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Sample records for profibrogenic cytokine gene

  1. Accelerated CCl4-induced liver fibrosis in Hjv-/- mice, associated with an oxidative burst and precocious profibrogenic gene expression.

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    Giada Sebastiani

    Full Text Available Hereditary hemochromatosis is commonly associated with liver fibrosis. Likewise, hepatic iron overload secondary to chronic liver diseases aggravates liver injury. To uncover underlying molecular mechanisms, hemochromatotic hemojuvelin knockout (Hjv-/- mice and wild type (wt controls were intoxicated with CCl(4. Hjv-/- mice developed earlier (by 2-4 weeks and more acute liver damage, reflected in dramatic levels of serum transaminases and ferritin and the development of severe coagulative necrosis and fibrosis. These responses were associated with an oxidative burst and early upregulation of mRNAs encoding α1-(I-collagen, the profibrogenic cytokines TGF-β1, endothelin-1 and PDGF and, notably, the iron-regulatory hormone hepcidin. Hence, CCl4-induced liver fibrogenesis was exacerbated and progressed precociously in Hjv-/- animals. Even though livers of naïve Hjv-/- mice were devoid of apparent pathology, they exhibited oxidative stress and immunoreactivity towards α-SMA antibodies, a marker of hepatic stellate cells activation. Furthermore, they expressed significantly higher (2-3 fold vs. wt, p<0.05 levels of α1-(I-collagen, TGF-β1, endothelin-1 and PDGF mRNAs, indicative of early fibrogenesis. Our data suggest that hepatic iron overload in parenchymal cells promotes oxidative stress and triggers premature profibrogenic gene expression, contributing to accelerated onset and precipitous progression of liver fibrogenesis.

  2. HIV and HCV Co-Culture Promotes Profibrogenic Gene Expression through an Epimorphin-Mediated ERK Signaling Pathway in Hepatic Stellate Cells.

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    Lei Shi

    Full Text Available Accelerated fibrosis in patients co-infected with hepatitis C virus (HCV and human immunodeficiency virus (HIV has been a major cause of mortality in the highly active anti-retroviral therapy (HAART era. However, the role of co-infection in accelerating the progression of liver fibrosis, particularly with regard to the effects of co-infection on hepatic stellate cells (HSCs, remains unclear. We hypothesized that HIV and HCV induce liver fibrosis synergistically by altering the regulation of epimorphin production, and thereby indirectly alter HSC function. Here, we examined the effects of epimorphin on HSC proliferation and invasion, and the changes in fibrogenesis-related gene activity in HSCs (LX2 in the presence of inactivated CXCR4-tropic HIV and HCV (JFH1. The combination of HIV and HCV significantly increased epimorphin expression, which increased the proliferation and invasion capabilities of HSCs. Epimorphin also induced the expression of profibrogenic tissue inhibitor of metalloproteinase 1 (TIMP1 in an extracellular signal-regulated kinase (ERK-dependent manner. These data indicated that the effects of HIV/HCV co-infection on hepatic fibrosis might be mediated in part by EPM. Strategies to limit the expression of EPM might represent a novel therapeutic approach to prevent the progression of hepatic fibrosis during HIV/HCV co-infection.

  3. βig-h3 Potentiates the Profibrogenic Effect of TGFβ Signaling on Connective Tissue Progenitor Cells Through the Negative Regulation of Master Chondrogenic Genes

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    Lorda-Diez, Carlos I.; Montero, Juan A.; Diaz-Mendoza, Manuel J.; Garcia-Porrero, Juan A.

    2013-01-01

    Tendons and cartilage are specialized forms of connective tissues originated from common progenitor cells. Initial stages of differentiation of these tissues are characterized by the formation of cell aggregates, which share many molecular markers. Once differentiated, these cells retain considerable plasticity, and chondral metaplasia of tendon and fibrous connective tissues and eventual ossification often accompany degenerative diseases in the adult musculoskeletal system. While this fact is of great relevance for regenerative medicine and aging biology, its molecular basis remains to be elucidated. Gene expression analysis in several physiological and experimental paradigms suggests that differentiation of tendon and cartilage is regulated by a balance in the expression of chondrogenic versus tenogenic genes in the connective tissue cell precursors. Transforming growth factor β (TGFβ) may function both as a profibrogenic or as a prochondrogenic factor for embryonic limb mesoderm and mesenchymal stem cell cultures, but mice that are null for TGFβ 2 and 3 lack tendons. Here, we identify βig-h3 as a factor downstream TGFβ signaling regulated by Smad 2 and 3, which is highly expressed in the differentiating tendons and joint capsules. Furthermore, gain- and loss-of-function experiments using limb mesoderm micromass cultures show that βig-h3 downregulates the expression of cartilage master genes, including Sox9, type II collagen, and Hif-1α. Positive regulation of Sox9 and type II Collagen observed in micromass cultures grown under hypoxic conditions is prevented by exogenous administration of βIG-H3, and the antichondrogenic influence of βIG-H3 is lost after Hif-1α silencing with shRNA. Collectively, our findings indicate that βig-h3 promotes the fibrogenic influence of TGFβ signaling, neutralizing the prochondrogenic influence of the hypoxic-inducible factor 1 activated by the hypoxic microenvironment characteristic of limb mesenchymal aggregates. PMID

  4. miRNA regulation of cytokine genes

    OpenAIRE

    Asirvatham, Ananthi J.; Magner, William J.; Tomasi, Thomas B.

    2009-01-01

    In this review we discuss specific examples of regulation of cytokine genes and focus on a new mechanism involving post-transcriptional regulation via miRNAs. The post-transcriptional regulation of cytokine genes via the destabilizing activity of AU-rich elements [AREs] and miRNAs is a pre-requisite for regulating the half-life of many cytokines and achieving the temporal and spatial distributions required for regulation of these genes.

  5. Impact of cytokine and cytokine receptor gene polymorphisms on cellular immunity after smallpox vaccination.

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    Ovsyannikova, Inna G; Haralambieva, Iana H; Kennedy, Richard B; Pankratz, V Shane; Vierkant, Robert A; Jacobson, Robert M; Poland, Gregory A

    2012-11-15

    We explored associations between SNPs in cytokine/cytokine receptor genes and cellular immunity in subjects following primary smallpox vaccination. We also analyzed the genotype-phenotype associations discovered in the Caucasian subjects among a cohort of African-Americans. In Caucasians we found 277 associations (psmallpox vaccine-induced cytokine responses are modulated by genetic polymorphisms in cytokine and cytokine receptor genes. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Cytokine gene expression of peripheral blood lymphocytes ...

    African Journals Online (AJOL)

    Lipopolysaccharide (LPS) is a predominant glycolipid in the outer membranes of gam-negative bacteria that stimulates monocytes, macrophages, and neutrophils to produce cytokines. The aim was to study the expression profile of TLRs and cytokines and determine the role of LPS in the peripheral blood lymphocytes.

  7. Cytokine genes as potential biomarkers for muscle weakness in OPMD

    DEFF Research Database (Denmark)

    Riaz, Muhammad; Raz, Yotam; van der Slujis, Barbara

    2016-01-01

    Molecular biomarkers emerge as an accurate diagnostic tool, but are scarce for myopathies. Lack of outcome measures sensitive to disease onset and symptom severity hamper evaluation of therapeutic developments. Cytokines are circulating immunogenic molecules, and their potential as biomarkers has...... been exploited in the last decade. Cytokines are released from many tissues, including skeletal muscles, but their application to monitor muscle pathology is sparse. We report that the cytokine functional group is altered in the transcriptome of oculopharyngeal muscular dystrophy (OPMD). OPMD...... is a dominant, late-onset myopathy, caused by an alanine-expansion mutation in the gene encoding for poly(A) binding protein nuclear 1 (expPABPN1). Here, we investigated the hypothesis that cytokines could mark OPMD disease state. We determined cytokines levels the vastus lateralis muscle from genetically...

  8. Associations between cytokine gene polymorphisms and recurrent pregnancy loss.

    Science.gov (United States)

    Daher, Silvia; Shulzhenko, Natalia; Morgun, Andrey; Mattar, Rosiane; Rampim, Gisele F; Camano, Luiz; DeLima, Maria Gerbase

    2003-02-01

    Since certain cytokines may play a role in unexplained recurrent pregnancy loss (RPL) and also some cytokine gene polymorphisms may affect the level of cytokine production, the aim of the present study was to investigate the relationship between RPL and polymorphisms of the genes coding for TNF-alpha (-308 G-->A), IL-10 (-1082 G-->A), IL-6 (-174 G-->C), and IFN-gamma (+874 A-->T). Genotyping was performed in 48 RPL women and 108 ethnically matched healthy individuals. In addition, we performed a meta-analysis encompassing the present results and those from studies on the association of TNF-alpha, IL-10 and IFN-gamma polymorphisms with RPL published in the literature until December 2001. The results showed: (1) no evidence of association with IL-6 gene polymorphisms; (2) significant associations, revealed by the meta-analysis, with the high cytokine production genotypes of IFN-gamma (+874 T/T: odds ratio (OR)=1.92, P=0.04) and IL-10 (-1082 G/G: OR=1.75, P=0.03), and a trend for association with the high TNF-alpha production genotypes -308 A/A and A/G (OR=1.61; P=0.18). We believe that the associations of these genotypes with RPL are interesting not only as risk factors but also because they represent another piece of evidence that these cytokines might be important in the pathogenesis of RPL.

  9. EVALUATION OF CYTOKINE GENE POLYMORPHISM IN B CELL LYMPHOID MALIGNANCIES

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    E. L. Nazarova

    2014-01-01

    Full Text Available Previous studies with some solid tumors has shown that polymorphisms of certain cytokine genes may be used as predictors of clinical outcome in the patients. It seemed important to evaluate potential correlations between production of certain pro- and anti-inflammatory cytokines and co-receptor molecules, and promoter polymorphism of the cytokine genes involved into regulation of cell proliferation, differentiation, apoptosis, lipid metabolism and blood clotting in the patients with hematological malignancies. The article contains our results concerning associations between of IL-1β, -2, -4, -10, -17, TNFα, and allelic polymorphisms of their genes in 62 patients with B cell lymphoid malignancies in an ethnically homogenous group (self-identified as Russians. We have shown that the GА and AA genotypes of the G-308A polymorphism in TNFα gene are significantly associated with increased production of this cytokine, being more common in aggressive non-Hodgkin lymphomas, more rare in multiple myeloma and in indolent non-Hodgkin lymphomas.

  10. Characterising Cytokine Gene Expression Signatures in Patients with Severe Sepsis

    OpenAIRE

    Grealy, Robert; White, Mary; Stordeur, Patrick; Kelleher, Dermot; Doherty, Derek G.; McManus, Ross; Ryan, Thomas

    2013-01-01

    PUBLISHED Introduction. Severe sepsis in humans may be related to an underlying profound immune suppressive state. We investigated the link between gene expression of immune regulatory cytokines and the range of illness severity in patients with infection and severe sepsis. Methods. A prospective observational study included 54 ICU patients with severe sepsis, 53 patients with infection without organ failure, and 20 healthy controls. Gene expression in peripheral blood mononuclear cells (P...

  11. Polymorphisms of Cytokine Genes and Polycystic Ovary Syndrome: A Review.

    Science.gov (United States)

    de Alencar, Josiane Bazzo; Alves, Hugo Vicentin; Elpidio, Laise Nayana Sala; Visentainer, Jeane Eliete Laguila; Sell, Ana Maria

    2016-12-01

    Polycystic ovary syndrome (PCOS) is the endocrinopathy that affects women in their reproductive age. The physiopathology involves multifactorial mechanisms, including cytokine gene regulation. The review was conducted in the database PubMed, with articles published between 2005 and 2015. The selected studies evaluated the single-nucleotide polymorphisms (SNPs) of cytokines genes in association with PCOS. Twenty-four studies met the inclusion criteria and showed the SNPs of cytokines that were associated or not with PCOS. The disease susceptibility was associated with interleukin (IL) 1A, IL1B, IL1RN, and IL6 alleles and genotypes. The tumor necrosis factor (TNF) -1032 C/T genotype and C allele were risk factors and T/T genotype was a protector marker to disease. The IL18 SNPs were not associated with PCOS per se, but IL18-137 C and G alleles were related to the protection of insulin resistance and glucose tolerance, respectively. One research found association between TGFB1 and PCOS. However, the TNF -308, IL10, and interferon (IFN) SNPs did not appear to influence PCOS genetic susceptibility. This study sought to contribute and clarify the SNPs in cytokine genes that influence the development of PCOS. Most studies occurred in Asia; most SNPs studied were in IL1B -511, TNF -1031, and IL6-174; and most of them were associated with the susceptibility to PCOS development. Nevertheless, further investigations based on genome-wide association studies and cytokine gene SNPs are needed to better characterize the risk factors to PCOS.

  12. Role of HLA, KIR, MICA, and Cytokines Genes in Leprosy

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    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

  13. Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms

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    Joanna Balding

    2004-01-01

    Full Text Available THE mechanisms responsible for development of inflammatory bowel disease (IBD have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n=172 and healthy controls (n=389 for polymorphisms in genes encoding various cytokines (interleukin (IL-1β, IL-6, tumour necrosis factor (TNF, IL-10, IL-1 receptor antagonist. Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-α-308 polymorphism (p=0.0135. There was also variation in the frequency of IL-6-174 and TNF-α-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p=0.01. We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear.

  14. Polymorphisms in cytokine genes and serum cytokine levels among New Mexican women with and without breast cancer.

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    Erdei, Esther; Kang, Huining; Meisner, Angela; White, Kirsten; Pickett, Gavin; Baca, Cynthia; Royce, Melanie; Berwick, Marianne

    2010-07-01

    Among New Mexican Hispanic women, breast cancer is detected at a more advanced stage than compared to Non-Hispanic White women. One central factor that has been little studied is the role of critical cytokines. We genotyped incident breast cancer cases and their age-, gender- and smoking-matched controls (N=40 matched pairs) for 25 single nucleotide polymorphisms (SNPs) in cytokine genes. We measured corresponding serum cytokine levels as well. Five cytokines (IL-1beta, IL-5, TNF-alpha, IL-6 and IL-2) were significantly associated with disease and based on their serum levels, concentrations were higher in the cases than in the controls. Disease odds ratios corresponding to one standard deviation change in log-transformed concentrations of these cytokines were 18.87, 4.10, 3.61, 3.27 and 2.52. Three most statistically significant SNPs were rs2069705, located in the promoter region of the interferon gamma gene (INF-gamma); rs2243248, in the promoter of IL-4 (rs2243248); and rs1800925, in the promoter of the IL-13 gene. Increased serum cytokine levels at diagnosis are indicative for immunological alterations and possibly related to genetic susceptibility markers as well. These findings might guide us to understand the presence of SNPs in cytokine genes and serum concentrations among breast cancer patients and potentially in other cancers. Copyright 2010 Elsevier Ltd. All rights reserved.

  15. Influence of proinflammatory cytokine gene polymorphism on childhood obesity.

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    Popko, K; Górska, E; Pyrzak, B; Telmaszczyk-Emmel, A; Wisniewska, A; Majcher, A; Wasik, M; Demkow, U

    2009-12-07

    Obesity development is a complex process which can be influenced by genetic predisposition modified by environmental factors. Nowadays, the problem of overweight and obesity, including related complications, occurs in increasingly younger children. Thus, there is a need for new genetic markers of increased risk of excessive body mass. The aim of the present study was to examine the relation between polymorphisms located in promoter regions of IL-1beta, IL-6, and TNF-alpha genes and obesity development in children. Fifty obese and 55 normal weighing children were enrolled into the study. Genetic examination was performed using PCR-RFLP technique. We found a relation between G174C polymorphism in IL-6 gene and G308A in TNF-alpha gene with the occurrence of obesity. Allele A in G308A was more frequent in the obese group than in the control one (P=0.04). The presence of allele C in promoter region of IL-6 gene was more frequent in obese children and connected with a statistically significant increase in the sum of 10 skin fold thickness measurements (P=0.03). The polymorphism C3954T in IL-1beta gene showed no such relation. The examined polymorphisms of proinflammatory cytokines play a role in the regulation of body mass through their influence on metabolism and energetic homeostasis.

  16. Influence of proinflammatory cytokine gene polymorphism on childhood obesity

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    Popko K

    2009-12-01

    Full Text Available Abstract Background Obesity development is a complex process which can be influenced by genetic predisposition modified by environmental factors. Nowadays, the problem of overweight and obesity, including related complications, occurs in increasingly younger children. Thus, there is a need for new genetic markers of increased risk of excessive body mass. Objective The aim of the present study was to examine the relation between polymorphisms located in promoter regions of IL-1beta, IL-6, and TNF-alpha genes and obesity development in children. Fifty obese and 55 normal weighing children were enrolled into the study. Genetic examination was performed using PCR-RFLP technique. Results We found a relation between G174C polymorphism in IL-6 gene and G308A in TNF-alpha gene with the occurrence of obesity. Allele A in G308A was more frequent in the obese group than in the control one (P = 0.04. The presence of allele C in promoter region of IL-6 gene was more frequent in obese children and connected with a statistically significant increase in the sum of 10 skin fold thickness measurements (P = 0.03. Conclusions The polymorphism C3954T in IL-1beta gene showed no such relation. The examined polymorphisms of proinflammatory cytokines play a role in the regulation of body mass through their influence on metabolism and energetic homeostasis.

  17. Aggressive periodontitis and chronic arthritis: blood mononuclear cell gene expression and plasma protein levels of cytokines and cytokine inhibitors

    DEFF Research Database (Denmark)

    Sørensen, Lars K; Havemose-Poulsen, Anne; Bendtzen, Klaus

    2009-01-01

    inflammation in general, patients with arthritis (juvenile idiopathic arthritis [JIA] and rheumatoid arthritis [RA]) were included. METHODS: The study population consisted of white adults aggressive periodontitis (LAgP; n = 18), generalized aggressive periodontitis......TNF-RI plasma levels in patients with LAgP and RA. CONCLUSIONS: The study demonstrated only a few changes in the PBMC expression of various cytokine and cytokine inhibitor genes in aggressive periodontitis and chronic arthritis compared to controls. There were a few similarities among disease groups......-inflammatory cytokines and cytokine receptors in patients with periodontitis and patients with arthritis representing two examples of chronic inflammatory diseases, such as periodontitis and arthritis. To identify possible disease-specific characteristics of subjects with periodontitis relative to subjects with chronic...

