-α, IL-6 and macrophage chemoattractant protein (MCP)-1. Furthermore, pretreatment with 1,5-AF (500 μg/ml) attenuated cytokine release, and 1,5-AF directly inhibited the nuclear translocalization of the NF-κB p65 subunit in LPS-stimulated murine macrophage-like RAW264.7 cells. This inhibition was responsible for decreased LPS-induced phosphorylation on Ser536 of the NF-κB p65 subunit, which is a posttranslational modification involved in the non-canonical pathway. Collectively, these findings indicate that the anti-inflammatory activity of 1,5-AF occurs via inactivation of NF-κB.

Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation.

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Strempel, Sebastian; Schroeder, Christoph; Hemmersbach, Ruth; Boese, Andrea; Tank, Jens; Diedrich, André; Heer, Martina; Luft, Friedrich C; Jordan, Jens

2008-03-01

Sympathetically mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness. Norepinephrine transporter (NET) inhibition prevents neurally mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. We performed a double-blind, randomized, placebo-controlled crossover study in 11 healthy men (26 +/- 1 yr, body mass index 24 +/- 1 kg/m2), who ingested the selective NET inhibitor reboxetine (4 mg) or matching placebo 25, 13, and 1 h before testing on separate days. We monitored heart rate, blood pressure, and thoracic impedance in three different body positions (supine, seated, standing) and during a graded centrifuge run (incremental steps of 0.5 g for 3 min each, up to a maximal vertical acceleration load of 3 g). NET inhibition increased supine blood pressure and heart rate. With placebo, blood pressure increased in the seated position and was well maintained during standing. However, with NET inhibition, blood pressure decreased in the seated and standing position. During hypergravitation, blood pressure increased in a graded fashion with placebo. With NET inhibition, the increase in blood pressure during hypergravitation was profoundly diminished. Conversely, the tachycardic responses to sitting, standing, and hypergravitation all were greatly increased with NET inhibition. In contrast to our expectation, short-term NET inhibition did not improve tolerance to hypergravitation. Redistribution of sympathetic activity to the heart or changes in baroreflex responses could explain the excessive tachycardia that we observed.

The role of multiple negative social relationships in inflammatory cytokine responses to a laboratory stressor

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Sunmi Song

2015-06-01

Full Text Available The present study examined the unique impact of perceived negativity in multiple social relationships on endocrine and inflammatory responses to a laboratory stressor. Via hierarchical cluster analysis, those who reported negative social exchanges across relationships with a romantic partner, family, and their closest friend had higher mean IL-6 across time and a greater increase in TNF-α from 15 min to 75 min post stress. Those who reported negative social exchanges across relationships with roommates, family, and their closest friend showed greater IL-6 responses to stress. Differences in mean IL-6 were accounted for by either depressed mood or hostility, whereas differences in the cytokine stress responses remained significant after controlling for those factors. Overall, this research provides preliminary evidence to suggest that having multiple negative relationships may exacerbate acute inflammatory responses to a laboratory stressor independent of hostility and depressed mood.

The role of multiple negative social relationships in inflammatory cytokine responses to a laboratory stressor.

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Song, Sunmi; Graham-Engeland, Jennifer E; Corwin, Elizabeth J; Ceballos, Rachel M; Taylor, Shelley E; Seeman, Teresa; Klein, Laura Cousino

2015-01-01

The present study examined the unique impact of perceived negativity in multiple social relationships on endocrine and inflammatory responses to a laboratory stressor. Via hierarchical cluster analysis, those who reported negative social exchanges across relationships with a romantic partner, family, and their closest friend had higher mean IL-6 across time and a greater increase in TNF-α from 15 min to 75 min post stress. Those who reported negative social exchanges across relationships with roommates, family, and their closest friend showed greater IL-6 responses to stress. Differences in mean IL-6 were accounted for by either depressed mood or hostility, whereas differences in the cytokine stress responses remained significant after controlling for those factors. Overall, this research provides preliminary evidence to suggest that having multiple negative relationships may exacerbate acute inflammatory responses to a laboratory stressor independent of hostility and depressed mood.