  18. Depression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Naïve First Episode Psychosis.

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    Noto, Cristiano; Ota, Vanessa Kiyomi; Santoro, Marcos Leite; Gouvea, Eduardo Sauerbronn; Silva, Patricia Natalia; Spindola, Leticia Maria; Cordeiro, Quirino; Bressan, Rodrigo Affonseca; Gadelha, Ary; Brietzke, Elisa; Belangero, Sintia Iole; Maes, Michael

    2016-10-01

    In schizophrenia, genetic and environmental factors affect neurodevelopment and neuroprogressive trajectory. Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression. However, it remains unclear whether circulating levels of cytokines and expression of these genes are associated, and how antipsychotic treatments impact this association. Relationships between messenger RNA (mRNA) expression of 11 schizophrenia-related genes and circulating levels of cytokines (interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α) were analyzed in 174 antipsychotic naïve first episode psychosis (FEP) and in 77 healthy controls. A subgroup of 72 patients was reassessed after treatment with risperidone. FEP patients were divided into those with and without depression. FEP patients with depression showed increased COMT expression and decreased NDEL1 expression. Increased IL-6 was associated with lowered AKT1 and DROSHA expression, while increased IL-10 was associated with increased NDEL1, DISC1, and MBP expression. IL-6 levels significantly increased the risperidone-induced expression of AKT1, DICER1, DROSHA, and COMT mRNA. The differential mRNA gene expression in FEP is largely associated with increased cytokine levels. While increased IL-6 may downregulate AKT-mediated cellular functions and dysregulate genes involved in microRNA (miRNA) machinery, increased IL-10 has neuroprotective properties. Increased IL-6 levels may prime the expression of genes (AKT1, DICER1, DROSHA, and COMT) in response to risperidone, suggesting that cytokine × treatment × gene interactions may improve cell function profiles. FEP patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype.

  19. Cytokine gene polymorphisms and their association with cervical ...

    African Journals Online (AJOL)

    Introduction: The production of cytokines, growth factors and adhesion molecules promotes tumor progression and involves inflammation, angiogenesis and thrombosis, thus providing optimal conditions for cancer development. Materials and methods: The present study was undertaken to evaluate association of cytokine ...

  20. Associations between single nucleotide polymorphisms and haplotypes in cytokine and cytokine receptor genes and immunity to measles vaccination.

    Science.gov (United States)

    Haralambieva, Iana H; Ovsyannikova, Inna G; Kennedy, Richard B; Vierkant, Robert A; Pankratz, V Shane; Jacobson, Robert M; Poland, Gregory A

    2011-10-19

    Identification of host genetic determinants of measles vaccine-induced immunity can be used to design better vaccines and ultimately predict immune responses to vaccination. We performed a comprehensive candidate gene association study across 801 genetic markers in 56 cytokine/cytokine receptor genes, in a racially diverse cohort of 745 schoolchildren after two doses of MMR vaccine. Using linear regression methodologies we examined associations between SNPs/haplotypes and measles virus-specific immunity. Forty-eight significant SNP associations with variations in neutralizing antibodies and measles-specific IFNγ Elispot responses were identified (pvaccine-induced immunity in the Caucasian group (global p-value=0.003). Our results validate previous findings and identify new plausible genetic determinants, including IL7R polymorphisms, regulating measles vaccine-induced immunity in a race-specific manner. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. CYTOKINE GENE POLYMORPHISMS AS PREDICTORS OF CHRONIC PAIN SYNDROME IN ONCOLOGY

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    O. P. Bobrova

    2017-01-01

    Full Text Available The literature review on the role of cytokine gene polymorphisms in the development of chronic pain in cancer patients was presented using MedLine, PubMed, NEB elibrary.ru, WileyOnlineLibrary, WebofScience, OxfordUniversityPress and SAGEPremier databases for years 1995 to 2016. The role of inter-individual differences based on cytokine gene polymorphisms and their receptors for personalized anesthetic and accompanying treatment in oncology was shown.

  2. The effect of the colostral cells on gene expression of cytokines in cord blood cells.

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    Hrdý, Jiří; Novotná, Olga; Kocourková, Ingrid; Prokešová, Ludmila

    2017-11-01

    Beneficial effect of maternal milk is acknowledged, but there is still question whether maternal milk from allergic mother is as good as from healthy one. In our study, we have assayed the effect of cells from colostrum of healthy and allergic mothers on gene expression of cytokines in cord blood cells of newborns of healthy and allergic mothers. Cytokines typical for Th1 (IL-2, IFN-gamma), Th2 (IL-4, IL-13), Tregs (IL-10, TGF-beta), and IL-8 were followed. We were not able to detect significant influence of colostral cells on gene expression of cytokines in cord blood after 2-day coculture using Transwell system. There was no difference in gene expression of cytokines in nonstimulated cord blood cells of newborns of healthy and allergic mothers, but generally increased gene expression of cytokines except IL-10 and TGF-beta after polyclonal stimulation was detected in cord blood cells of children of allergic mothers. There was no difference in IL-10 expression in stimulated cord blood cells of children of healthy and allergic mothers. Gene expression of TGF-beta was even decreased in stimulated cord blood cells of children of allergic mothers in comparison to healthy ones. We have not observed difference in the capacity of colostral cells of healthy and allergic mothers to influence gene expression of cytokines in cord blood cells, but we have described difference in the reactivity of cord blood cells between children of allergic and healthy mothers.

  3. Cytokine gene polymorphisms and their association with cervical ...

    African Journals Online (AJOL)

    Maneesh Kumar Gupta

    2015-11-17

    Nov 17, 2015 ... Abstract Introduction: The production of cytokines, growth factors and adhesion molecules pro- motes tumor progression and involves inflammation, angiogenesis and thrombosis, thus providing optimal conditions for cancer development. Materials and methods: The present study was undertaken to ...

  4. Impact of genetic polymorphisms of four cytokine genes on treatment ...

    African Journals Online (AJOL)

    Manar Obada

    2016-04-25

    Apr 25, 2016 ... Abstract Background: Many factors contribute for viral clearance and response to antiviral therapy. Genetic polymorphisms of cytokines, chemokines, and their receptors can alter the immune response against Hepatitis C virus (HCV). Aim of the study: The aim of the current study is to assess single ...

  5. Impact of genetic polymorphisms of four cytokine genes on treatment ...

    African Journals Online (AJOL)

    Background: Many factors contribute for viral clearance and response to antiviral therapy. Genetic polymorphisms of cytokines, chemokines, and their receptors can alter the immune response against Hepatitis C virus (HCV). Aim of the study: The aim of the current study is to assess single nucleotide polymorphism (SNP) in ...

  6. 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

  7. The mouthwash : A non-invasive sampling method to study cytokine gene polymorphisms

    NARCIS (Netherlands)

    Laine, ML; Farre, MA; Crusius, JBA; van Winkelhoff, AJ; Pena, AS

    Background: We describe a simple, non-invasive mouthwash sampling method for rapid DNA isolation to detect cytokine gene polymorphisms. In the present paper, interleukin-1 beta (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) gene polymorphisms were studied. Methods: Two mouthwash samples and

  8. Evaluation of gene expression levels for cytokines in ocular toxoplasmosis.

    Science.gov (United States)

    Maia, M M; Meira-Strejevitch, C S; Pereira-Chioccola, V L; de Hippólito, D D C; Silva, V O; Brandão de Mattos, C C; Frederico, F B; Siqueira, R C; de Mattos, L C

    2017-10-01

    This study evaluated levels for mRNA expression of 7 cytokines in ocular toxoplasmosis. Peripheral blood mononuclear cells (PBMC) of patients with ocular toxoplasmosis (OT Group, n = 23) and chronic toxoplasmosis individuals (CHR Group, n = 9) were isolated and stimulated in vitro with T. gondii antigen. Negative controls (NC) were constituted of 7 PBMC samples from individuals seronegative for toxoplasmosis. mRNA expression for cytokines was determined by qPCR. Results showed a significant increase in mRNA levels from antigen stimulated PBMCs derived from OT Group for expressing IL-6 (at P < .005 and P < .0005 for CHR and NC groups, respectively), IL-10 (at P < .0005 and P < .005 for CHR and NC groups, respectively) and TGF-β (at P < .005) for NC group. mRNA levels for TNF-α and IL-12 were also upregulated in patients with OT compared to CHR and NC individuals, although without statistical significance. Additionally, mRNA levels for IL-27 and IFN-γ in PBMC of patients with OT were upregulated in comparison with NC individuals. Differences between OT and NC groups were statistically significant at P < .05 and P < .0005, respectively. © 2017 John Wiley & Sons Ltd.

  9. ASSOCIATION BETWEEN CYTOKINE GENE POLYMORPHISMS AND RECURRENT MISCARRIAGE

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    L A. Gordeeva

    2017-01-01

    Full Text Available Associations between IL1B (rs1143634, IL1RN (VNTR, intron 2, IL4 (VNTR, intron 3, TNFA (rs1800629, rs361525, IL6 (rs1800795, and IL10 (rs1800896 genetic polymorphisms in women with recurrent miscarriage (RM were analyzed. We studied DNA samples of 112 women with RM and 267 women with physiological pregnancy. The IL1RN, IL4 genotypes were identified by PCR techniques, the IL1B, IL6 gene polymorphisms were defined by means of RFLP approach. To detect TNFA and IL10 gene polymorphisms, TaqMan real-time PCR was used. The results have shown that polymorphic loci of IL1B, IL1RN, IL10, TNFA genes were not associated with RM, and early spontaneous abortion risk. The 2R allele of IL4 gene was found to be associated with higher RM risk (OR = 1.52; 95% CI = [1.08-2.14]; P-value (cor = 0.05, and G allele of IL6 gene was associated with a risk for > 3 early spontaneous abortions (OR = 2.10; 95% CI = [1.24-3.56]; P-value (cor = 0.05, in an additive inheritance model. Upon evaluation of the data obtained, one may conclude that the IL4 (VNTR intron 3 and IL6 (rs1800795 gene polymorphisms could influence the RM development. These results may be useful for assessment of molecular mechanisms underlying early spontaneous abortion.

  10. CYTOKINE GENE VARIATIONS ASSOCIATED WITH TRAIT AND STATE ANXIETY IN ONCOLOGY PATIENTS AND THEIR FAMILY CAREGIVERS

    Science.gov (United States)

    Miaskowski, Christine; Cataldo, Janine K.; Baggott, Christina R.; West, Claudia; Dunn, Laura B.; Dhruva, Anand; Merriman, John D.; Langford, Dale J.; Kober, Kord M.; Paul, Steven M.; Cooper, Bruce A.; Aouizerat, Bradley E.

    2017-01-01

    Purpose Anxiety is common among cancer patients and their family caregivers (FCs) and is associated with poorer outcomes. Recently, associations between inflammation and anxiety were identified. However, the relationship between variations in cytokine genes and anxiety warrants investigation. Therefore, phenotypic and genotypic characteristics associated with trait and state anxiety were evaluated in a sample of 167 oncology patients with breast, prostate, lung, or brain cancer and 85 of their FCs. Methods Using multiple regression analyses, the associations between participants’ demographic and clinical characteristics, as well as variations in cytokine genes and trait and state anxiety were evaluated. Results In the bivariate analyses, a number of phenotypic characteristics were associated with both trait and state anxiety (e.g., age, functional status). However, some associations were specific only to trait anxiety (e.g., number of comorbid conditions) or state anxiety (e.g., participation with a FC). Variations in three cytokine genes (i.e., interleukin (IL) 1 beta, IL1 receptor 2 (IL1R2), nuclear factor kappa beta 2 (NFKB2)) were associated with trait anxiety and variations in two genes (i.e., IL1R2, tumor necrosis factor alpha (TNFA)) were associated with state anxiety. Conclusions These findings suggest that both trait and state anxiety need to be assessed in oncology patients and their FCs. Furthermore, variations in cytokine genes may contribute to higher levels of anxiety in oncology patients and their FCs. PMID:25249351

  11. Proinflammatory cytokines decrease the expression of genes critical for RPE function.

    Science.gov (United States)

    Kutty, R Krishnan; Samuel, William; Boyce, Kaifa; Cherukuri, Aswini; Duncan, Todd; Jaworski, Cynthia; Nagineni, Chandrasekharam N; Redmond, T Michael

    2016-01-01

    Proinflammatory cytokines interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) secreted by infiltrating lymphocytes or macrophages may play a role in triggering RPE dysfunction associated with age-related macular degeneration (AMD). Binding of these proinflammatory cytokines to their specific receptors residing on the RPE cell surface can activate signaling pathways that, in turn, may dysregulate cellular gene expression. The purpose of the present study was to investigate whether IFN-γ, TNF-α, and IL-1β have an adverse effect on the expression of genes essential for RPE function, employing the RPE cell line ARPE-19 as a model system. ARPE-19 cells were cultured for 3-4 months until they exhibited epithelial morphology and expressed mRNAs for visual cycle genes. The differentiated cells were treated with IFN-γ, TNF-α, and/or IL-1β, and gene expression was analyzed with real-time PCR analysis. Western immunoblotting was employed for the detection of proteins. Proinflammatory cytokines (IFN-γ + TNF-α + IL-1β) greatly increased the expression of chemokines and cytokines in cultured ARPE-19 cells that exhibited RPE characteristics. However, this response was accompanied by markedly decreased expression of genes important for RPE function, such as CDH1 , RPE65 , RDH5 , RDH10 , TYR , and MERTK . This was associated with decreased expression of the genes MITF , TRPM1 , and TRPM3 , as well as microRNAs miR-204 and miR-211, which are known to regulate RPE-specific gene expression. The decreased expression of the epithelial marker gene CDH1 was associated with increased expression of mesenchymal marker genes ( CDH2 , VIM , and CCND1 ) and epithelial-mesenchymal transition (EMT) promoting transcription factor genes ( ZEB1 and SNAI1 ). RPE cells exposed to proinflammatory cytokines IFN-γ, TNF-α, and IL-1β showed decreased expression of key genes involved in the visual cycle, epithelial morphology, and phagocytosis. This

  12. Distribution of cytokine gene polymorphisms in six Orang Asli subgroups in Peninsular Malaysia.

    Science.gov (United States)

    Norhalifah, Hanim K; Syafawati, Wan U Wan; Che Mat, Nor F; Chambers, Geoffrey K; Edinur, Hisham A

    2016-04-01

    Cytokines are involved in immune responses and the pathogenesis of various diseases. Allelic variations within the genes coding for various ∼30 kDa cytokine protein/glycoproteins have been reported for many populations and have been the subjects of many ancestry and health analyses. In this study, we typed 22 single nucleotide polymorphisms (SNPs) in 13 cytokine genes of 165 Orang Asli individuals by using sequence specific primer-polymerase chain reaction (SSP-PCR) assay. The volunteers came from all across the Peninsular of Malaysia and belong to six Orang Asli subgroups; Batek, Kensiu, Lanoh, Che Wong, Semai and Orang Kanaq. Here we report our general findings and original genotype data and their associated analyses (Hardy-Weinberg proportions, estimation of allele and haplotype frequencies) can be found in the supplementary files and will be held at Allele Frequency Net Database (AFND). Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  13. Cytokine gene polymorphisms and their association with cervical cancer: A North Indian study

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    Maneesh Kumar Gupta

    2016-04-01

    Conclusion: Therefore, the promoter polymorphisms in cytokine genes can be used as biomarkers to predict cervical cancer susceptibility in a north Indian population. However, such studies need to be carried out in different ethnic populations in order to discover the specific risk alleles, genotypes and combinations for disease prediction.

  14. Dissecting the psoriasis transcriptome: inflammatory- and cytokine-driven gene expression in lesions from 163 patients

    Science.gov (United States)

    2013-01-01

    Background Psoriasis lesions are characterized by large-scale shifts in gene expression. Mechanisms that underlie differentially expressed genes (DEGs), however, are not completely understood. We analyzed existing datasets to evaluate genome-wide expression in lesions from 163 psoriasis patients. Our aims were to identify mechanisms that drive differential expression and to characterize heterogeneity among lesions in this large sample. Results We identified 1233 psoriasis-increased DEGs and 977 psoriasis-decreased DEGs. Increased DEGs were attributed to keratinocyte activity (56%) and infiltration of lesions by T-cells (14%) and macrophages (11%). Decreased DEGs, in contrast, were associated with adipose tissue (63%), epidermis (14%) and dermis (4%). KC/epidermis DEGs were enriched for genes induced by IL-1, IL-17A and IL-20 family cytokines, and were also disproportionately associated with AP-1 binding sites. Among all patients, 50% exhibited a heightened inflammatory signature, with increased expression of genes expressed by T-cells, monocytes and dendritic cells. 66% of patients displayed an IFN-γ-strong signature, with increased expression of genes induced by IFN-γ in addition to several other cytokines (e.g., IL-1, IL-17A and TNF). We show that such differences in gene expression can be used to differentiate between etanercept responders and non-responders. Conclusions Psoriasis DEGs are partly explained by shifts in the cellular composition of psoriasis lesions. Epidermal DEGs, however, may be driven by the activity of AP-1 and cellular responses to IL-1, IL-17A and IL-20 family cytokines. Among patients, we uncovered a range of inflammatory- and cytokine-associated gene expression patterns. Such patterns may provide biomarkers for predicting individual responses to biologic therapy. PMID:23915137

  15. Association of Cytokine Gene Polymorphism with Peri-implantitis Risk.

    Science.gov (United States)

    Petkovic-Curcin, Aleksandra; Zeljic, Katarina; Cikota-Aleksic, Bojana; Dakovic, Dragana; Tatic, Zoran; Magic, Zvonko

    To investigate whether polymorphisms of cluster of differentiation 14 (CD14), tumor necrosis factor alpha (TNFα), interleukin (IL)6, IL10, and IL1ra genes are associated with the risk of peri-implantitis susceptibility in patients with dental implants in the Serbian population. Isolated DNA from the blood was used for IL10-1082, TNFα-308, IL6-174, CD14-159, and interleukin 1 receptor antagonist (IL1ra) genotyping using polymerase chain reaction (PCR)-based methodology. Clinical parameters included: peri-implant pocket depth (PPD), Plaque Index (PI), Gingival Index (GI), bleeding on probing (BOP), and radiologic bone loss. The study included 98 patients with dental implants in function for at least 1 year, divided into peri-implantitis (34) and healthy peri-implant tissue (64) groups. The percentage distribution of smokers was significantly different between patients who developed peri-implantitis and patients with healthy peri-implant tissue (71% vs 42%, respectively) and associated with increased peri-implantitis risk (OR: 3.289, 95% CI: 1.352 to 8.001; P = .007). A positive history of periodontitis was more frequent in the peri-implantitis group (62%) than in the healthy peri-implant tissue (20%) group and associated with increased peri-implantitis risk (OR: 6.337, 95% CI: 2.522 to 15.927; P = .0001). Frequencies of CD14-159, TNFα-308, IL10-1082, and IL6-174 genotypes were significantly different between patients with and without peri-implantitis. However, logistic regression revealed only TNFα-308 polymorphic GA/AA genotypes (OR: 8.890, 95% CI: 2.15 to 36.7; P = .003) and smoking (OR: 6.2, 95% CI: 1.44 to 26.7; P = .014) as independent factors associated with increased peri-implantitis risk, while CD14-159 polymorphic CT/TT genotypes were associated with decreased risk for peri-implantitis (OR: 0.059, 95% CI: 0.009 to 0.355; P = .002). The findings suggest that smoking and the presence of TNFα-308 GA/AA genotypes may increase the risk for peri

  16. Cytokine gene polymorphisms and atopic disease in two European cohorts. (ECRHS-Basel and SAPALDIA

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    Ackermann-Liebrich U

    2006-06-01

    Full Text Available Abstract Background Atopy and allergic phenotypes are biologically characterized by an imbalanced T helper cell response skewed towards a type 2 (TH2 immune response associated with elevated serum immunoglobulin E (IgE levels. Polymorphisms in cytokine genes might modulate regulation of the TH1/TH2 balance. We thus aimed at reproducing our previous findings from a European study population on the association of various cytokine polymorphisms with self-reported hay fever as well as increased total and specific IgE levels in two comparable study populations. Methods Two prospective Caucasian cohorts were used. In the Basel center of the European Community Respiratory Health Survey (ECRHS, n = 418 ten distinct cytokine polymorphisms of putative functional relevance were genotyped. In the Swiss cohort Study on Air Pollution And Lung Disease In Adults (SAPALDIA, n = 6003 two cytokine polymorphisms were genotyped. The associations of these polymorphisms with atopy were estimated by covariance and logistic regression analysis. Results We confirmed IL4, IL10, IL6 and IL18 as candidate genes for atopic health outcomes. In the large, well-characterized SAPALDIA cohort the IL6(-174G>C and IL18(-137G>C polymorphisms were associated with circulating total IgE concentrations in subjects with hay fever. The IL18(-137G>C polymorphism was also associated with the prevalence of hay fever. Conclusion Comprehensive characterization of genetic variation in extended cytokine candidate gene regions is now needed. Large study networks must follow to investigate the association of risk patterns defined by genetic predisposing and environmental risk factors with specific atopic phenotypes.

  17. Cytokine gene polymorphisms and atopic disease in two European cohorts. (ECRHS-Basel and SAPALDIA)

    Science.gov (United States)

    Imboden, M; Nieters, A; Bircher, AJ; Brutsche, M; Becker, N; Wjst, M; Ackermann-Liebrich, U; Berger, W; Probst-Hensch, NM

    2006-01-01

    Background Atopy and allergic phenotypes are biologically characterized by an imbalanced T helper cell response skewed towards a type 2 (TH2) immune response associated with elevated serum immunoglobulin E (IgE) levels. Polymorphisms in cytokine genes might modulate regulation of the TH1/TH2 balance. We thus aimed at reproducing our previous findings from a European study population on the association of various cytokine polymorphisms with self-reported hay fever as well as increased total and specific IgE levels in two comparable study populations. Methods Two prospective Caucasian cohorts were used. In the Basel center of the European Community Respiratory Health Survey (ECRHS, n = 418) ten distinct cytokine polymorphisms of putative functional relevance were genotyped. In the Swiss cohort Study on Air Pollution And Lung Disease In Adults (SAPALDIA, n = 6003) two cytokine polymorphisms were genotyped. The associations of these polymorphisms with atopy were estimated by covariance and logistic regression analysis. Results We confirmed IL4, IL10, IL6 and IL18 as candidate genes for atopic health outcomes. In the large, well-characterized SAPALDIA cohort the IL6(-174G>C) and IL18(-137G>C) polymorphisms were associated with circulating total IgE concentrations in subjects with hay fever. The IL18(-137G>C) polymorphism was also associated with the prevalence of hay fever. Conclusion Comprehensive characterization of genetic variation in extended cytokine candidate gene regions is now needed. Large study networks must follow to investigate the association of risk patterns defined by genetic predisposing and environmental risk factors with specific atopic phenotypes. PMID:16759385

  18. SATB1 packages densely-looped, transciptionally-active chromatinfor coordinated expression of cytokine genes

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    Cai, Shutao; Lee, Charles C.; Kohwi-Shigematsu, Terumi

    2006-05-23

    SATB1 is an important regulator of nuclear architecture that anchors specialized DNA sequences onto its cage-like network and recruits chromatin remodeling/modifying factors to control gene transcription. We studied the role of SATB1 in regulating the coordinated expression of Il5, Il4, and Il13 from the 200kb cytokine gene cluster region of mouse chromosome 11 during T-helper 2 (Th2)-cell activation. We show that upon cell activation, SATB1 is rapidly induced to form a unique transcriptionally-active chromatin structure that includes the cytokine gene region. Chromatin is folded into numerous small loops all anchored by SATB1, is histone H3 acetylated at lysine 9/14, and associated with Th2-specific factors, GATA3, STAT6, c-Maf, the chromatin-remodeling enzyme Brg-1, and RNA polymerase II across the 200kb region. Before activation, the chromatin displays some of these features, such as association with GATA3 and STAT6, but these were insufficient for cytokine gene expression. Using RNA interference (RNAi), we show that upon cell activation, SATB1 is not only required for chromatin folding into dense loops, but also for c-Maf induction and subsequently for Il4, Il5, and Il13 transcription. Our results show that SATB1 is an important determinant for chromatin architecture that constitutes a novel higher-order, transcriptionally-active chromatin structure upon Th2-cell activation.

  19. Association of cytokine gene polymorphisms with gastritis in a Kazakh population.

    Science.gov (United States)

    Kulmambetova, Gulmira Nigmetzhanovna; Imanbekova, Meruert Kuatbekovna; Logvinenko, Andrey Alexeevich; Sukashev, Adilbek Temirzhanovich; Filipenko, Maxim Leonidovich; Ramanculov, Erlan Mirhaidarovich

    2014-01-01

    Gastritis and gastric cancer are the most common diseases in the Kazakh population. Polymorphisms in genes coding of cytokines have been played important role with gastric disease risk. The risk alleles of cytokines in patients with gastritis can predict the risk of developing gastric cancer. The aim of this study was to investigate cytokine gene polymorphisms as risk factors for the development of gastritis in a case-control study with gastritis patients and healthy individuals from the Kazakh ethnic group, living in North Kazakhstan. The polymerase chain reaction followed by direct sequencing were used for detection of two functional polymorphisms in the IL1 gene family, and TaqMan SNP Genotyping Assay Sets were applied for three potentially functional polymorphisms in the IL10 gene, and one in the TNFA promoter. Association analysis of studied allelic variants and the development of gastritis in H. pylori- positive patients showed that IL1B -31C/C, IL1B -511T/T and IL1RN -2/2 allelic variants were associated with development of gastritis (OR=1.8 (1.07-3.16), p=0.025; OR=1.7 (1.04-2.99), p=0.035, and OR=4.92 (2.45-9.85), prisk of gastritis in the Kazakh population. That genotype combination might be a factor increasing the risk of developing gastric cancer.

  20. Differential cytokine gene expression profiles in the three pathological forms of sheep paratuberculosis

    Science.gov (United States)

    Smeed, Jennifer A; Watkins, Craig A; Rhind, Susan M; Hopkins, John

    2007-01-01

    Background Johne's disease is a chronic inflammatory disease of the gut caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP). Symptoms include wasting, diarrhoea, loss of condition and eventual death. Three forms of Johne's disease have been described in sheep – paucibacillary, multibacillary and asymptomatic. The paucibacillary form is characterized by an inflammatory, Th1-type immune response. The multibacillary form of the disease, which disseminates the infection, is characterized by macrophage infiltration mediated by a Th2-type immune response, and asymptomatic animals have no clinical symptoms or pathology but are infected with MAP. What determines these three forms of the disease is unknown. To further understand these differences, we used real-time RT-PCR to compare the expression of thirteen cytokine and cytokine-related genes in ileal tissue from sheep with the three forms of the disease. Results Three pathological forms of sheep paratuberculosis were defined on the basis of histopathology, cytochemistry (Zeihl-Neelsen) and IS900 PCR. Paucibacillary lesions have largely T cell and eosinophil infiltration and are ZN negative; multibacillary lesions have macrophage infiltration and large numbers of acid-fast bacteria. The pauci- and multibacillary forms are linked to the differential expression of IFNγ and IL-10 respectively. In addition the increased levels of the proinflammatory cytokines (IL-1β and TNFα), IL-8, IL-18 and TRAF-1 in both diseased forms is indicative of persistent inflammatory lesions. No changes were seen in IL-1α in any sheep ileum tissues. Asymptomatic animals are IS900+ with normal histology but have significantly decreased levels of IL-18 and increased levels TNFα. Conclusion We have quantified the expression levels of thirteen cytokine and cytokine related genes in three forms of ovine paratuberculosis using real-time PCR analyses and confirm that sheep pauci- and multibacillary disease are linked to

  1. Differential cytokine gene expression profiles in the three pathological forms of sheep paratuberculosis

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    Rhind Susan M

    2007-08-01

    Full Text Available Abstract Background Johne's disease is a chronic inflammatory disease of the gut caused by infection with Mycobacterium avium subspecies paratuberculosis (MAP. Symptoms include wasting, diarrhoea, loss of condition and eventual death. Three forms of Johne's disease have been described in sheep – paucibacillary, multibacillary and asymptomatic. The paucibacillary form is characterized by an inflammatory, Th1-type immune response. The multibacillary form of the disease, which disseminates the infection, is characterized by macrophage infiltration mediated by a Th2-type immune response, and asymptomatic animals have no clinical symptoms or pathology but are infected with MAP. What determines these three forms of the disease is unknown. To further understand these differences, we used real-time RT-PCR to compare the expression of thirteen cytokine and cytokine-related genes in ileal tissue from sheep with the three forms of the disease. Results Three pathological forms of sheep paratuberculosis were defined on the basis of histopathology, cytochemistry (Zeihl-Neelsen and IS900 PCR. Paucibacillary lesions have largely T cell and eosinophil infiltration and are ZN negative; multibacillary lesions have macrophage infiltration and large numbers of acid-fast bacteria. The pauci- and multibacillary forms are linked to the differential expression of IFNγ and IL-10 respectively. In addition the increased levels of the proinflammatory cytokines (IL-1β and TNFα, IL-8, IL-18 and TRAF-1 in both diseased forms is indicative of persistent inflammatory lesions. No changes were seen in IL-1α in any sheep ileum tissues. Asymptomatic animals are IS900+ with normal histology but have significantly decreased levels of IL-18 and increased levels TNFα. Conclusion We have quantified the expression levels of thirteen cytokine and cytokine related genes in three forms of ovine paratuberculosis using real-time PCR analyses and confirm that sheep pauci- and

  2. Virulence genes and cytokine profile in systemic murine Campylobacter coli infection.

    Science.gov (United States)

    Klančnik, Anja; Pogačar, Maja Šikić; Raspor, Peter; Abram, Maja; Možina, Sonja Smole; Vučković, Darinka

    2015-01-01

    Campylobacter coli are one of the most common bacteria in bacterial gastroenteritis and acute enterocolitis in humans. However, relatively little is known regarding the mechanisms of pathogenesis and host response to C. coli infections. To investigate the influence of genetic changes, we first used PCR to demonstrate the presence of the known virulence genes cadF, virB11, cdtB, cdtC and ceuE in the clinical isolate C. coli 26536, which was isolated from the liver of infected BALB/c mice. Sequence analyses of the cadF, virB11, cdtB and ceuE genes in C. coli 26536 confirmed the stability in these virulence genes during their transmission through the host. We further investigated C. coli infection for the bacterial clearance from the liver and spleen of infected mice, and for their immune response. C. coli persisted well in both organs, with better survival in the liver. We also determined the levels of several pro-inflammatory cytokines (i.e., interleukin [IL]-6, IL-12, interferon-γ, tumor necrosis factor-α) and the anti-inflammatory cytokine IL-10 in plasma and in liver homogenates from the infected mice, using enzyme-linked immunosorbent assays. The lowest levels among these cytokines were for tumor necrosis factor-α in the plasma and IL-6 in the liver on days 1, 3 and 8 post-infection. The most pronounced production was for IL-10, in both plasma (days 1 and 8 post-infection) and liver (day 8 post-infection), which suggests that it has a role in healing of the organ inflammation. Our findings showed dynamic relationships between pro- and anti-inflammatory cytokines and thus contribute toward clarification of the healing processes involved in the resolution of C. coli infections.

  3. General and Specific Genetic Polymorphism of Cytokines-Related Gene in AITD

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    Chen Xiaoheng

    2017-01-01

    Full Text Available Autoimmune thyroid disease (AITD shows the highest incidence among organ-specific autoimmune diseases and is the most common thyroid disease in humans, including Graves’ disease (GD and Hashimoto’s thyroiditis (HT. The susceptibility to autoimmune diseases is affected by increased autoantibody levels, susceptibility gene polymorphisms, environmental factors, and psychological factors, but the pathogenesis remains unclear. Various cytokines and related genes encoding them play important roles in the development and progression of AITD. CD152, an expression product of the CTLA-4 gene, downregulates T cell activation. The A/A genotype polymorphism in the CT60 locus may reduce the production of thyroid autoantibodies. The C1858T polymorphism of the PTNP22 gene reduces the expression of its encoded LYP, which increases the risk of GD and HT. GD is an organ-specific autoimmune disease involving increased secretion of thyroid hormone, whereas HT may be associated with the destruction of thyroid gland tissue and hypothyroidism. These two diseases exhibit similar pathogenesis but opposite trends in the clinical manifestations. In this review, we focus on the structure and function of these cytokines and related genes in AITD, as well as the association of polymorphisms with susceptibility to GD and HT, and attempt to describe their differences in pathogenesis and clinical manifestations.

  4. General and Specific Genetic Polymorphism of Cytokines-Related Gene in AITD

    Science.gov (United States)

    Yizhou, Mei; Bei, He; Huilong, Li; Xin, Wang; Rui, Hu; Lu, Li

    2017-01-01

    Autoimmune thyroid disease (AITD) shows the highest incidence among organ-specific autoimmune diseases and is the most common thyroid disease in humans, including Graves' disease (GD) and Hashimoto's thyroiditis (HT). The susceptibility to autoimmune diseases is affected by increased autoantibody levels, susceptibility gene polymorphisms, environmental factors, and psychological factors, but the pathogenesis remains unclear. Various cytokines and related genes encoding them play important roles in the development and progression of AITD. CD152, an expression product of the CTLA-4 gene, downregulates T cell activation. The A/A genotype polymorphism in the CT60 locus may reduce the production of thyroid autoantibodies. The C1858T polymorphism of the PTNP22 gene reduces the expression of its encoded LYP, which increases the risk of GD and HT. GD is an organ-specific autoimmune disease involving increased secretion of thyroid hormone, whereas HT may be associated with the destruction of thyroid gland tissue and hypothyroidism. These two diseases exhibit similar pathogenesis but opposite trends in the clinical manifestations. In this review, we focus on the structure and function of these cytokines and related genes in AITD, as well as the association of polymorphisms with susceptibility to GD and HT, and attempt to describe their differences in pathogenesis and clinical manifestations. PMID:28133421

  5. Understanding Autoimmune Mechanisms in Multiple Sclerosis Using Gene Expression Microarrays: Treatment Effect and Cytokine-related Pathways

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    A. Achiron

    2004-01-01

    Full Text Available Multiple sclerosis (MS is a central nervous system disease in which activated autoreactive T-cells invade the blood brain barrier and initiate an inflammatory response that leads to myelin destruction and axonal loss. The etiology of MS, as well as the mechanisms associated with its unexpected onset, the unpredictable clinical course spanning decades, and the different rates of progression leading to disability over time, remains an enigma. We have applied gene expression microarrays technology in peripheral blood mononuclear cells (PBMC to better understand MS pathogenesis and better target treatment approaches. A signature of 535 genes were found to distinguish immunomodulatory treatment effects between 13 treated and 13 untreated MS patients. In addition, the expression pattern of 1109 gene transcripts that were previously reported to significantly differentiate between MS patients and healthy subjects were further analyzed to study the effect of cytokine-related pathways on disease pathogenesis. When relative gene expression for 26 MS patients was compared to 18 healthy controls, 30 genes related to various cytokine-associated pathways were identified. These genes belong to a variety of families such as interleukins, small inducible cytokine subfamily and tumor necrosis factor ligand and receptor. Further analysis disclosed seven cytokine-associated genes within the immunomodulatory treatment signature, and two cytokine-associated genes SCYA4 (small inducible cytokine A4 and FCAR (Fc fragment of IgA, CD89 that were common to both the MS gene expression signature and the immunomodulatory treatment gene expression signature. Our results indicate that cytokine-associated genes are involved in various pathogenic pathways in MS and also related to immunomodulatory treatment effects.

  6. Hospital-acquired pneumonia after lung resection surgery is associated with characteristic cytokine gene expression.

    LENUS (Irish Health Repository)

    White, Mary

    2012-02-01

    BACKGROUND: Infection in humans has been linked with altered cytokine gene transcription. It is unclear whether this phenomenon is a consequence of an established disease process or precedes the infective process. The primary end point of this study was to determine whether hospital-acquired pneumonia (HAP) was associated with differential gene expression of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and IL-23p19. The secondary end point was to identify whether alteration in gene expression preceded the clinical onset of infection. METHODS: Sixty consecutive patients undergoing elective thoracic surgery were recruited. HAP was diagnosed as per National Nosocomial Infection Surveillance guidelines. Messenger RNA (mRNA) and protein levels were analyzed preoperatively and 24 h and 5 days postoperatively. RESULTS: Forty-one patients had an uncomplicated recovery. Nineteen patients developed HAP. IL-6, IL-10, IL-12p35, IL-23p19, IL-27p28, TNF-alpha, and IFN-gamma mRNA and protein levels of IL-6, IL-23, and IFN-gamma in peripheral blood leukocytes were analyzed before surgery and 24 h and 5 days postsurgery. IL-23p19 mRNA levels were reduced in the pneumonia group (median, 4.19; 10th-90th centile range, 3.90-4.71) compared with the nonpneumonia group (4.50; 3.85-5.32) day 1 postsurgery (P=02). IFN-gamma mRNA levels were reduced in the pneumonia group (2.48; 1.20-3.20) compared with nonpneumonia group (2.81; 2.10-3.26) (P=03) day 5 postsurgery. Results are expressed as log to base 10 copy numbers of cytokine mRNA per 10 million beta-actin mRNA copy numbers. All values are given as median and 10th to 90th centile range. CONCLUSIONS: Cytokine gene expression is altered immediately following surgery in patients with postoperative HAP.

  7. 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.

  8. Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells.

    Science.gov (United States)

    Arjona, Alvaro; Sarkar, Dipak K

    2005-06-15

    A growing body of knowledge is revealing the critical role of circadian physiology in the development of specific pathological entities such as cancer. NK cell function participates in the immune response against infection and malignancy. We have reported previously the existence of a physiological circadian rhythm of NK cell cytolytic activity in rats, suggesting the existence of circadian mechanisms subjacent to NK cell function. At the cellular level, circadian rhythms are originated by the sustained transcriptional-translational oscillation of clock genes that form the cellular clock apparatus. Our aim in this study was to investigate the presence of molecular clock mechanisms in NK cells as well as the circadian expression of critical factors involved in NK cell function. For that purpose, we measured the circadian changes in the expression of clock genes (Per1, Per2, Bmal1, Clock), Dbp (a clock-controlled output gene), CREB (involved in clock signaling), cytolytic factors (granzyme B and perforin), and cytokines (IFN-gamma and TNF-alpha) in NK cells enriched from the rat spleen. The results obtained from this study demonstrate for the first time the existence of functional molecular clock mechanisms in NK cells. Moreover, the circadian expression of cytolytic factors and cytokines in NK cells reported in this study emphasizes the circadian nature of NK cell function.

  9. Post-operative infection and sepsis in humans is associated with deficient gene expression of γc cytokines and their apoptosis mediators.

    LENUS (Irish Health Repository)

    White, Mary

    2011-06-01

    Lymphocyte homeostasis is dependent on the γc cytokines. We hypothesised that sepsis in humans is associated with differential gene expression of the γc cytokines and their associated apoptosis mediators.