Gefitinib and pyrrolidine dithiocarbamate decrease viral replication and cytokine production in dengue virus infected human monocyte cultures.

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Duran, Anyelo; Valero, Nereida; Mosquera, Jesús; Fuenmayor, Edgard; Alvarez-Mon, Melchor

2017-12-15

The epidermal growth factor receptor (EGFR) and nucleotide-binding and oligomerization-domain containing 2 (NOD2) are important in cancer and in microbial recognition, respectively. These molecules trigger intracellular signaling pathways inducing the expression of inflammatory genes by NF-kB translocation. Gefitinib (GBTC) and pyrrolidine dithiocarbamate (PDTC) are capable of inhibiting EGFR/NOD2 and NF-kB, respectively. In earlier stages of dengue virus (DENV) infection, monocytes are capable of sustaining viral replication and increasing cytokine production, suggesting that monocyte/macrophages play an important role in early DENV replication. GBTC and PDTC have not been used to modify the pathogenesis of DENV in infected cells. This study was aimed to determine the effect of GBTC and PDTC on viral replication and cytokine production in DENV serotype 2 (DENV2)-infected human monocyte cultures. GBTC and PDTC were used to inhibit EGFR/NOD2 and NF-kB, respectively. Cytokine production was measured by ELISA and viral replication by plaque forming unit assay. Increased DENV2 replication and anti-viral cytokine production (IFN-α/β, TNF-α, IL-12 and IL-18) in infected cultures were found. These parameters were decreased after EGFR/NOD2 or NF-kB inhibitions. The inhibitory effects of GBTC and PDTC on viral replication and cytokine production can be beneficial in the treatment of patients infected by dengue and suggest a possible role of EGFR/NOD2 receptors and NF-kB in dengue pathogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Methyl salicylate lactoside inhibits inflammatory response of fibroblast-like synoviocytes and joint destruction in collagen-induced arthritis in mice.

Science.gov (United States)

Xin, Wenyu; Huang, Chao; Zhang, Xue; Xin, Sheng; Zhou, Yiming; Ma, Xiaowei; Zhang, Dan; Li, Yongjie; Zhou, Sibai; Zhang, Dongming; Zhang, Tiantai; Du, Guanhua

2014-07-01

Methyl salicylate 2-O-β-d-lactoside (MSL), whose chemical structure is similar to that of salicylic acid, is a natural product derivative isolated from a traditional Chinese herb. The aim of this study was to investigate the therapeutic effect of MSL in mice with collagen-induced arthritis (CIA) and explore its underlying mechanism. The anti-arthritic effects of MSL were evaluated on human rheumatoid fibroblast-like synoviocytes (FLS) in vitro and CIA in mice in vivo by obtaining clinical scores, measuring hind paw thickness and inflammatory cytokine levels, radiographic evaluations and histopathological assessments. Treatment with MSL after the onset of arthritis significantly prevented the progression and development of rheumatoid arthritis (RA) in CIA mice without megascopic gastric mucosa damage. In addition, MSL inhibited the production of pro-inflammatory mediators, the phosphorylation and translocation of NF-κB, and cell proliferation induced by TNF-α in FLS. MSL non-selectively inhibited the activity of COX in vitro, but was a more potent inhibitor of COX-2 than COX-1. MSL also inhibited the phosphorylation of inhibitor of NF-κB kinase, IκBα and p65, thus blocking the nuclear translocation of NF-κB in TNF-α-stimulated FLS. MSL exerts therapeutic effects on CIA mice, suppressing the inflammatory response and joint destruction by non-selectively inhibiting the activity of COX and suppressing activation of the NF-κB signalling pathway, but without damaging the gastric mucosa. Therefore, MSL has great potential to be developed into a novel therapeutic agent for the treatment of RA. © 2014 The British Pharmacological Society.

Proanthocyanidins from the bark of Metasequoia glyptostroboides ameliorate allergic contact dermatitis through directly inhibiting T cells activation and Th1/Th17 responses.