  10. CYTOKINE GENES AS GENETIC MARKERS OF CONTROLLED AND UNCONTROLLED ATOPIC BRONCHIAL ASTHMA

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    M. V. Smolnikova

    2017-01-01

    Full Text Available Atopic bronchial asthma (ABA is a multifactorial disease; its development is dependent on many environmental and genetic factors. Genetic risk factors can affect the clinical phenotype of ABA and the level of therapeutic control over the disease. Cytokine genes are crucially important in pathogenesis of ABA as they encode proteins participating in immune response and development of inflammation in bronchi. It was suggested that the therapeutic control of the disease is genetically mediated and depends on the presence of one or another allele in genes of mediators, participating in ABA pathogenesis. The knowledge about genetic markers will allow to predict clinical course of ABA in children. We carried out the analysis of association between genes of pro- and anti-inflammatory cytokines with the level of therapeutic control of ABA. In children with controlled and uncontrolled ABA (CABA and UABA, respectively; n = 110, and in general a population sample (n = 138, we analysed 11 polymorphisms: IL2 (rs2069762, IL4 (rs2070874 и rs2243250, IL5 (rs2069812, IL10 (rs1800872 and rs1800896, IL12B (rs3212227, TNFA (rs1800629 and rs1800630, TGFB1 (rs1800469, and IFNG (rs2069705, encoding cytokines actively participating at the development of allergic inflammation. According to results of present study, the prevalence of alleles and genotypes of the analysed loci in the East Siberia Caucasians is consistent with the data in other world Caucasian populations. We have found statistically significant differences between UABA and control groups for the prevalence of IL2 (rs2069762 polymorphism: GG genotype was more common in control group (14.1% compared to 5.9%, р = 0.03. It was shown that the IL2*T allele and ТТ genotype of the rs2069762 are associated with the increased risk of uncontrolled ABA. A comparison of the haplotypes of IL4 (rs2070874 and rs2243250 gene with correction for sex and age within an additive model revealed that the most common

  11. Peripheral blood-derived cytokine gene polymorphisms and metabolic profile in women with polycystic ovary syndrome.

    Science.gov (United States)

    Sóter, Mirelle O; Ferreira, Cláudia N; Sales, Mariana F; Candido, Ana L; Reis, Fernando M; Milagres, Kátia S; Ronda, Carla; Silva, Ieda O; Sousa, Marinez O; Gomes, Karina B

    2015-12-01

    The imbalance between proinflammatory and anti-inflammatory pathways plays a role in polycystic ovary syndrome (PCOS) etiology. We aimed to investigate the relationship between polymorphisms of genes encoding inflammation-associated cytokines and the metabolic profile of Brazilian women with PCOS. Case-control study. The study included 196 women - 97 with PCOS (diagnosed based on Rotterdam criteria, 2003) and 99 age-matched, healthy women (controls). It was investigated polymorphisms in cytokines genes from peripheral blood-derived DNA by using PCR. The frequencies of alleles, genotypes, and phenotypes were similar between women with PCOS and controls. The GG genotype of the -179C/G polymorphism (IL6) was associated with higher glucose levels, while the GA and AA genotypes of the -1082A/G polymorphism (IL10), CT and TT genotypes of the -819A/T polymorphism (IL10), CA and AA genotypes of the -522A/G (IL10) polymorphism, and TA genotype of the +874T/A polymorphism (IFN-γ) were associated with lower total cholesterol and triglycerides levels. The GA genotype of the -1082A/G polymorphism (IL10) and the CC genotype of the 10T/C polymorphism (TGF-β1) were associated with lower and higher Ferriman indices, respectively, in women with PCOS. The AA genotype of the -1082A/G polymorphism (IL10) was associated with lower glucose levels, while the TC genotype of the 10T/C polymorphism (TGF-β1) was associated with a lower lipid accumulation product index and higher high-density lipoprotein cholesterol levels in the PCOS group. The genetic polymorphisms of cytokines are not associated with PCOS development, but may contribute to common metabolic disorders associated with PCOS. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Comparison of cytokine gene polymorphisms among Greek patients with invasive meningococcal disease or viral meningitis.

    Science.gov (United States)

    Titmarsh, Callum J; Moscovis, Sophia M; Hall, Sharron; Tzanakaki, Georgina; Kesanopoulos, Konstantinos; Xirogianni, Athanasia; Scott, Rodney J; Blackwell, C Caroline

    2013-05-01

    High levels of pro-inflammatory cytokines are implicated in the severity of invasive meningococcal disease (IMD) and viral meningitis (VM). This study compared single-nucleotide polymorphisms (SNPs) in pro- and anti-inflammatory cytokine genes among patients with VM or IMD. Patient DNA samples were prepared by the National Meningitis Reference Laboratory in Athens: n=98 for IMD and n=53 for VM. The results for both patient groups were compared with data published for healthy Greek control data. Real-time PCR was used to assess the interleukin (IL) gene SNPs IL6 G-174C, IL1B C-511T, IL1RN T+2018C, IL10 G-1082A and IL8 A-251T and the tumour necrosis factor α (TNF-α) SNP TNFA G-308A. Differences were compared by Fisher's exact test. The genotype for high IL-6 responses was predominant among IMD (51%, P=0.0008) and VM (74.5%, P<0.0001) patients compared with the controls (31%). The genotype associated with high TNF-α responses was 5% among controls and lower for IMD (1.1%, P=0.0014) and VM (0%, P=0.052). There was no difference for IL-8 SNPs between controls and IMD (P=0.162), but the difference was significant for VM (P=0.0025). IL-6 (P=0.024) and IL-8 (P=0.00004) SNPs differed between IMD and VM. Reports on associations between IL-8 SNPs and cytokine responses differ. Because of its role in neutrophil attraction, differences in frequencies of the IL-8 SNP for IMD and VM require further investigation.

  13. Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle.

    Science.gov (United States)

    Louis, Emily; Raue, Ulrika; Yang, Yifan; Jemiolo, Bozena; Trappe, Scott

    2007-11-01

    The aim of this study was to examine the time course induction of select proteolytic [muscle ring finger-1 (MuRF-1), atrogin-1, forkhead box 3A (FOXO3A), calpain-1, calpain-2], myostatin, and cytokine (IL -6, -8, -15, and TNF-alpha) mRNA after an acute bout of resistance (RE) or run (RUN) exercise. Six experienced RE (25 +/- 4 yr, 74 +/- 14 kg, 1.71 +/- 0.11 m) and RUN (25 +/- 4 yr, 72 +/- 5 kg, 1.81 +/- 0.07 m) subjects had muscle biopsies from the vastus lateralis (RE) or gastrocnemius (RUN) before, immediately after, and 1, 2, 4, 8, 12, and 24 h postexercise. RE increased (P suppressed (3.6-fold; P suppression of myostatin. These data provide basic information for the timing of human muscle biopsy samples for gene expression studies involving exercise. Furthermore, this information suggests a greater induction of proteolytic genes following RUN compared with RE.

  14. Polymorphisms in Genes Coding for Cytokines, Mannose-Binding Lectin, Collagen Metabolism and Thrombophilia in Women with Cervical Insufficiency

    DEFF Research Database (Denmark)

    Sundtoft, Iben; Uldbjerg, Niels; Steffensen, Rudi

    2015-01-01

    OBJECTIVE: To study the association between cervical insufficiency and single nucleotide polymorphisms in seven genes coding for pro- and anti-inflammatory cytokine-related factors, mannose-binding lectin 2 (MBL2), collagen1α1 (COL1A1), factor II and factor V Leiden genes. METHODS: In a case-cont...

  15. Differential cytokine gene expression according to outcome in a hamster model of leptospirosis.

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    Frédérique Vernel-Pauillac

    Full Text Available BACKGROUND: Parameters predicting the evolution of leptospirosis would be useful for clinicians, as well as to better understand severe leptospirosis, but are scarce and rarely validated. Because severe leptospirosis includes septic shock, similarities with predictors evidenced for sepsis and septic shock were studied in a hamster model. METHODOLOGY/PRINCIPAL FINDINGS: Using an LD50 model of leptospirosis in hamsters, we first determined that 3 days post-infection was a time-point that allowed studying the regulation of immune gene expression and represented the onset of the clinical signs of the disease. In the absence of tools to assess serum concentrations of immune effectors in hamsters, we determined mRNA levels of various immune genes, especially cytokines, together with leptospiraemia at this particular time-point. We found differential expression of both pro- and anti-inflammatory mediators, with significantly higher expression levels of tumor necrosis factor alpha, interleukin 1alpha, cyclo-oxygenase 2 and interleukin 10 genes in nonsurvivors compared to survivors. Higher leptospiraemia was also observed in nonsurvivors. Lastly, we demonstrated the relevance of these results by comparing their respective expression levels using a LD100 model or an isogenic high-passage nonvirulent variant. CONCLUSIONS/SIGNIFICANCE: Up-regulated gene expression of both pro- and anti-inflammatory immune effectors in hamsters with fatal outcome in an LD50 model of leptospirosis, together with a higher Leptospira burden, suggest that these gene expression levels could be predictors of adverse outcome in leptospirosis.

  16. Dataset of proinflammatory cytokine and cytokine receptor gene expression in rainbow trout (Oncorhynchus mykiss measured using a novel GeXP multiplex, RT-PCR assay

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    Ivan Kutyrev

    2017-04-01

    Full Text Available A GeXP multiplex, RT-PCR assay was developed and optimized that simultaneously measures expression of a suite of immune-relevant genes in rainbow trout (Oncorhynchus mykiss, concentrating on tumor necrosis factor and interleukin-1 ligand/receptor systems and acute phase response genes. The dataset includes expression values for drpt, il11a, il1b1, il1b2, il1b3, il1r-like-1(e3-5, il1r-like-1(e9-11, il1r1-like-a, il1r1-like-b, il1r2, saa, tnfa1, tnfa2, tnfa3, tnfrsf1a, tnfrsf1a-like-a, tnfrsf1a-like-b, tnfrsf5, and tnfrsf9. Gene expression was measured at four time-points post-challenge in both a resistant line (ARS-Fp-R and a susceptible line (ARS-Fp-S of rainbow trout. In addition, fish body weight, spleen index and the Flavobacterium psychrophilum load are reported. These data are an extension of information presented and discussed in “Proinflammatory cytokine and cytokine receptor gene expression kinetics following challenge with Flavobacterium psychrophilum in resistant and susceptible lines of rainbow trout (Oncorhynchus mykiss” (Kutyrev et al., 2016 [1].

  17. Dataset of proinflammatory cytokine and cytokine receptor gene expression in rainbow trout (Oncorhynchus mykiss) measured using a novel GeXP multiplex, RT-PCR assay.

    Science.gov (United States)

    Kutyrev, Ivan; Cleveland, Beth; Leeds, Timothy; Wiens, Gregory D

    2017-04-01

    A GeXP multiplex, RT-PCR assay was developed and optimized that simultaneously measures expression of a suite of immune-relevant genes in rainbow trout (Oncorhynchus mykiss), concentrating on tumor necrosis factor and interleukin-1 ligand/receptor systems and acute phase response genes. The dataset includes expression values for drpt, il11a, il1b1, il1b2, il1b3, il1r-like-1(e3-5), il1r-like-1(e9-11), il1r1-like-a, il1r1-like-b, il1r2, saa, tnfa1, tnfa2, tnfa3, tnfrsf1a, tnfrsf1a-like-a, tnfrsf1a-like-b, tnfrsf5, and tnfrsf9. Gene expression was measured at four time-points post-challenge in both a resistant line (ARS-Fp-R) and a susceptible line (ARS-Fp-S) of rainbow trout. In addition, fish body weight, spleen index and the Flavobacterium psychrophilum load are reported. These data are an extension of information presented and discussed in "Proinflammatory cytokine and cytokine receptor gene expression kinetics following challenge with Flavobacterium psychrophilum in resistant and susceptible lines of rainbow trout (Oncorhynchus mykiss)" (Kutyrev et al., 2016) [1].

  18. Cytokine Gene Polymorphisms Associated With Symptom Clusters in Oncology Patients Undergoing Radiation Therapy.

    Science.gov (United States)

    Miaskowski, Christine; Conley, Yvette P; Mastick, Judy; Paul, Steven M; Cooper, Bruce A; Levine, Jon D; Knisely, Mitchell; Kober, Kord M

    2017-09-01

    Most of the reviews on the biological basis for symptom clusters suggest that inflammatory processes are involved in the development and maintenance of the symptom clusters. However, no studies have evaluated for associations between genetic polymorphisms and common symptom clusters (e.g., mood disturbance, sickness behavior). Examine the associations between cytokine gene polymorphisms and the severity of three distinct symptom clusters (i.e., mood-cognitive, sickness-behavior, treatment-related) in a sample of patients with breast and prostate cancer (n = 157) at the completion of radiation therapy. Symptom severity was assessed using the Memorial Symptom Assessment Scale. Symptom clusters were created using exploratory factor analysis. The associations between cytokine gene polymorphisms and the symptom cluster severity scores were evaluated using regression analyses. Polymorphisms in C-X-C motif chemokine ligand 8 (CXCL8), interleukin (IL13), and nuclear factor kappa beta 2 (NFKB2) were associated with severity scores for the mood-cognitive symptom cluster. In addition to interferon gamma (IFNG1), the same polymorphism in NFKB2 (i.e., rs1056890) that was associated with the mood-cognitive symptom cluster score was associated with the sickness-behavior symptom cluster. Polymorphisms in interleukin 1 receptor 1 (IL1R1), IL6, and NFKB1 were associated with severity factor scores for the treatment-related symptom cluster. Our findings support the hypotheses that symptoms that cluster together have a common underlying mechanism and the most common symptom clusters in oncology patients are associated polymorphisms in genes involved in a variety of inflammatory processes. Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

  19. Cytokines and tumor metastasis gene variants in oral cancer and precancer in Puerto Rico.

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    Esther Erdei

    Full Text Available A cross-sectional epidemiological study explored genetic susceptibility to oral precancer and cancer in Puerto Rico (PR.Three hundred three individuals with a benign oral condition, oral precancer (oral epithelial hyperplasia/hyperkeratosis, oral epithelial dysplasia, or oral squamous cell carcinoma (SCCA were identified via PR pathology laboratories. A standardized, structured questionnaire obtained information on epidemiological variables; buccal cells were collected for genetic analysis. Genotyping was performed using Taqman® assays. Allelic frequencies of single nucleotide polymorphisms (SNPs were evaluated in cytokine genes and genes influencing tumor metastasis. Risk estimates for a diagnosis of oral precancer or SCCA while having a variant allele were generated using logistic regression. Adjusted models controlled for age, gender, ancestry, education, smoking and alcohol consumption.Relative to persons with a benign oral lesion, individuals with homozygous recessive allelic variants of tumor necrosis factor (TNF-α -238 A/G SNP had a reduced odds of having an oral precancer (ORadjusted = 0.15; 95% CI 0.03-0.70. The transforming growth factor beta-1 (TGFβ-1 -509 C/T polymorphism was inversely associated with having an oral SCCA among persons homozygous for the recessive variant (ORcrude = 0.27; 95% CI 0.09-0.79. The matrix metalloproteinase gene (MMP-1 variant, rs5854, was associated with oral SCCA; participants with even one variant allele were more likely to have oral SCCA (ORadjusted = 2.62, 95% CI 1.05-6.53 compared to people with ancestral alleles.Our exploratory analyses suggest that genetic alterations in immune system genes and genes with metastatic potential are associated with oral precancer and SCCA risk in PR.

  20. Cytokines and tumor metastasis gene variants in oral cancer and precancer in Puerto Rico.

    Science.gov (United States)

    Erdei, Esther; Luo, Li; Sheng, Huiping; Maestas, Erika; White, Kirsten A M; Mackey, Amanda; Dong, Yan; Berwick, Marianne; Morse, Douglas E

    2013-01-01

    A cross-sectional epidemiological study explored genetic susceptibility to oral precancer and cancer in Puerto Rico (PR). Three hundred three individuals with a benign oral condition, oral precancer (oral epithelial hyperplasia/hyperkeratosis, oral epithelial dysplasia), or oral squamous cell carcinoma (SCCA) were identified via PR pathology laboratories. A standardized, structured questionnaire obtained information on epidemiological variables; buccal cells were collected for genetic analysis. Genotyping was performed using Taqman® assays. Allelic frequencies of single nucleotide polymorphisms (SNPs) were evaluated in cytokine genes and genes influencing tumor metastasis. Risk estimates for a diagnosis of oral precancer or SCCA while having a variant allele were generated using logistic regression. Adjusted models controlled for age, gender, ancestry, education, smoking and alcohol consumption. Relative to persons with a benign oral lesion, individuals with homozygous recessive allelic variants of tumor necrosis factor (TNF-α) -238 A/G SNP had a reduced odds of having an oral precancer (ORadjusted = 0.15; 95% CI 0.03-0.70). The transforming growth factor beta-1 (TGFβ-1 -509 C/T) polymorphism was inversely associated with having an oral SCCA among persons homozygous for the recessive variant (ORcrude = 0.27; 95% CI 0.09-0.79). The matrix metalloproteinase gene (MMP-1) variant, rs5854, was associated with oral SCCA; participants with even one variant allele were more likely to have oral SCCA (ORadjusted = 2.62, 95% CI 1.05-6.53) compared to people with ancestral alleles. Our exploratory analyses suggest that genetic alterations in immune system genes and genes with metastatic potential are associated with oral precancer and SCCA risk in PR.

  1. Altered Cytokine Gene Expression in Peripheral Blood Monocytes across the Menstrual Cycle in Primary Dysmenorrhea: A Case-Control Study

    Science.gov (United States)

    Ma, Hongyue; Hong, Min; Duan, Jinao; Liu, Pei; Fan, Xinsheng; Shang, Erxin; Su, Shulan; Guo, Jianming; Qian, Dawei; Tang, Yuping

    2013-01-01

    Primary dysmenorrhea is one of the most common gynecological complaints in young women, but potential peripheral immunologic features underlying this condition remain undefined. In this paper, we compared 84 common cytokine gene expression profiles of peripheral blood mononuclear cells (PBMCs) from six primary dysmenorrheic young women and three unaffected controls on the seventh day before (secretory phase), and the first (menstrual phase) and the fifth (regenerative phase) days of menstruation, using a real-time PCR array assay combined with pattern recognition and gene function annotation methods. Comparisons between dysmenorrhea and normal control groups identified 11 (nine increased and two decreased), 14 (five increased and nine decreased), and 15 (seven increased and eight decreased) genes with ≥2-fold difference in expression (Pmenstrual phase, genes encoding pro-inflammatory cytokines (IL1B, TNF, IL6, and IL8) were up-regulated, and genes encoding TGF-β superfamily members (BMP4, BMP6, GDF5, GDF11, LEFTY2, NODAL, and MSTN) were down-regulated. Functional annotation revealed an excessive inflammatory response and insufficient TGF-β superfamily member signals with anti-inflammatory consequences, which may directly contribute to menstrual pain. In the secretory and regenerative phases, increased expression of pro-inflammatory cytokines and decreased expression of growth factors were also observed. These factors may be involved in the regulation of decidualization, endometrium breakdown and repair, and indirectly exacerbate primary dysmenorrhea. This first study of cytokine gene expression profiles in PBMCs from young primary dysmenorrheic women demonstrates a shift in the balance between expression patterns of pro-inflammatory cytokines and TGF-β superfamily members across the whole menstrual cycle, underlying the peripheral immunologic features of primary dysmenorrhea. PMID:23390521

  2. Expression of cytokine genes and receptors in white blood cells associated with divergent body weight gain in beef steers

    Science.gov (United States)

    Previous work examining the transcriptome of steer tissue samples from animals with divergent gain have shown a relationship with the expression of genes with functions in immune and inflammatory pathways. The aim of this study was to determine whether changes in cytokine expression in the circulati...