Science.gov (United States)

Chen, Fengyang; Ye, Xiaodi; Yang, Yadong; Teng, Tianli; Li, Xiaoyu; Xu, Shifang; Ye, Yiping

2015-04-15

The leaves and bark of Metasequoia glyptostroboides are used as anti-microbic, analgesic and anti-inflammatory drug for dermatic diseases in Chinese folk medicine. However, the pharmacological effects and material basis responsible for the therapeutic use of this herb have not yet been well studied. The objectives of this study were to evaluate the anti-inflammatory effects of the proanthocyanidin fraction from the bark of M. glyptostroboides (MGEB) and to elucidate its immunological mechanisms. The anti-inflammatory activity of MGEB was evaluated using 2,4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD) in mice. Its potential mechanisms were further investigated by determining its effects on Con A-induced T cell activation and Th1/Th17 responses in vitro. Both intraperitoneal injection and oral administration of MGEB significantly reduced the ear swelling in DNFB-induced ACD mice. MGEB inhibited Con A-induced proliferation and the expression levels of cell surface molecules CD69 and CD25 of T cells in vitro. MGEB also significantly decreased the production of Th1/Th17 specific cytokines (IL-2, IFN-γ and IL-17) and down-regulated their mRNA expression levels in activated T-cells. MGEB could ameliorate ACD, at least in part, through directly inhibiting T cells activation and Th1/Th17 responses. Copyright © 2015 Elsevier GmbH. All rights reserved.

The C protein of measles virus inhibits the type I interferon response

International Nuclear Information System (INIS)

Shaffer, Jessica A.; Bellini, William J.; Rota, Paul A.

2003-01-01

Type I interferons (IFNα/β) are an important part of innate immunity to viral infections because they induce an antiviral response and limit viral replication until the adaptive response clears the infection. Since the nonstructural proteins of several paramyxoviruses inhibit the IFNα/β response, we chose to explore the role of the C protein of measles virus (MV) in such inhibition. Previous studies have suggested that the MV C protein may serve as a virulence factor, but its role in the pathogenesis of MV remains undefined. In the present study, a recombinant MV strain that does not express the C protein (MV C-) and its parental strain (Ed Tag) were used. Growth of MV C- was restricted in human peripheral blood mononuclear cells and HeLa cells, but in the presence of neutralizing antibodies to IFNα/β, MV C- produced titers that were equivalent to those of Ed Tag. In addition, expression of the MV C protein from plasmid DNA inhibited the production of an IFNα/β responsive reporter gene and, to a lesser extent, inhibited an IFNγ responsive reporter gene. The ability of the MV C protein to suppress the IFNα/β response was confirmed using a biologic assay. After IFNβ stimulation, HeLa cells infected with Ed Tag produced five-fold less IFNα/β than cells infected with MV C-. While the mechanism of inhibition remains unclear, these data suggest that the MV C protein plays an important role in the pathogenesis of MV by inhibiting IFNα/β signaling

Autophagy in the immune response to tuberculosis: clinical perspectives.

LENUS (Irish Health Repository)

Ní Cheallaigh, C

2011-06-01

A growing body of evidence points to autophagy as an essential component in the immune response to tuberculosis. Autophagy is a direct mechanism of killing intracellular Mycobacterium tuberculosis and also acts as a modulator of proinflammatory cytokine secretion. In addition, autophagy plays a key role in antigen processing and presentation. Autophagy is modulated by cytokines; it is stimulated by T helper type 1 (Th1) cytokines such as tumour necrosis factor (TNF)-α and interferon (IFN)-γ, and is inhibited by the Th2 cytokines interleukin (IL)-4 and IL-13 and the anti-inflammatory cytokine IL-10. Vitamin D, via cathelicidin, can also induce autophagy, as can Toll-like receptor (TLR)-mediated signals. Autophagy-promoting agents, administered either locally to the lungs or systemically, could have a clinical application as adjunctive treatment of drug-resistant and drug-sensitive tuberculosis. Moreover, vaccines which effectively induce autophagy could be more successful in preventing acquisition or reactivation of latent tuberculosis.

GSK-3β Inhibition Attenuates CLP-Induced Liver Injury by Reducing Inflammation and Hepatic Cell Apoptosis

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Hui Zhang

2014-01-01

Full Text Available Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK- 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP, and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB but enhanced the transcriptional activity of cAMP response element binding protein (CREB in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

Neutrophil-Derived Proteases Escalate Inflammation through Activation of IL-36 Family Cytokines.

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Henry, Conor M; Sullivan, Graeme P; Clancy, Danielle M; Afonina, Inna S; Kulms, Dagmar; Martin, Seamus J

2016-02-02

Recent evidence has strongly implicated the IL-1 family cytokines IL-36α, IL-36β, and IL-36γ as key initiators of skin inflammation. Similar to the other members of the IL-1 family, IL-36 cytokines are expressed as inactive precursors and require proteolytic processing for activation; however, the responsible proteases are unknown. Here, we show that IL-36α, IL-36β, and IL-36γ are activated differentially by the neutrophil granule-derived proteases cathepsin G, elastase, and proteinase-3, increasing their biological activity ~500-fold. Active IL-36 promoted a strong pro-inflammatory signature in primary keratinocytes and was sufficient to perturb skin differentiation in a reconstituted 3D human skin model, producing features resembling psoriasis. Furthermore, skin eluates from psoriasis patients displayed significantly elevated cathepsin G-like activity that was sufficient to activate IL-36β. These data identify neutrophil granule proteases as potent IL-36-activating enzymes, adding to our understanding of how neutrophils escalate inflammatory reactions. Inhibition of neutrophil-derived proteases may therefore have therapeutic benefits in psoriasis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Response inhibition and interference control in obsessive-compulsive spectrum disorders

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Laura S van Velzen

2014-06-01

Full Text Available Over the past twenty years, motor response inhibition and interference control have received considerable scientific effort and attention, due to their important role in behavior and the development of neuropsychiatric disorders. Results of neuroimaging studies indicate that motor response inhibition and interference control are dependent on cortical-striatal-thalamic-cortical (CSTC circuits. Structural and functional abnormalities within the CSTC circuits have been reported for many neuropsychiatric disorders, including obsessive-compulsive disorder (OCD and related disorders, such as attention deficit hyperactivity disorder (ADHD, Tourette’s syndrome (TS and trichotillomania. These disorders also share impairments in motor response inhibition and interference control, which may underlie some of their behavioral and cognitive symptoms. Results of task-related neuroimaging studies on inhibitory functions in these disorders show that impaired task performance is related to altered recruitment of the CSTC circuits. Previous research has shown that inhibitory performance is dependent upon dopamine, noradrenaline and serotonin signaling, neurotransmitters that have been implicated in the pathophysiology of these disorders. In this review we discuss the common and disorder-specific pathophysiological mechanisms of inhibition-related dysfunction in OCD and related disorders.

Improving response inhibition systems in frontotemporal dementia with citalopram.

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Hughes, Laura E; Rittman, Timothy; Regenthal, Ralf; Robbins, Trevor W; Rowe, James B

2015-07-01

Disinhibition is a cardinal feature of the behavioural variant of frontotemporal dementia, presenting as impulsive and impetuous behaviours that are often difficult to manage. The options for symptomatic treatments are limited, but a potential target for therapy is the restoration of serotonergic function, which is both deficient in behavioural variant frontotemporal dementia and closely associated with inhibitory control. Based on preclinical studies and psychopharmacological interventions in other disorders, we predicted that inhibition would be associated with the right inferior frontal gyrus and dependent on serotonin. Using magnetoencephalography and electroencephalography of a Go-NoGo paradigm, we investigated the neural basis of behavioural disinhibition in behavioural variant frontotemporal dementia and the effect of selective serotonin reuptake inhibition on the neural systems for response inhibition. In a randomized double-blinded placebo-controlled crossover design study, 12 patients received either a single 30 mg dose of citalopram or placebo. Twenty age-matched healthy controls underwent the same magnetoencephalography/electroencephalography protocol on one session without citalopram, providing normative data for this task. In the control group, successful NoGo trials evoked two established indices of successful response inhibition: the NoGo-N2 and NoGo-P3. Both of these components were significantly attenuated by behavioural variant frontotemporal dementia. Cortical sources associated with successful inhibition in control subjects were identified in the right inferior frontal gyrus and anterior temporal lobe, which have been strongly associated with behavioural inhibition in imaging and lesion studies. These sources were impaired by behavioural variant frontotemporal dementia. Critically, citalopram enhanced the NoGo-P3 signal in patients, relative to placebo treatment, and increased the evoked response in the right inferior frontal gyrus. Voxel