  3. Commonly studied polymorphisms in inflammatory cytokine genes show only minor effects on mortality and related risk factors in nonagenarians

    DEFF Research Database (Denmark)

    Dato, Serena; Krabbe, Karen S; Thinggaard, Mikael

    2010-01-01

    Systemic low-grade inflammation is consistently associated with functional status, cognitive functioning, multimorbidity, and survival in oldest olds. If inflammation is either a cause or a consequence of age-related pathology, genetic determinants of late-life survival can reside in cytokine genes...

  4. Evidence of associations between cytokine genes and subjective reports of sleep disturbance in oncology patients and their family caregivers.

    Directory of Open Access Journals (Sweden)

    Christine Miaskowski

    Full Text Available The purposes of this study were to identify distinct latent classes of individuals based on subjective reports of sleep disturbance; to examine differences in demographic, clinical, and symptom characteristics between the latent classes; and to evaluate for variations in pro- and anti-inflammatory cytokine genes between the latent classes. Among 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their FCs, growth mixture modeling (GMM was used to identify latent classes of individuals based on General Sleep Disturbance Scale (GSDS obtained prior to, during, and for four months following completion of radiation therapy. Single nucleotide polymorphisms (SNPs and haplotypes in candidate cytokine genes were interrogated for differences between the two latent classes. Multiple logistic regression was used to assess the effect of phenotypic and genotypic characteristics on GSDS group membership. Two latent classes were identified: lower sleep disturbance (88.5% and higher sleep disturbance (11.5%. Participants who were younger and had a lower Karnofsky Performance status score were more likely to be in the higher sleep disturbance class. Variation in two cytokine genes (i.e., IL6, NFKB predicted latent class membership. Evidence was found for latent classes with distinct sleep disturbance trajectories. Unique genetic markers in cytokine genes may partially explain the interindividual heterogeneity characterizing these trajectories.

  5. Cold stress equally enhances in vivo pro-inflammatory cytokine gene expression in chicken lines divergently selected for antibody responses

    NARCIS (Netherlands)

    Hangalapura, B.N.; Kaiser, M.G.; Poel, van der J.J.; Parmentier, H.K.; Lamont, S.J.

    2006-01-01

    The effects of cold stress, immunization and genetic selection on the expression of mRNA for cytokine genes in poultry have not been completely elucidated. Therefore, in the present experiment, using real-time quantitative RT-PCR, we evaluated the effect of cold stress and immunization with complete

  6. Meta-Analysis of Cytokine Gene Polymorphisms and Outcome of Heart Transplantation

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    Sasitorn Yongcharoen

    2013-01-01

    Full Text Available We performed a systematic review and meta-analysis with the aim of assessing the association between cytokine gene polymorphisms and graft rejection in heart transplantation. We identified relevant studies from Medline and Embase using PubMed and Ovid search engines, respectively. Allele frequencies and allele and genotypic effects were pooled. Heterogeneity and publication bias were explored. Four to 5 studies were included in pooling of 3 gene polymorphisms. The prevalences of the minor alleles for TNFα-308, TGFβ1-c10, and TGFβ1-c25 were 0.166 (95% CI: 0.129, 0.203, 0.413 (95% CI: 0.363, 0.462, and 0.082 (95% CI: 0.054, 0.111 in the control groups, respectively. Carrying the A allele for the TNFα-308 had 18% (95% CI of OR: 0.46, 3.01 increased risk, but this was not significant for developing graft rejection than the G allele. Conversely, carrying the minor alleles for both TGFβ1-c10 and c25 had nonsignificantly lower odds of graft rejection than major alleles, with the pooled ORs of 0.87 (95% CI: 0.65, 1.18 and 0.70 (95% CI: 0.40, 1.23, respectively. There was no evidence of publication bias for all poolings. An updated meta-analysis is required when more studies are published to increase the power of detection for the association between these polymorphisms and allograft rejection.

  7. LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease.

    Science.gov (United States)

    Ceccarelli, Sara; Panera, Nadia; Mina, Marco; Gnani, Daniela; De Stefanis, Cristiano; Crudele, Annalisa; Rychlicki, Chiara; Petrini, Stefania; Bruscalupi, Giovannella; Agostinelli, Laura; Stronati, Laura; Cucchiara, Salvatore; Musso, Giovanni; Furlanello, Cesare; Svegliati-Baroni, Gianluca; Nobili, Valerio; Alisi, Anna

    2015-12-08

    Lipopolysaccharide (LPS) is currently considered one of the major players in non-alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-α factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH).We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1β, IL-6 and TNF-α in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-α was significantly reduced with the aid of p65NF-ĸB, while IL-1β transcription exclusively required LITAF expression/activity. Finally, IL-1β levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF-positive HSCs in children with NASH.In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1β levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro-inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH.

  8. Immunological responses and cytokine gene expression analysis to Cooperia punctata infections in resistant and susceptible Nelore cattle.

    Science.gov (United States)

    Bricarello, P A; Zaros, L G; Coutinho, L L; Rocha, R A; Silva, M B; Kooyman, F N J; De Vries, E; Yatsuda, A P; Amarante, A F T

    2008-08-01

    Cellular and humoral immune response, as well as cytokine gene expression, was assessed in Nelore cattle with different degrees of resistance to Cooperia punctata natural infection. One hundred cattle (male, weaned, 11-12 months old), kept together on pasture, were evaluated. Faecal and blood samples were collected for parasitological and immunological assays. Based on nematode faecal egg counts (FEC) and worm burden, the seven most resistant and the eight most susceptible animals were selected. Tissue samples of the small intestine were collected for histological quantification of inflammatory cells and analysis of cytokine gene expression (IL-2, IL-4, IL-8, IL-12p35, IL-13, TNF-alpha, IFN-gamma, MCP-1, MCP-2, and MUC-1) using real-time RT-PCR. Mucus samples were also collected for IgA levels determination. Serum IgG1 mean levels against C. punctata antigens were higher in the resistant group, but significant differences between groups were only observed 14 days after the beginning of the experiment against infective larvae (L3) and 14 and 84 days against adult antigens. The resistant group also presented higher IgA levels against C. punctata (L3 and adult) antigens with significant difference 14 days after the beginning of the trial (P<0.05). In the small-intestine mucosa, levels of IgA anti-L3 and anti-adult C. punctata were higher in the resistant group, compared with the susceptible group (P<0.05). Gene expression of both T(H)2 cytokines (IL-4 and IL-13) in the resistant group and T(H)1 cytokines (IL-2, IL-12p35, IFN-gamma and MCP-1) in the susceptible group was up-regulated. Such results suggested that immune response to C. punctata was probably mediated by T(H)2 cytokines in the resistant group and by T(H)1 cytokines in the susceptible group.

  9. Immunogenicity of intrathecal plasmid gene delivery: cytokine release and effects on transgene expression

    Science.gov (United States)

    Hughes, Travis S.; Langer, Stephen J.; Virtanen, Salla I.; Chavez, Raymond A.; Watkins, Linda R.; Milligan, Erin D.; Leinwand, Leslie A.

    2013-01-01

    Background One method for the delivery of therapeutic proteins to the spinal cord is to inject nonviral gene vectors including plasmid DNA into the cerebrospinal fluid (CSF) that surrounds the spinal cord (intrathecal space). This approach has produced therapeutic benefits in animal models of disease and several months of protein expression; however, there is little information available on the immune response to these treatments in the intrathecal space, the relevance of plasmid CpG sequences to any plasmid-induced immune response, or the effect of this immune response on transgene expression. Methods In the present study, coding or noncoding plasmids were delivered to the intrathecal space of the lumbar spinal region in rats. Lumbosacral CSF was then collected at various time points afterwards for monitoring of cytokines and transgene expression. Results This work demonstrates, for the first time, increased tumor necrosis factor-α and interleukin-1 in response to intrathecal plasmid vector injection and provides evidence indicating that this response is largely absent in a CpG-depleted vector. Transgene expression in the CSF is not significantly affected by this immune response. Expression after intrathecal plasmid injection is variable across rats but correlates with the amount of tissue associated plasmid and is increased by disrupting normal CSF flow. Conclusions The data obtained in the present study indicate that plasmid immunogenicity may affect intrathecal plasmid gene therapy safety but not transgene expression in the CSF. Furthermore, the development of methods to prevent loss of plasmid via CSF flow out of the central nervous system through the injection hole and/or natural outflow routes may increase intrathecal plasmid gene delivery efficacy. PMID:19533588

  10. Gene expression profile of cytokines and chemokines in skin lesions from Brazilian Indians with localized cutaneous leishmaniasis.

    Science.gov (United States)

    Costa-Silva, Matheus Fernandes; Gomes, Luciana Inácia; Martins-Filho, Olindo Assis; Rodrigues-Silva, Renata; Freire, Janaína de Moura; Quaresma, Patrícia Flávia; Pascoal-Xavier, Marcelo Antônio; Mendes, Tiago Antônio de Oliveira; Serakides, Rogéria; Zauli, Danielle Alves Gomes; Campi-Azevedo, Ana Carolina; Melo, Maria Norma; Gontijo, Célia Maria Ferreira; Peruhype-Magalhães, Vanessa; Teixeira-Carvalho, Andréa

    2014-02-01

    Cutaneous leishmaniasis (CL) is a chronic inflammatory disease caused by dermotropic Leishmania species belonging to the Viannia subgenera, with Leishmania (V.) braziliensis considered the main agent in Brazil. After infection, a local inflammatory process is initiated, inducing the expression of several cytokine/chemokine genes. We evaluated the immunity to CL of patients living in the indigenous community Xakriabá, Minas Gerais state, Brazil, by performing detailed analyses of the mRNA expression of different cytokines and chemokines in CL lesions, considering the time evolution (recent or late). We also studied the profile of the inflammatory infiltrate by histopathological analysis. The histopathological features of recent CL lesions showed an intense inflammatory reaction, characterized by the presence of both mononuclear and polymorphonuclear cells, whereas late CL lesions exhibited a predominance of mononuclear leukocytes. The gene expression of cytokines/chemokines in skin biopsies from the CL group showed higher transcript levels of modulatory (IL10 and TGFB1), anti-inflammatory (IL4), and pro-inflammatory (TNF, IFNG, IL12B, CCL2, CCL3, CCL5, CXCL10) biomarkers in recent lesions than in late lesions. Our findings suggest that differential gene expression of cytokines and chemokines found in skin lesions from CL patients is associated with time evolution of lesions. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. The Effect of IL-4 Gene Polymorphisms on Cytokine Production in Patients with Chronic Periodontitis and in Healthy Controls

    Directory of Open Access Journals (Sweden)

    Jirina Bartova

    2014-01-01

    Full Text Available Chronic periodontitis (CP is an inflammatory disease of the teeth-supporting tissues in which genetic predisposition, dental plaque bacteria, and immune mechanisms all play important roles. The aim of this study was to evaluate the occurrence of IL-4 gene polymorphisms in chronic periodontitis and to investigate the association between polymorphisms and cytokines production after bacterial stimulation. Sixty-two subjects (47 CP patients and 15 healthy controls with detected two polymorphisms in the IL-4 gene (-590C/T and intron 3 VNTR were examined. Production of cytokines (IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-10, IL-17, TNFα, INFγ, and VEGF was studied after in vitro stimulation of isolated peripheral blood by mitogens (Pokeweed mitogen, Concanavalin A, dental plaque bacteria (Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Porphyromonas gingivalis, and Prevotella intermedia, and Heat Shock Protein (HSP 70 by the Luminex multiplex cytokine analysis system. The results were correlated with IL-4 genotypes in patients with CP and healthy controls. The mononuclear cells isolated from peripheral blood of CP patients with selected IL-4 polymorphisms significantly altered the production of IFNγ, IL-10, IL-1β, IL-1α, TNFα, and IL-6 after stimulation by HSP 70 or selected bacteria (from P<0.001 to P<0.05. IL-4 gene polymorphisms may influence the function of mononuclear cells to produce not only interleukin-4 but also other cytokines, especially in patients with CP.

  12. The relationship of recurrent aphthous stomatitis and Helicobacter pylori, cytokine gene polymorphism and cobalamin.

    Science.gov (United States)

    Yakar, Tolga; Serin, Ender; Coşar, Arif Mansur; Arslan Taş, Didem; Ataç, Fatma Belgin

    2015-07-01

    The aim of the present study was to investigate whether Helicobacter pylori causes or triggers recurrent aphthous stomatitis (RAS) through cytokine gene polymorphism and/or cobalamin deficiency. Thirty-six patients with RAS and 130 patients without RAS were genotyped for IL-1β (-511C/T) and IL-6 (-174G/C) and evaluated for H. pylori infection and serum cobalamin level. The patient groups according to RAS had similar rates of H. pylori gastritis and interleukin genotypes/alleles, and there was a non-significant difference between serum cobalamin levels (p>0.05). RAS patients with H. pylori gastritis showed a higher frequency (51.9%) of GC IL-6 genotype than RAS patients without H. pylori gastritis (11.1%) (p=0.036). Non-GG genotype and C allele were increased in patients without RAS and with H. pylori gastritis (p<0.05). Patients with H. pylori gastritis showed a lower value of serum cobalamin without statistical significance, although this difference was more prominent in RAS patients (p=0.07). The carriage of the C allele of IL-6 may lead a susceptibility to chronic gastric inflammation after contamination with H. pylori. If H. pylori infection is justified as a predisposing factor for RAS and its severity by further studies, we can speculate that subjects with genetic susceptibility to this infection may benefit from H. pylori eradication treatment with respect to RAS.

  13. Efficacy of Selenium Supplement on Gene Expression of Inflammatory Cytokines and Vascular Endothelial Growth Factor in Gestational Diabetes

    Directory of Open Access Journals (Sweden)

    Mehri Jamilian

    2018-01-01

    Full Text Available Abstract Background: Selenium supplement has multiple important effects, including anti-inflammatory effect. The aim of this study was to assess the effects of selenium supplement on gene expression of inflammatory cytokines and vascular endothelial growth factor in gestational diabetes. Materials and Methods: This randomized double blind placebo control trial was performed on 40 patients suffering from GDM aged 18–40 years old. Participants were randomly divided into interventional group receiving 200mg/day selenium supplements (n=20 and control group receiving placebo (n=20 for 6 weeks. Primary outcome was gene expression of inflammatory cytokines and VEGF which were assessed in lymphocyte of GDM patients by RT-PCR method. Results: After 6 weeks intervention, in comparison with the control group, interventional group showed down regulation of gene expression of tumor necrosis factor alpha (TNF–α (p=0.02 and transforming growth factor beta (TGF–β (p=0.01 and up-regulation of gene expression of vascular endothelial (VEGF (p = 0.03 in lymphocytes of GDM. There was not any significant change following intervention with selenium regarding gene expression of interleukin IL-1 β and IL-8 in lymphocytes of GDM patients. Conclusion: 6 weeks supplementation with selenium in patients with GDM can cause down regulated gene expression of TNF-α and TGF–β, and up regulated gene expression of VEGF. Selenium supplement had not any effect on gene expression of IL-1 β and IL-8.

  14. Cytokine gene expression profiles in chicken spleen and intestinal tissues during Ascaridia galli infection

    DEFF Research Database (Denmark)

    Pleidrup, Janne A.; Norup, Liselotte R.; Dalgaard, Tina S.

    2014-01-01

    , the anti-inflammatory cytokines IL-10 and TGF-beta 4 and the proinflammatory cytokine IL-17F were determined over a period of 3 weeks in A. galli and non-A. galli-infected chickens. A characteristic Th2 response was observed in the jejunum of A. galli-infected chickens with increased expression of IL-13...

  15. Differences in gene expression and cytokine production by crystalline vs. amorphous silica in human lung epithelial cells.

    Science.gov (United States)

    Perkins, Timothy N; Shukla, Arti; Peeters, Paul M; Steinbacher, Jeremy L; Landry, Christopher C; Lathrop, Sherrill A; Steele, Chad; Reynaert, Niki L; Wouters, Emiel F M; Mossman, Brooke T

    2012-02-02

    Exposure to respirable crystalline silica particles, as opposed to amorphous silica, is associated with lung inflammation, pulmonary fibrosis (silicosis), and potentially with lung cancer. We used Affymetrix/GeneSifter microarray analysis to determine whether gene expression profiles differed in a human bronchial epithelial cell line (BEAS 2B) exposed to cristobalite vs. amorphous silica particles at non-toxic and equal surface areas (75 and 150 × 106μm2/cm2). Bio-Plex analysis was also used to determine profiles of secreted cytokines and chemokines in response to both particles. Finally, primary human bronchial epithelial cells (NHBE) were used to comparatively assess silica particle-induced alterations in gene expression. Microarray analysis at 24 hours in BEAS 2B revealed 333 and 631 significant alterations in gene expression induced by cristobalite at low (75) and high (150 × 106μm2/cm2) amounts, respectively (p silica micro-particles at high amounts (150 × 106μm2/cm2) induced 108 significant gene changes. Bio-Plex analysis of 27 human cytokines and chemokines revealed 9 secreted mediators (p crystalline silica, but none were induced by amorphous silica. QRT-PCR revealed that cristobalite selectively up-regulated stress-related genes and cytokines (FOS, ATF3, IL6 and IL8) early and over time (2, 4, 8, and 24 h). Patterns of gene expression in NHBE cells were similar overall to BEAS 2B cells. At 75 × 106μm2/cm2, there were 339 significant alterations in gene expression induced by cristobalite and 42 by amorphous silica. Comparison of genes in response to cristobalite (75 × 106μm2/cm2) revealed 60 common, significant gene alterations in NHBE and BEAS 2B cells. Cristobalite silica, as compared to synthetic amorphous silica particles at equal surface area concentrations, had comparable effects on the viability of human bronchial epithelial cells. However, effects on gene expression, as well as secretion of cytokines and chemokines, drastically differed

  16. Cytokine gene signatures in neural tissue of horses with equine protozoal myeloencephalitis or equine herpes type 1 myeloencephalopathy.