Early human pregnancy serum cytokine levels predict autoimmunity in offspring.

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Lindehammer, Sabina Resic; Björck, Sara; Lynch, Kristian; Brundin, Charlotte; Marsal, Karel; Agardh, Daniel; Fex, Malin

2011-09-01

It is generally believed that pregnancy is mediated by a Th2 response, which includes cytokines that promote placental growth and are involved in inducing tolerance to the foetus. If the balance between Th1/and Th2-mediated cytokines is disrupted, systemic and local changes could predispose the foetus to future disease. Therefore, a shift in the Th1/Th2 balance during pregnancy, possibly caused by underlying environmental factors, could be associated with post-partum autoimmune disease in the offspring. Based on this presumption, we used celiac disease as a model to investigate whether autoimmunity is triggered in the foetus during early pregnancy, observed as changes in the mother's cytokine profile. Ten cytokines were measured by electro-chemi-luminescent multiplex ELISA in serum samples obtained from mothers during early pregnancy. Cases included women with children who had developed verified celiac disease before the age of 5, who were compared with other women as matched controls. We observed that 7 out of 10 cytokine levels were significantly increased in our case mothers when compared to controls. Five of these belonged to what is generally known as a Th1-mediated response (TNFα, IFNγ, IL-2, IL-1β and IL-12) and two were Th2 cytokines (IL-13 and IL-10). However, the IL-10 cytokine is known to have features from both arms of the immune system. These results were confirmed in a logistic regression model where five out of the initial seven cytokines remained. This study suggests that increase in Th1 serum cytokines may be associated with celiac disease in offspring.

Changes in the Th1 : Th2 Cytokine Bias in Pregnancy and the Effects of the Anti-Inflammatory Cyclopentenone Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2

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Lynne Sykes

2012-01-01

Full Text Available Pregnancy is a complex immunological state in which a bias towards T helper 2 (Th2 protects the fetus. Evidence suggests that proinflammatory cytokines increase the risk of poor neonatal outcome, independently of the direct effect of preterm labour. The anti-inflammatory prostaglandin 15-deoxy-Δ12,14-Prostaglandin J2 (15dPGJ2 inhibits nuclear factor Kappa B (NF-κB in amniocytes and myocytes in vitro and is a ligand for the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 receptor. Here we examine the Th1:Th2 cytokine bias in pregnancy and whether 15dPGJ2 could be used to inhibit the production of the proinflammatory cytokines through inhibition of NF-κB while simultaneously promoting Th2 interleukin 4 (IL-4 synthesis via CRTH2 in T helper cells. Peripheral blood mononuclear cells (PBMCs from women at 28 weeks, term pre-labour, term labour as well as non-pregnant female controls were cultured with 15dPGJ2 or vehicle control and stimulated with phorbol myristyl acetate (PMA/ionomycin. The percentage of CD4+ cells producing interferon gamma (IFN-γ and tumor necrosis factor alpha (TNF-α in response to PMA/ionomycin was significantly reduced in pregnancy. 15dPGJ2 reduced IFN-γ and TNF-α production in stimulated T helper cells, but did not alter IL-4 production in CRTH2+ve cells. 15dPGJ2 also reduced phospho-p65 in stimulated PBMCs. In summary, 15dPGJ2 suppresses the Th1 response of PBMCs during pregnancy and active labour whilst maintaining the Th2 response suggesting a therapeutic benefit in reducing neonatal morbidity in inflammation-induced PTL.