    Science.gov (United States)

    Pusterla, N; Wilson, W D; Conrad, P A; Barr, B C; Ferraro, G L; Daft, B M; Leutenegger, C M

    2006-09-09

    This study was designed to determine the relative levels of gene transcription of selected pathogens and cytokines in the brain and spinal cord of 12 horses with equine protozoal myeloencephalitis (EPM), 11 with equine herpesvirus type 1 (EHV-1) myeloencephalopathy, and 12 healthy control horses by applying a real time pcr to the formalin-fixed and paraffin-embedded tissues. Total rna was extracted from each tissue, transcribed to complementary dna (cDNA) and assayed for Sarcocystis neurona, Neospora hughesi, EHV-1, equine GAPDH (housekeeping gene), tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10 AND IL-12 p40. S neurona cdna was detected in the neural tissue from all 12 horses with EPM, and two of them also had amplifiable cDNA of N hughesi. The relative levels of transcription of protozoal cdna ranged from 1 to 461 times baseline (mean 123). All the horses with ehv-1 myeloencephalopathy had positive viral signals by PCR with relative levels of transcription ranging from 1 to 1618 times baseline (mean 275). All the control horses tested negative for S neurona, N hughesi and EHV-1 cdna. The cytokine profiles of each disease indicated a balance between pro- and anti-inflammatory markers. In the horses with epm the pro-inflammatory Th1 cytokines (IL-8, TNF-alpha and IFN-gamma) were commonly expressed but the anti-inflammatory Th2 cytokines (IL-4, IL-6 AND IL-10) were absent or rare. In the horses with ehv-1 the proinflammatory cytokine IL-8 was commonly expressed, but IL-10 and IFN-gamma were not, and TNF-alpha was rare. Tissue from the control horses expressed only the gene GAPDH.

  17. Commonly studied polymorphisms in inflammatory cytokine genes show only minor effects on mortality and related risk factors in nonagenarians

    DEFF Research Database (Denmark)

    Dato, Serena; Krabbe, Karen S; Thinggaard, Mikael

    2010-01-01

    Systemic low-grade inflammation is consistently associated with functional status, cognitive functioning, multimorbidity, and survival in oldest olds. If inflammation is either a cause or a consequence of age-related pathology, genetic determinants of late-life survival can reside in cytokine genes....... Additionally, associations were investigated between inflammatory markers and major predictors of mortality as cognitive and functional status. Modest sex-specific associations were found with survival, cognitive functioning, and handgrip strength. Evaluation of combined genotypes indicated that......, in nonagenarian men, the balance of pro- and anti-inflammatory activity at IL18 and IL10 loci is protective against cognitive decline. In conclusion, in this large study with virtually complete follow-up, commonly studied polymorphisms in cytokine genes do not have a major impact on late-life survival...

  18. Post operative infection and sepsis in humans is associated with deficient gene expression of gammac cytokines and their apoptosis mediators.

    LENUS (Irish Health Repository)

    White, Mary

    2011-06-28

    Abstract Introduction Lymphocyte homeostasis is dependent on the γc cytokines. We hypothesised that sepsis in humans is associated with differential gene expression of the γc cytokines and their associated apoptosis mediators. Methods The study population consisted of a total of 60 patients with severe sepsis, 15 with gram negative bacteraemia, 10 healthy controls and 60 patients undergoing elective lung resection surgery. Pneumonia was diagnosed by CDC NNIC criteria. Gene expression in peripheral blood leukocytes (PBLs) of interleukin (IL)-2, 7, 15 and interferon (IFN)-γ, Bax, Bim, Bcl-2 was determined by qRT-PCR and IL-2 and IL-7 serum protein levels by ELISA. Gene expression of IL-2, 7 and IFN-γ was measured in peripheral blood leukocytes (PBL), cultured in the presence of lipopolysacharide (LPS) and CD3 binding antibody (CD3ab) Results IL-2 gene expression was lower in the bacteraemia group compared with controls, and lower still in the sepsis group (P < 0.0001). IL-7 gene expression was similar in controls and bacteraemia, but lower in sepsis (P < 0.0001). IL-15 gene expression was similar in the three groups. Bcl-2 gene expression was less (P < 0.0001) and Bim gene expression was greater (P = 0.0003) in severe sepsis compared to bacteraemic and healthy controls. Bax gene expression was similar in the three groups. In lung resection surgery patients, post-operative pneumonia was associated with a perioperative decrease in IL-2 mRNA (P < 0.0001) and IL-7 mRNA (P = 0.003). IL-2 protein levels were reduced in sepsis and bacteraemia compared to controls (P = 0.02) but similar in pneumonia and non-pneumonia groups. IL-7 protein levels were similar in all groups. In cultured PBLs, IFN-γ gene expression was decreased in response to LPS and increased in response to CD3ab with sepsis: IL-7 gene expression increased in response to LPS in controls and to CD3ab with sepsis; Bcl-2 gene expression decreased in response to combined CD3ab and IL-2 with sepsis

  19. Cytokine Gene Associations with Self-report Ratings of Morning and Evening Fatigue in Oncology Patients and Their Family Caregivers

    OpenAIRE

    Dhruva, Anand; Aouizerat, Bradley E.; Cooper, Bruce; Paul, Steven M.; Dodd, Marylin; West, Claudia; Wara, William; Lee, Kathryn; Dunn, Laura B.; Langford, Dale J; Merriman, John D.; Baggott, Christina; Cataldo, Janine; Ritchie, Christine; Kober, Kord M.

    2014-01-01

    The purpose of this study was to evaluate for differences in variations in pro- and anti-inflammatory cytokine genes between participants who were classified as having low and high levels of morning and evening fatigue and to evaluate for differences in phenotypic characteristics between these two groups. In a sample of 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their family caregivers, growth mixture modeling (GMM) was used to identify l...

  20. Association of cytokine gene polymorphisms and risk factors with otitis media proneness in children.

    Science.gov (United States)

    Miljanović, Olivera; Cikota-Aleksić, Bojana; Likić, Dragan; Vojvodić, Danilo; Jovićević, Ognjen; Magić, Zvonko

    2016-06-01

    In order to assess the association between gene polymorphisms and otitis media (OM) proneness, tumor necrosis factor alpha (TNFA) -308, interleukin (IL) 10-1082 and -3575, IL6 -597, IL2 -330, and CD14 -159 genotyping was performed in 58 OM-prone children and 85 controls who were exposed to similar number and frequency of environmental and host risk factors. The frequencies of genotypes (wild type vs. genotypes containing at least one polymorphic allele) were not significantly different between groups, except for IL10 -1082. Polymorphic genotypes IL10 -1082 GA and GG were more frequent in OM-prone children than in control group (RR 1.145, 95 % CI 1.011-1.298; p = 0.047). However, logistic regression did not confirm IL10 -1082 polymorphic genotypes as an independent risk factor for OM proneness. The present study indicates that high-producing IL10 -1082 GA/GG genotypes may increase the risk for OM proneness in its carriers when exposed to other environmental/host risk factors (day care attendance, passive smoking, male sex, respiratory infections, and atopic manifestations). This study revealed no significant independent genetic association, but the lack of breastfeeding in infancy was found to be the only independent risk factor for development of OM-prone phenotype, implying that breastfeeding had a protective role in development of susceptibility to OM. • The pathogenesis of OM is of multifactorial nature, dependent on infection, environmental factors, and immune response of the child. • Cytokines and CD14 play an important role in the presentation and clinical course of otitis media, but a clear link with otitis media proneness was not established. What is new: • This is the first clinical and genetic study on Montenegrin children with the otitis media-prone phenotype. • The study revealed that high-producing IL10 -1082 genotypes may influence otitis media proneness in children exposed to other environmental/host risk factors.

  1. Association of Cytokine Gene Polymorphisms in Patients with Chronic Obstructive Pulmonary Disease

    Directory of Open Access Journals (Sweden)

    Rajni Kant Shukla

    2012-07-01

    Full Text Available Objective: Chronic obstructive pulmonary disease (COPD is a major health problem. The disease is driven by abnormal inflammatory reactions in response to inhaled particles and fumes. Therefore, inflammatory mediators are postulated to be of distinct importance. Keeping in view of the above facts; we investigate the role of polymorphisms of cytokine genes in the genetic predisposition of COPD.Methods: In this present case-control study, the allele and genotype distributions of IL1B, IL1RN, TNF-α, and IL4 were studied in COPD patients (N=204 and healthy individuals (N=208. Genomic DNA was obtained by whole blood and genotyping was carried out by a polymerase chain reaction (PCR based Restriction Fragment Length Polymorphism technique.Results: Genotype IL1RN*2/IL1RN*2 was identified as protective for male COPD, its frequency being 8.7% in COPD patients and 14.6% in healthy subjects (p=0.017; OR=0.53, but IL1RN*1/IL1RN*2 turned out to be a risk factor for females COPD. No significant differences were found between the groups of COPD patients and healthy subjects concerning the genotype frequencies of the polymorphisms T (-511 C of IL1B and 70bp VNTR of IL-4. Genotype GA of the TNF-α polymorphism G (-308 A was more common in the COPD patients than in the controls (20.5% vs.14.4%; p=0.107, and allele A was significantly associated with COPD patients (p=0.023; OR=0.65.Conclusion: IL-1RN *2 allele appears to be significantly associated with the COPD female patients and TNF-α-308A allele is a risk factor for the development of COPD.

  2. Differences in gene expression and cytokine production by crystalline vs. amorphous silica in human lung epithelial cells

    Directory of Open Access Journals (Sweden)

    Perkins Timothy N

    2012-02-01

    Full Text Available Abstract Background Exposure to respirable crystalline silica particles, as opposed to amorphous silica, is associated with lung inflammation, pulmonary fibrosis (silicosis, and potentially with lung cancer. We used Affymetrix/GeneSifter microarray analysis to determine whether gene expression profiles differed in a human bronchial epithelial cell line (BEAS 2B exposed to cristobalite vs. amorphous silica particles at non-toxic and equal surface areas (75 and 150 × 106μm2/cm2. Bio-Plex analysis was also used to determine profiles of secreted cytokines and chemokines in response to both particles. Finally, primary human bronchial epithelial cells (NHBE were used to comparatively assess silica particle-induced alterations in gene expression. Results Microarray analysis at 24 hours in BEAS 2B revealed 333 and 631 significant alterations in gene expression induced by cristobalite at low (75 and high (150 × 106μm2/cm2 amounts, respectively (p 6μm2/cm2 induced 108 significant gene changes. Bio-Plex analysis of 27 human cytokines and chemokines revealed 9 secreted mediators (p FOS, ATF3, IL6 and IL8 early and over time (2, 4, 8, and 24 h. Patterns of gene expression in NHBE cells were similar overall to BEAS 2B cells. At 75 × 106μm2/cm2, there were 339 significant alterations in gene expression induced by cristobalite and 42 by amorphous silica. Comparison of genes in response to cristobalite (75 × 106μm2/cm2 revealed 60 common, significant gene alterations in NHBE and BEAS 2B cells. Conclusions Cristobalite silica, as compared to synthetic amorphous silica particles at equal surface area concentrations, had comparable effects on the viability of human bronchial epithelial cells. However, effects on gene expression, as well as secretion of cytokines and chemokines, drastically differed, as the crystalline silica induced more intense responses. Our studies indicate that toxicological testing of particulates by surveying viability and

  3. Analysis of Gene Expression in Experimental Pressure Ulcers in the Rat with Special Reference to Inflammatory Cytokines.

    Directory of Open Access Journals (Sweden)

    Tomoyuki Kurose

    Full Text Available Pressure ulcers have been investigated in a few animal models, but the molecular mechanisms of pressure ulcers are not well understood. We hypothesized that pressure results in up-regulation of inflammatory cytokines and those cytokines contribute to the formation of pressure ulcers. We measured genome-wide changes in transcript levels after compression, and focused especially on inflammatory cytokines. The abdominal wall of rats was compressed at 100 mmHg for 4 hours by two magnets. Specimens were obtained 12 hours, 1, or 3 days after compression, and analyzed by light microscopy, microarray, Real-Time PCR, and ELISA. The skin and subcutaneous tissue in the compressed area were markedly thickened. The microarray showed that numerous genes were up-regulated after the compression. Up-regulated genes were involved in apoptosis, inflammation, oxidative stress, proteolysis, hypoxia, and so on. Real-Time PCR showed the up-regulation of granulocyte-macrophage colony stimulating factor (GM-CSF, interferon γ (IFN-γ, interleukin 1β (IL-1β, interleukin 1 receptor antagonist gene (IL1Ra, interleukin 6 (IL-6, interleukin 10 (IL-10, matrix metalloproteinase 3 (MMP-3, tissue inhibitor of metalloproteinase 1 (TIMP-1, and tumor necrosis factor α (TNF-α at 12 hours, IFN-γ, IL-6, IL-10, MMP-3, and TIMP-1 at 1 day, and IFN-γ, IL-6, and MMP-3 at 3 days. Some genes from subcutaneous tissue were up-regulated temporarily, and others were kept at high levels of expression. ELISA data showed that the concentrations of IL-1β and IL-6 proteins were most notably increased following compression. Prolonged up-regulation of IL-1β, and IL-6 might enhance local inflammation, and continuous local inflammation may contribute to the pressure ulcer formation. In addition, GM-CSF, IFN-γ, MMP-3, and TIMP-1 were not reported previously in the wound healing process, and those genes may have a role in development of the pressure ulcers. Expression data from Real-Time PCR were

  4. CARD15 gene overexpression reduces effect of etanercept, infliximab, and adalimumab on cytokine secretion from PMA activated U937 cells.

    Science.gov (United States)

    Teimourian, Shahram; Masoudzadeh, Nooshin

    2015-09-05

    Crohn's disease (CD), a subcategory of inflammatory bowel disease, is an immune-related disorder characterized by inflammation of the gastrointestinal mucosa, which can take place in any region along the alimentary tract. The most important gene involved in the etiology of CD is NOD2/CARD15 located on chromosome 16. It has been shown that CARD15 is overexpressed in monocytes of CD patients. The common treatment for the disease is anti-TNF-alpha drugs, the most hopeful of which are probably infliximab and etanercept. Infliximab rapidly reduces signs and symptoms of active Crohn's disease. In contrast, etanercept shows no such effect. In the present study, we evaluated the effects of the CARD15 gene overexpression in monocytic cell line U937 in the production of anti-inflammatory cytokine, IL-10, and proinflammatory cytokine, Il-1 beta, produced after incubation with infliximab, adalimumab, and etanercept separately. Our results show that infliximab and adalimumab significantly decreased IL-10 and IL-1beta secretion levels. However, etanercept inhibition of secretion was less compared with infliximab or adalimumab. In all three cases, suppression of cytokine production is reduced by CARD15 overexpression. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. A meta-analysis of kidney microarray datasets: investigation of cytokine gene detection and correlation with rt-PCR and detection thresholds

    Directory of Open Access Journals (Sweden)

    Stegall Mark D

    2007-03-01

    Full Text Available Abstract Background Microarrays provide a means to simultaneously examine the gene expression of the entire transcriptome in a single sample. Many studies have highlighted the need for novel software and statistical approaches to assess the measured gene expression. Less attention has been directed toward whether genes considered undetectable by microarray can be detected by other strategies or whether these genes can provide accurate gene expression determinations. In the kidney this is a concern for genes such as cytokines which dramatically influence the immune response but are often considered low abundance genes produced by a small number of cells. Results Using both publicly available and our own microarray datasets we analyzed the detection p-value and detection call values for 81 human kidney samples run on the U133A or U133Plus2.0 Affymetrix microarrays (Affymetrix, Santa Clara, CA. For the cytokine genes, the frequency of detection in each sample group (normal, transplant and renal cell carcinoma was examined and revealed that a majority of cytokine related genes are not detectable in human kidney by microarray. Using a subset of 29 Mayo transplant samples, a group of seven transplant-related cytokines and eight non-cytokine genes were evaluated by real-time PCR (rt-PCR. For these 15 genes we compared the impact of decreasing microarray detection frequency with the changes in gene expression observed by both microarray and rt-PCR. We found that as microarray detection frequency decreased the correlation between microarray and rt-PCR data also decreased. Conclusion We conclude that, when analyzing microarray data from human kidney samples, genes generally expressed at low abundance (i.e. cytokines should be evaluated with more sensitive approaches such as rt-PCR. In addition, our data suggest that the use of detection frequency cutoffs for inclusion or exclusion of microarray data may be appropriate when comparing microarray and rt

  6. A meta-analysis of kidney microarray datasets: investigation of cytokine gene detection and correlation with rt-PCR and detection thresholds.

    Science.gov (United States)

    Park, Walter D; Stegall, Mark D

    2007-03-30

    Microarrays provide a means to simultaneously examine the gene expression of the entire transcriptome in a single sample. Many studies have highlighted the need for novel software and statistical approaches to assess the measured gene expression. Less attention has been directed toward whether genes considered undetectable by microarray can be detected by other strategies or whether these genes can provide accurate gene expression determinations. In the kidney this is a concern for genes such as cytokines which dramatically influence the immune response but are often considered low abundance genes produced by a small number of cells. Using both publicly available and our own microarray datasets we analyzed the detection p-value and detection call values for 81 human kidney samples run on the U133A or U133Plus2.0 Affymetrix microarrays (Affymetrix, Santa Clara, CA). For the cytokine genes, the frequency of detection in each sample group (normal, transplant and renal cell carcinoma) was examined and revealed that a majority of cytokine related genes are not detectable in human kidney by microarray. Using a subset of 29 Mayo transplant samples, a group of seven transplant-related cytokines and eight non-cytokine genes were evaluated by real-time PCR (rt-PCR). For these 15 genes we compared the impact of decreasing microarray detection frequency with the changes in gene expression observed by both microarray and rt-PCR. We found that as microarray detection frequency decreased the correlation between microarray and rt-PCR data also decreased. We conclude that, when analyzing microarray data from human kidney samples, genes generally expressed at low abundance (i.e. cytokines) should be evaluated with more sensitive approaches such as rt-PCR. In addition, our data suggest that the use of detection frequency cutoffs for inclusion or exclusion of microarray data may be appropriate when comparing microarray and rt-PCR gene expression data and p-value calculations.

  7. Post-operative infection and sepsis in humans is associated with deficient gene expression of ?c cytokines and their apoptosis mediators

    OpenAIRE

    White, Mary; Mahon, Vivienne; Grealy, Robert; Doherty, Derek G; Stordeur, Patrick; Kelleher, Dermot P; McManus, Ross; Ryan, Thomas

    2011-01-01

    Introduction Lymphocyte homeostasis is dependent on the ?c cytokines. We hypothesised that sepsis in humans is associated with differential gene expression of the ?c cytokines and their associated apoptosis mediators. Methods The study population consisted of a total of 60 patients with severe sepsis, 15 with gram negative bacteraemia, 10 healthy controls and 60 patients undergoing elective lung resection surgery. Pneumonia was diagnosed by CDC NNIC criteria. Gene expression in peripheral blo...

  8. Post-operative infection and sepsis in humans is associated with deficient gene expression of Yc cytokines and their apoptosis mediators.

    OpenAIRE

    MC MANUS, ROSS; KELLEHER, DERMOT P; DOHERTY, DEREK; RYAN, THOMAS

    2011-01-01

    PUBLISHED INTRODUCTION: Lymphocyte homeostasis is dependent on the ?c cytokines. We hypothesised that sepsis in humans is associated with differential gene expression of the ?c cytokines and their associated apoptosis mediators. METHODS: The study population consisted of a total of 60 patients with severe sepsis, 15 with gram negative bacteraemia, 10 healthy controls and 60 patients undergoing elective lung resection surgery. Pneumonia was diagnosed by CDC NNIC criteria. Gene expr...

  9. Gene-specific repression of proinflammatory cytokines in stimulated human macrophages by nuclear IκBα.

    Science.gov (United States)

    Ghosh, Chandra C; Ramaswami, Sitharam; Juvekar, Ashish; Vu, Hai-Yen; Galdieri, Luciano; Davidson, Dennis; Vancurova, Ivana

    2010-09-15

    We have previously shown that increased nuclear accumulation of IkappaBalpha inhibits NF-kappaB activity and induces apoptosis in human leukocytes. In this study, we wanted to explore the possibility that the nucleocytoplasmic distribution of IkappaBalpha can be used as a therapeutic target for the regulation of NF-kappaB-dependent cytokine synthesis. Treatment of LPS-stimulated human U937 macrophages with an inhibitor of chromosome region maintenance 1-dependent nuclear export, leptomycin B, resulted in the increased nuclear accumulation of IkappaBalpha and inhibition of NF-kappaB DNA binding activity, caused by the nuclear IkappaBalpha-p65 NF-kappaB interaction. Surprisingly, however, whereas mRNA expression and cellular release of TNF-alpha, the beta form of pro-IL-1 (IL-1beta), and IL-6 were inhibited by the leptomycin B-induced nuclear IkappaBalpha, IL-8 mRNA expression and cellular release were not significantly affected. Analysis of in vivo recruitment of p65 NF-kappaB to NF-kappaB-regulated promoters by chromatin immunoprecipitation in U937 cells and human PBMCs indicated that although the p65 recruitment to TNF-alpha, IL-1beta, and IL-6 promoters was inhibited by the nuclear IkappaBalpha, p65 recruitment to IL-8 promoter was not repressed. Chromatin immunoprecipitation analyses using IkappaBalpha and S536 phosphospecific p65 NF-kappaB Abs demonstrated that although the newly synthesized IkappaBalpha induced by postinduction repression is recruited to TNF-alpha, IL-1beta, and IL-6 promoters but not to the IL-8 promoter, S536-phosphorylated p65 is recruited to IL-8 promoter, but not to TNF-alpha, IL-1beta, or IL-6 promoters. Together, these data indicate that the inhibition of NF-kappaB-dependent transcription by nuclear IkappaBalpha in LPS-stimulated macrophages is gene specific and depends on the S536 phosphorylation status of the recruited p65 NF-kappaB.

  10. Temporal profiling of cytokine-induced genes in pancreatic β-cells by meta-analysis and network inference

    DEFF Research Database (Denmark)

    Lopes, Miguel; Kutlu, Burak; Miani, Michela

    2014-01-01

    Type 1 Diabetes (T1D) is an autoimmune disease where local release of cytokines such as IL-1β and IFN-γ contributes to β-cell apoptosis. To identify relevant genes regulating this process we performed a meta-analysis of 8 datasets of β-cell gene expression after exposure to IL-1β and IFN-γ. Two...... of these datasets are novel and contain time-series expressions in human islet cells and rat INS-1E cells. Genes were ranked according to their differential expression within and after 24 h from exposure, and characterized by function and prior knowledge in the literature. A regulatory network was then inferred...... from the human time expression datasets, using a time-series extension of a network inference method. The two most differentially expressed genes previously unknown in T1D literature (RIPK2 and ELF3) were found to modulate cytokine-induced apoptosis. The inferred regulatory network is thus supported...

  11. Cytokine Profiles in Human Metapneumovirus Infected Children: Identification of Genes Involved in the Antiviral Response and Pathogenesis.

    Directory of Open Access Journals (Sweden)

    Jostein Malmo

    Full Text Available Human metapneumovirus (hMPV causes severe airway infection in children that may be caused by an unfavorable immune response. The nature of the innate immune response to hMPV in naturally occurring infections in children is largely undescribed, and it is unknown if inflammasome activation is implicated in disease pathogenesis. We examined nasopharynx aspirates and blood samples from hMPV-infected children without detectable co-infections. The expression of inflammatory and antiviral genes were measured in nasal airway secretions by relative mRNA quantification while blood plasma proteins were determined by a multiplex immunoassay. Several genes were significantly up-regulated at mRNA and protein level in the hMPV infected children. Most apparent was the expression of the chemokine IP-10, the pro-inflammatory cytokine IL-18 in addition to the interferon inducible gene ISG54. Interestingly, children experiencing more severe disease, as indicated by a severity index, had significantly more often up-regulation of the inflammasome-associated genes IL-1β and NLRP3. Overall, our data point to cytokines, particularly inflammasome-associated, that might be important in hMPV mediated lung disease and the antiviral response in children with severe infection. Our study is the first to demonstrate that inflammasome components are associated with increased illness severity in hMPV-infected children.

  12. Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast cancer risk in American women of African and European ancestry.

    Science.gov (United States)

    Quan, Lei; Gong, Zhihong; Yao, Song; Bandera, Elisa V; Zirpoli, Gary; Hwang, Helena; Roberts, Michelle; Ciupak, Gregory; Davis, Warren; Sucheston, Lara; Pawlish, Karen; Bovbjerg, Dana H; Jandorf, Lina; Cabasag, Citadel; Coignet, Jean-Gabriel; Ambrosone, Christine B; Hong, Chi-Chen

    2014-03-15

    Disparities in breast cancer biology are evident between American women of African ancestry (AA) and European ancestry (EA) and may be due, in part, to differences in immune function. To assess the potential role of constitutional host immunity on breast carcinogenesis, we tested associations between breast cancer risk and 47 single nucleotide polymorphisms (SNPs) in 26 cytokine-related genes of the adaptive immune system using 650 EA (n = 335 cases) and 864 AA (n = 458 cases) women from the Women's Circle of Health Study (WCHS). With additional participant accrual to the WCHS, promising SNPs from the initial analysis were evaluated in a larger sample size (1,307 EAs and 1,365 AAs). Multivariate logistic regression found SNPs in genes important for T helper type 1 (Th1) immunity (IFNGR2 rs1059293, IL15RA rs2296135, LTA rs1041981), Th2 immunity (IL4R rs1801275), and T regulatory cell-mediated immunosuppression (TGFB1 rs1800469) associated with breast cancer risk, mainly among AAs. The combined effect of these five SNPs was highly significant among AAs (P-trend = 0.0005). When stratified by estrogen receptor (ER) status, LTA rs1041981 was associated with ER-positive breast cancers among EAs and marginally among AAs. Only among AA women, IL15 rs10833 and IL15RA rs2296135 were associated with ER-positive tumors, and IL12RB1 rs375947, IL15 rs10833 and TGFB1 rs1800469 were associated with ER-negative tumors. Our study systematically identified genetic variants in the adaptive immune response pathway associated with breast cancer risk, which appears to differ by ancestry groups, menopausal status and ER status. © 2013 UICC.

  13. Melatonin mitigates thioacetamide-induced hepatic fibrosis via antioxidant activity and modulation of proinflammatory cytokines and fibrogenic genes.

    Science.gov (United States)

    Lebda, Mohamed A; Sadek, Kadry M; Abouzed, Tarek K; Tohamy, Hossam G; El-Sayed, Yasser S

    2018-01-01

    The potential antifibrotic effects of melatonin against induced hepatic fibrosis were explored. Rats were allocated into four groups: placebo; thioacetamide (TAA) (200mg/kg bwt, i.p twice weekly for two months); melatonin (5mg/kgbwt, i.p daily for a week before TAA and continued for an additional two months); and melatonin plus TAA. Hepatic fibrotic changes were evaluated biochemically and histopathologically. Hepatic oxidative/antioxidative indices were assessed. The expression of hepatic proinflammatory cytokines (tumor necrosis factor-α, and interleukin-1β), fibrogenic-related genes (transforming growth factor-1β, collagen I, collagen, III, laminin, and autotaxin) and an antioxidant-related gene (thioredoxin-1) were detected by qRT-PCR. In fibrotic rats, melatonin lowered serum aspartate aminotransferase, alanine aminotransferase, and autotaxin activities, bilirubin, hepatic hydroxyproline and plasma ammonia levels. Melatonin displayed hepatoprotective and antifibrotic potential as indicated by mild hydropic degeneration of some hepatocytes and mild fibroplasia. In addition, TAA induced the depletion of glutathione, glutathione s-transferase, glutathione peroxidase, superoxide dismutase, catalase, and paraoxonase-1 (PON-1), while inducing the accumulation of malondialdehyde, protein carbonyl (C=O) and nitric oxide (NO), and DNA fragmentation. These effects were restored by melatonin pretreatment. Furthermore, melatonin markedly attenuated the expression of proinflammatory cytokines and fibrogenic genes via the upregulation of thioredoxin-1 mRNA transcripts. Melatonin exhibits potent anti-inflammatory, antioxidant and fibrosuppressive activities against TAA-induced hepatic fibrogenesis via the suppression of oxidative stress, DNA damage, proinflammatory cytokines and fibrogenic gene transcripts. In addition, we demonstrate that the antifibrotic activity of melatonin is mediated by the induction of thioredoxin-1 with attenuation of autotaxin expressions

  14. Polymorphisms in major cytokine genes: A study among human immunodeficiency Virus-1 serodiscordant couples in Mumbai, India

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    D V Chaudhari

    2013-01-01

    Full Text Available Purpose: Polymorphism in cytokine genes may affect its production, which play an important role in modulation of human immunodeficiency virus (HIV infection. Evaluation of these polymorphisms might help to understand why some individuals remain uninfected in spite of several exposures to HIV infection, such as the negative spouses of discordant couples. The aim of this study was to evaluate the association of 22 single nucleotide polymorphisms (SNPs in 13 cytokine genes and their receptors with HIV infection in serodiscordant couples, attending the Integrated Counselling and Testing Centre of a Municipality Hospital. Materials and Methods: At the end of at least 2 years of follow up, 42 couples were confirmed as being serodiscordant. Genotyping was carried out in blood samples of these couples using the polymerase chain reaction-sequence-specific amplification method. Results: Significantly high frequency of interleukin-1 receptor antagonist IL-1RA mspa 11100 CC ( P = 0.04, tumor necrosis factor-alpha TNF-α −238 AG ( P = 0.01 and IL-4 −33 TT ( P = 0.01 was observed in HIV seropositives (HSP while frequency of TNF-α −238 GG ( P = 0.02 was significantly high among the exposed uninfected (EU. However, application of Bonferroni correction identified only two SNPs i.e., TNF-α −238 AG and IL-4 −33 TT to be significantly associated with the acquisition of HIV. In remaining cytokine genes, no significant association was observed. Conclusion: Our study highlighted possible association of certain specific polymorphisms with HIV transmission, whereas presence or absence of certain other polymorphism in EU individuals might be offering protection from HIV infection. These variations at the genetic level might help to explore new insights into treatment and HIV prevention strategies.

  15. Alzheimer’s disease and cytokine IL-10 gene polymorphisms: is there an association?

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    Carolina Antunes Magalhães

    Full Text Available ABSTRACT Alzheimer’s disease (AD is the most common form of dementia. In the last 15 years, a new theory has proposed the autoimmune mechanism as a trigger for AD. Studies on the association between AD and inflammatory biomarkers have yielded controversial results. Interleukin-10 (IL-10, an anti-inflammatory mediator, has been pointed out as one of the main cytokines associated with the occurrence of AD. Moreover, treatment that increases IL-10 levels could be a potential therapy for AD, since this cytokine acts on amyloid and pro-inflammatory molecule reduction. Based on the current literature, this study reviews evidence regarding the role of IL-10 polymorphisms in the context of AD, which has been shown to be of paramount importance for attenuating neuroinflammation, cognitive dysfunction and neurodegeneration.

  16. Gene Expression Profile of Human Cytokines in Response to B.pseudomallei Infection

    Science.gov (United States)

    2017-04-19

    responses 81 to an infection (6). Activation of leukocytes and cytokine networks are prominent 82 features of inflammation and the septic response (7...and of leukocyte Interleukin 8 mRNA 539 levels during septicemic and localized pseudomonas pseudomallei infection. 540 Infection and Immunity 60...which is chemotactic for T cells, eosnophils and basophils, plays an active role in recruiting leukocytes into inflammatory sites IFNγ Interferon

  17. Molecular characterization of two suppressor of cytokine signaling 1 genes (SOCS1a and SOCS1b in chickens

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    Xue XU,Jiannan ZHANG,Juan LI,Yajun WANG

    2015-03-01

    Full Text Available Suppressor of cytokine signaling 1 (SOCS1 protein can inhibit the signal transduction triggered by some cytokines or hormones and thus are important in many physiological/pathological processes, including innate and adaptive immunity, inflammation, and development in mammals. However, there is sparse information about their structure, tissue expression, in birds, where their biological functions remain unknown. In this study, we cloned and characterized two SOCS1 genes (named cSOCS1a and cSOCS1b from chickens. SOCS1a is predicted to encode a 207-amino acid protein, which shares high amino acid sequence identity (64%–67% with human and mouse SOCS1. Besides SOCS1a, a novel SOCS1b gene was also identified in chickens and other non-mammalian vertebrates including Xenopus tropicalis. Chicken SOCS1b is predicted to encode a 212-amino acid protein, which shares only 30%–32% amino acid sequence identity with human SOCS1 and cSOCS1a. RT-PCR assay revealed that both cSOCS1a and cSOCS1b are widely expressed in all chicken tissues. Using a luciferase reporter assay system, we further demonstrated that transient expression of cSOCS1a and cSOCS1b can significantly inhibit chicken growth hormone (GH- or prolactin (PRL-induced luciferase activities of Hep G2 cells expressing cGH receptor (or cPRL receptor, indicating that SOCS1a and SOCS1b proteins can negatively regulate GH/PRL signaling. Taken together, these data suggest that both cSOCS1a and cSOCS1b may function as negative regulators of cytokine/hormone actions, such as modulation of GH/PRL actions in chickens.

  18. Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states

    Science.gov (United States)

    Adamson, Antony; Boddington, Christopher; Downton, Polly; Rowe, William; Bagnall, James; Lam, Connie; Maya-Mendoza, Apolinar; Schmidt, Lorraine; Harper, Claire V.; Spiller, David G.; Rand, David A.; Jackson, Dean A.; White, Michael R. H.; Paszek, Pawel

    2016-01-01

    Cells respond dynamically to pulsatile cytokine stimulation. Here we report that single, or well-spaced pulses of TNFα (>100 min apart) give a high probability of NF-κB activation. However, fewer cells respond to shorter pulse intervals (refractory state. This refractory state is established in the signal transduction network downstream of TNFR and upstream of IKK, and depends on the level of the NF-κB system negative feedback protein A20. If a second pulse within the refractory phase is IL-1β instead of TNFα, all of the cells respond. This suggests a mechanism by which two cytokines can synergistically activate an inflammatory response. Gene expression analyses show strong correlation between the cellular dynamic response and NF-κB-dependent target gene activation. These data suggest that refractory states in the NF-κB system constitute an inherent design motif of the inflammatory response and we suggest that this may avoid harmful homogenous cellular activation. PMID:27381163

  19. Dynamics of hepatic gene expression and serum cytokine profiles in single and double-hit burn and sepsis animal models

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    Rohit Rao

    2015-06-01

    Full Text Available We simulate the pathophysiology of severe burn trauma and burn-induced sepsis, using rat models of experimental burn injury and cecal ligation and puncture (CLP either individually (singe-hit model or in combination (double-hit model. The experimental burn injury simulates a systemic but sterile pro-inflammatory response, while the CLP simulates the effect of polymicrobial sepsis. Given the liver׳s central role in mediating the host immune response and onset of hypermetabolism after burn injury, elucidating the alterations in hepatic gene expression in response to injury can lead to a better understanding of the regulation of the inflammatory response, whereas circulating cytokine protein expression, reflects key systemic inflammatory mediators. In this article, we present both the hepatic gene expression and circulating cytokine/chemokine protein expression data for the above-mentioned experimental model to gain insights into the temporal dynamics of the inflammatory and hypermetabolic response following burn and septic injury. This data article supports results discussed in research articles (Yang et al., 2012 [1,4]; Mattick et al. 2012, 2013 [2,3]; Nguyen et al., 2014 [5]; Orman et al., 2011, 2012 [6–8].

  20. Camel milk and bee honey regulate profibrotic cytokine gene transcripts in liver cirrhosis induced by carbon tetrachloride.

    Science.gov (United States)

    Sadek, Kadry; Beltagy, Doha; Saleh, Ebeed; Abouelkhair, Reham

    2016-05-30

    The lack of studies regarding the mechanism of the protective effects of camel milk and bee honey against hepatotoxic compounds led us to perform this study. Thirty-six male rats were divided into two main groups. The first group (n = 9) comprised control non-cirrhotic rats. The rats of the second group (n = 27) were administered carbon tetrachloride (CCl4) by intraperitoneal injection to induce liver cirrhosis. The cirrhotic rats were then divided into three equal subgroups, each comprising nine animals, as follows: (i) cirrhotic rats, (ii) cirrhotic rats treated with camel milk, and (iii) cirrhotic rats treated with camel milk and bee honey. The present findings revealed that CCl4 elevated the activities of liver enzymes, blood glucose levels, non-esterified fatty acids (NEFA) in the serum and glycogen content in the liver. On the other hand, CCl4 significantly decreased phosphorylase activity in the liver tissue and significantly increased carbohydrate intolerance and insulin resistance index (HOMA-IR). Moreover, CCl4 induced a significant increase in oxidative stress, along with increased expression of the profibrotic cytokine genes TNF-α and TGF-β. However, camel milk either alone or in combination with bee honey ameliorated these toxic actions. The antioxidant properties of these protective agents and their effects of downregulating certain procirrhotic cytokine gene transcripts underlie this protection.

  1. Feeding a high dosage of zinc oxide affects suppressor of cytokine gene expression in Salmonella Typhimurium infected piglets.

    Science.gov (United States)

    Schulte, Jasper N; Brockmann, Gudrun A; Kreuzer-Redmer, Susanne

    2016-10-01

    Suppressor of cytokine signaling (SOCS) proteins play an important role in the regulation of the immune response by inhibiting cytokines. Here we investigated the effects of zinc oxide fed at three different dosages (LZN=57ppm, MZN=167ppm, HZN=2425ppm) to weaned piglets that were or were not orally infected with Salmonella enterica serovar Typhimurium DT 104. We detected higher expression of SOCS3 six days after weaning for all analyzed piglets, regardless of the infection or the zinc feeding, suggesting a stress induced immune response. Whereas, SOCS1 showed only higher transcript amounts in S. Typhimurium infected piglets, especially the LZN group. This might indicate an infection regulating effect of zinc oxide in the infection model. After 42days of infection, the expression of SOCS2, SOCS4, and SOCS7 was increased only in animals fed the highest concentrations of zinc oxide, while non-infected piglets at the age of 56days showed no regulation for these genes. The up-regulation of SOCS genes in the mesenteric lymph nodes of piglets fed a diet with a very high concentration of zinc over 6 weeks suggests that such treatments may impair the immune response. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Cytokine gene associations with self-report ratings of morning and evening fatigue in oncology patients and their family caregivers.

    Science.gov (United States)

    Dhruva, Anand; Aouizerat, Bradley E; Cooper, Bruce; Paul, Steven M; Dodd, Marylin; West, Claudia; Wara, William; Lee, Kathryn; Dunn, Laura B; Langford, Dale J; Merriman, John D; Baggott, Christina; Cataldo, Janine; Ritchie, Christine; Kober, Kord M; Leutwyler, Heather; Miaskowski, Christine

    2015-03-01

    The purpose of this study was to evaluate for differences in variations in pro- and anti-inflammatory cytokine genes between participants who were classified as having low and high levels of morning and evening fatigue and to evaluate for differences in phenotypic characteristics between these two groups. In a sample of 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their family caregivers, growth mixture modeling was used to identify latent classes of individuals based on ratings of morning and evening fatigue obtained prior to, during, and for 4 months following completion of radiation therapy. Differences in single nucleotide polymorphisms and haplotypes in 15 cytokine genes were evaluated between the latent classes. Multiple logistic regression was used to assess the effect of phenotypic and genotypic characteristics on morning and evening fatigue class membership. Associations were found between morning fatigue and number of comorbidities as well as variations in tumor necrosis factor alpha (TNFA) rs1800629 and rs3093662. Evening fatigue was associated with caring for children at home and variations in interleukin 4 (IL4) rs2243248 and TNFA rs2229094. Younger age and lower performance status were associated with both morning and evening fatigue. These findings suggest that inflammatory mediators are associated with the development of morning and evening fatigue. However, because different phenotypic characteristics and genomic markers are associated with diurnal variations in fatigue, morning and evening fatigue may be distinct but related symptoms. © The Author(s) 2014.

  3. Cytokine Gene Associations with Self-report Ratings of Morning and Evening Fatigue in Oncology Patients and Their Family Caregivers

    Science.gov (United States)

    Dhruva, Anand; Aouizerat, Bradley E.; Cooper, Bruce; Paul, Steven M.; Dodd, Marylin; West, Claudia; Wara, William; Lee, Kathryn; Dunn, Laura B.; Langford, Dale J.; Merriman, John D.; Baggott, Christina; Cataldo, Janine; Ritchie, Christine; Kober, Kord M.; Leutwyler, Heather; Miaskowski, Christine

    2017-01-01

    The purpose of this study was to evaluate for differences in variations in pro- and anti-inflammatory cytokine genes between participants who were classified as having low and high levels of morning and evening fatigue and to evaluate for differences in phenotypic characteristics between these two groups. In a sample of 167 oncology outpatients with breast, prostate, lung, or brain cancer and 85 of their family caregivers, growth mixture modeling (GMM) was used to identify latent classes of individuals based on ratings of morning and evening fatigue obtained prior to, during, and for 4 months following completion of radiation therapy. Differences in single nucleotide polymorphisms (SNPs) and haplotypes in 15 cytokine genes were evaluated between the latent classes. Multiple logistic regression was used to assess the effect of phenotypic and genotypic characteristics on morning and evening fatigue class membership. Associations were found between morning fatigue and number of comorbidities as well as variations in TNFA rs1800629 and rs3093662. Evening fatigue was associated with caring for children at home and variations in IL4 rs2243248 and TNFA rs2229094. Younger age and lower performance status was associated with both morning and evening fatigue. These findings suggest that inflammatory mediators are associated with the development of morning and evening fatigue. However, because different phenotypic characteristics and genomic markers are associated with diurnal variations in fatigue, morning and evening fatigue may be distinct but related symptoms. PMID:24872120

  4. Dysregulation of temperature and liver cytokine gene expression in immunodeficient wasted mice

    Energy Technology Data Exchange (ETDEWEB)

    Libertin, C.R. [Loyola Univ. Medical Center, Maywood, IL (United States); Ling-Indeck, L.; Weaver, P. [Loyola Univ. Medical Center, Maywood, IL (United States). Dept. of Pathology; Chang-Liu, Chin-Mei; Strezoska, V.; Heckert, B. [Argonne National Lab., IL (United States). Center for Mechanistic Biology and Biotechnology; Woloschak, G.E. [Loyola Univ. Medical Center, Maywood, IL (United States). Dept. of Pathology]|[Argonne National Lab., IL (United States). Center for Mechanistic Biology and Biotechnology

    1995-04-25

    Wasted mice bear the spontaneous autosomal recessive mutation wst/wst; this genotype is associated with weight loss beginning at 21 days of age, neurologic dysfunction, immunodeficiency at mucosal sites, and increased sensitivity to the killing effects of ionizing radiation. The pathology underlying the disease symptoms is unknown. Experiments reported here were designed to examine thermoregulation and liver expression of specific cytokines in wasted mice and in littermate and parental controls. Our experiments found that wasted mice begin to show a drop in body temperature at 21-23 days following birth, continuing until death at the age of 28 days. Concomitant with that, livers from wasted mice expressed increased amounts of mRNAs specific for cytokines IL,6 and IL-1, the acute phase reactant C-reactive protein, c-jun, and apoptosis-associated Rp-8 when compared to littermate and parental control animals. Levels of {beta}-transforming growth factor (TGF), c-fos, proliferating cell nuclear antigen (PCNA), and ornithine amino transferase (OAT) transcripts were the same in livers from wasted mice and controls. These results suggest a relationship between an acute phase reactant response in wasted mice and temperature dysregulation.

  5. Expression of cytokine genes in head kidney and spleen cells of Japanese flounder (Paralichthys olivaceus) infected with Nocardia seriolae.

    Science.gov (United States)

    Tanekhy, M; Matsuda, S; Itano, T; Kawakami, H; Kono, T; Sakai, M

    2010-04-15

    Nocardiosis caused by Nocardia seriolae is an important disease affecting marine fish for which neither control nor preventive measures are available. In this study, we investigated cytokine gene expression in Japanese flounder (Paralichthys olivaceus) infected with N. seriolae to understand the innate immune response. Japanese flounder were challenged with different concentrations of N. seriolae suspensions (0, 1, and 10 mg/L) by immersion for 10min. Mortality was 75% and 95% in fish infected by 1 and 10 mg/L, respectively. The expression of cytokine genes (TNF-alpha, IL-1beta, CC-chemokine) in head kidney and spleen cells to N. seriolae challenge was investigated 2, 24 h, 3 days, and 10 days post-challenge. TNF-alpha expression was significantly increased in spleen after 24 h in 1 mg/L group and in HK after 2 h in 10 mg/L group, but after 24 h and 3 days in 10 mg/L group and after 3 days in 1 mg/L group, it was significantly decreased. IL-1beta expression was significantly up-regulated in spleen after 24 h in 1 mg/l group while in HK only after 2 h in 10 mg/L group before suddenly down-regulated significantly 24 h in 10 mg/L group. The expression of CC-chemokine gene in both spleen and HK was significantly up-regulated in 10 mg/L group 2 h post-challenge and down-regulated in HK after 24 h and after 10 days in 1 mg/L group in spleen, compared to the control group. Copyright 2009 Elsevier B.V. All rights reserved.

  6. Characterization of porcine cytokine inducible SH2-containing protein gene and its association with piglet diarrhea traits

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    Buyue Niu

    2017-12-01

    Full Text Available Objective The cytokine inducible SH2-containing protein (CISH, which might play a role in porcine intestine immune responses, was one of the promising candidate genes for piglet anti-disease traits. An experiment was conducted to characterize the porcine CISH (pCISH gene and to evaluate its genetic effects on pig anti-disease breeding. Methods Both reverse transcription polymerase chain reaction (RT-PCR and PCR were performed to obtain the sequence of pCISH gene. A pEGFP-C1-CISH vector was constructed and transfected into PK-15 cells to analysis the distribution of pCISH. The sequences of individuals were compared with each other to find the polymorphisms in pCISH gene. The association analysis was performed in Min pigs and Landrace pigs to evaluate the genetic effects on piglet diarrhea traits. Results In the present research, the coding sequence and genomic sequence of pCISH gene was obtained. Porcine CISH was mainly localized in cytoplasm. TaqI and HaeIII PCR restriction fragment length polymorphism (RFLP assays were established to detect single nucleotide polymorphisms (SNPs; A-1575G in promoter region and A2497C in Intron1, respectively. Association studies indicated that SNP A-1575G was significantly associated with diarrhea index of Min piglets (p<0.05 and SNP A2497C was significantly associated with the diarrhea trait of both Min pig and Landrace piglets (p<0.05. Conclusion This study suggested that the pCISH gene might be a novel candidate gene for pig anti-disease traits, and further studies are needed to confirm the results of this preliminary research.

  7. Discovery of potential new gene variants and inflammatory cytokine associations with fibromyalgia syndrome by whole exome sequencing.

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    Jinong Feng

    Full Text Available Fibromyalgia syndrome (FMS is a chronic musculoskeletal pain disorder affecting 2% to 5% of the general population. Both genetic and environmental factors may be involved. To ascertain in an unbiased manner which genes play a role in the disorder, we performed complete exome sequencing on a subset of FMS patients. Out of 150 nuclear families (trios DNA from 19 probands was subjected to complete exome sequencing. Since >80,000 SNPs were found per proband, the data were further filtered, including analysis of those with stop codons, a rare frequency (<2.5% in the 1000 Genomes database, and presence in at least 2/19 probands sequenced. Two nonsense mutations, W32X in C11orf40 and Q100X in ZNF77 among 150 FMS trios had a significantly elevated frequency of transmission to affected probands (p = 0.026 and p = 0.032, respectively and were present in a subset of 13% and 11% of FMS patients, respectively. Among 9 patients bearing more than one of the variants we have described, 4 had onset of symptoms between the ages of 10 and 18. The subset with the C11orf40 mutation had elevated plasma levels of the inflammatory cytokines, MCP-1 and IP-10, compared with unaffected controls or FMS patients with the wild-type allele. Similarly, patients with the ZNF77 mutation have elevated levels of the inflammatory cytokine, IL-12, compared with controls or patients with the wild type allele. Our results strongly implicate an inflammatory basis for FMS, as well as specific cytokine dysregulation, in at least 35% of our FMS cohort.

  8. The cytokine-mediated crosstalk between primary human acute myeloid cells and mesenchymal stem cells alters the local cytokine network and the global gene expression profile of the mesenchymal cells

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    Håkon Reikvam

    2015-11-01

    Full Text Available Interactions between acute myeloid leukemia (AML blasts and neighboring stromal cells are important for disease development and chemosensitivity. However, the molecular mechanisms involved in the cytokine-mediated crosstalk between mesenchymal stem cells (MSCs and AML cells are largely unknown. Leukemic cells derived from 18 unselected AML patients were cultured with bone marrow MSCs derived from healthy donors; the populations then being separated by a semipermeable membrane. Coculture had only minor effects on MSC proliferation. The unique cytokine network in cocultures was determined by high constitutive MSC release of certain cytokines (especially IL-6 and vascular endothelial growth factor and constitutive release of a wide range of soluble mediators by primary AML cells. However, the AML cell release varied considerably between patients, and these differences between patients were also reflected in the coculture levels even though supra-additive effects were seen for many mediators. These effects on the local cytokine network were dependent on a functional crosstalk between the two cell subsets. The crosstalk altered the global gene expression profile of the MSCs, especially expression of genes encoding proteins involved in downstream signaling from Toll like receptors, NFκB signaling and CCL/CXCL chemokine release. Thus, primary AML cells alter the functional phenotype of normal MSCs.

  9. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines.

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    Décio L Eizirik

    Full Text Available Type 1 diabetes (T1D is an autoimmune disease in which pancreatic beta cells are killed by infiltrating immune cells and by cytokines released by these cells. Signaling events occurring in the pancreatic beta cells are decisive for their survival or death in diabetes. We have used RNA sequencing (RNA-seq to identify transcripts, including splice variants, expressed in human islets of Langerhans under control conditions or following exposure to the pro-inflammatory cytokines interleukin-1β (IL-1β and interferon-γ (IFN-γ. Based on this unique dataset, we examined whether putative candidate genes for T1D, previously identified by GWAS, are expressed in human islets. A total of 29,776 transcripts were identified as expressed in human islets. Expression of around 20% of these transcripts was modified by pro-inflammatory cytokines, including apoptosis- and inflammation-related genes. Chemokines were among the transcripts most modified by cytokines, a finding confirmed at the protein level by ELISA. Interestingly, 35% of the genes expressed in human islets undergo alternative splicing as annotated in RefSeq, and cytokines caused substantial changes in spliced transcripts. Nova1, previously considered a brain-specific regulator of mRNA splicing, is expressed in islets and its knockdown modified splicing. 25/41 of the candidate genes for T1D are expressed in islets, and cytokines modified expression of several of these transcripts. The present study doubles the number of known genes expressed in human islets and shows that cytokines modify alternative splicing in human islet cells. Importantly, it indicates that more than half of the known T1D candidate genes are expressed in human islets. This, and the production of a large number of chemokines and cytokines by cytokine-exposed islets, reinforces the concept of a dialog between pancreatic islets and the immune system in T1D. This dialog is modulated by candidate genes for the disease at both the

  10. Allele and genotype frequencies of polymorphisms in cytokine genes in ethnic Russian individuals from Moscow, Russia.

    Science.gov (United States)

    Shadrina, Alexandra; Voronina, Elena; Zolotukhin, Igor; Filipenko, Maxim

    2017-02-01

    Two hundred and twenty eight ethnic Russian individuals from Moscow, Russia, were genotyped at 14 single nucleotide polymorphisms CCL2 A-2578G; VEGFA C-2578A, G-634C, and C+936T; TNF G+419A and G-308A; IL1A G-889A; IL1RN T+1018C; IL6G-174C and G-572C; IFNG T+874A; IL1B C-511T; IL10 A+1082G; TGFB1 C-509T. Genotypes were determined using real-time polymerase chain reaction with TaqMan probes and polymerase chain reaction followed by melting analysis of dual-labeled probe. Genotype distribution was in accordance with Hardy-Weinberg equilibrium for all studied polymorphisms. Genotype data are available in the Allele Frequencies Net Database under identifier AFND 3367 and the population name "Russia Moscow Cytokine". Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  11. The Relevance of Coding Gene Polymorphysms of Cytokines and Cellular Receptors in Sepsis

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    Georgescu Anca Meda

    2017-02-01

    Full Text Available Sepsis is an injurious systemic host response to infection, which can often lead to septic shock and death. Recently, the immune-pathogenesis and genomics of sepsis have become a research topic focusing on the establishment of diagnostic and prognostic biomarkers. As yet, none have been identified as having the necessary specificity to be used independently of other factors in this respect. However the accumulation of current evidence regarding genetic variations, especially the single nucleotide polymorphisms (SNPs of cytokines and other innate immunity determinants, partially explains the susceptibility and individual differences of patients with regard to the evolution of sepsis. This article outlines the role of genetic variation of some serum proteins which have the potential to be used as biomarker values in evaluating sepsis susceptibility and the progression of the condition.

  12. Gene deleted live attenuated Leishmania vaccine candidates against visceral leishmaniasis elicit pro-inflammatory cytokines response in human PBMCs.

    Science.gov (United States)

    Avishek, Kumar; Kaushal, Himanshu; Gannavaram, Sreenivas; Dey, Ranadhir; Selvapandiyan, Angamuthu; Ramesh, V; Negi, Narender Singh; Dubey, Uma S; Nakhasi, Hira L; Salotra, Poonam

    2016-09-14

    Currently no effective vaccine is available for human visceral leishmaniasis(VL) caused by Leishmania donovani. Previously, we showed that centrin1 and p27gene deleted live attenuated Leishmania parasites (LdCen1(-/-) and Ldp27(-/-)) are safe, immunogenic and protective in animal models. Here, to assess the correlates of protection, we evaluated immune responses induced by LdCen1(-/-) and Ldp27(-/-) in human blood samples obtained from healthy, healed VL (HVL), post kala-azar dermal leishmaniasis(PKDL) and VL subjects. Both parasites infected human macrophages, as effectively as the wild type parasites. Further, LdCen1(-/-) and Ldp27(-/-) strongly stimulated production of pro-inflammatory cytokines including, IL-12, IFN-γ, TNF-α, IL-2, IL-6 and IL-17 in the PBMCs obtained from individuals with a prior exposure to Leishmania (HVL and PKDL). There was no significant stimulation of anti-inflammatory cytokines (IL-4 and IL-10). Induction of Th1 biased immune responses was supported by a remarkable increase in IFN-γ secreting CD4(+) and CD8(+) T cells and IL-17 secreting CD4(+) cells in PBMCs from HVL cases with no increase in IL-10 secreting T cells. Hence, LdCen1(-/-) and Ldp27(-/-) are promising as live vaccine candidates against VL since they elicit strong protective immune response in human PBMCs from HVL, similar to the wild type parasite infection, mimicking a naturally acquired protection following cure.

  13. Baboon envelope pseudotyped LVs outperform VSV-G-LVs for gene transfer into early-cytokine-stimulated and resting HSCs.

    Science.gov (United States)

    Girard-Gagnepain, Anais; Amirache, Fouzia; Costa, Caroline; Lévy, Camille; Frecha, Cecilia; Fusil, Floriane; Nègre, Didier; Lavillette, Dimitri; Cosset, François-Loïc; Verhoeyen, Els

    2014-08-21

    Hematopoietic stem cell (HSC)-based gene therapy holds promise for the cure of many diseases. The field is now moving toward the use of lentiviral vectors (LVs) as evidenced by 4 successful clinical trials. These trials used vesicular-stomatitis-virus-G protein (VSV-G)-LVs at high doses combined with strong cytokine-cocktail stimulation to obtain therapeutically relevant transduction levels; however, they might compromise the HSC character. Summarizing all these disadvantages, alternatives to VSV-G-LVs are urgently needed. We generated here high-titer LVs pseudotyped with a baboon retroviral envelope glycoprotein (BaEV-LVs), resistant to human complement. Under mild cytokine prestimulation to preserve the HSC characteristics, a single BaEV-LV application at a low dose, resulted in up to 90% of hCD34(+) cell transduction. Even more striking was that these new BaEV-LVs allowed, at low doses, efficient transduction of up to 30% of quiescent hCD34(+) cells, whereas high-dose VSV-G-LVs were insufficient. Importantly, reconstitution of NOD/Lt-SCID/γc(-/-) (NSG) mice with BaEV-LV-transduced hCD34(+) cells maintained these high transduction levels in all myeloid and lymphoid lineages, including early progenitors. This transduction pattern was confirmed or even increased in secondary NSG recipient mice. This suggests that BaEV-LVs efficiently transduce true HSCs and could improve HSC-based gene therapy, for which high-level HSC correction is needed for life-long cure. © 2014 by The American Society of Hematology.

  14. [The influence of interleukin gene polymorphism on the serum cytokine level in the patients presenting with chonic suppurative otitis media].

    Science.gov (United States)

    Baike, E V; Vitkovsky, Yu A; Dutova, A A

    The objective of the present work was to study the influence of allelic variant associations of 1-beta interleukin (C3953T, &511C, T31C), interleukin-6 (C174G), and tumour necrosis factor-alpha (G308A) gene polymorphisms on the serum cytokine level in the patients presenting with chronic suppurative otitis media. A total of 299 patients at the age varying from 16 to 55 years with this condition divided into three groups were examined. Group 1 was comprised of 146 patients suffering from the tubotympanic form of chronic suppurative otitis media (CSOM). Group 2 was composed of 153 patients with epitympanic antral form of this condition. The control group included 183 subjects who have never suffered pathological changes in the middle ear. Human genomic DNA was analyzed with the use of the polymerase chain reaction (PCR). The serum cytokine levels were measured by the solid-state enzyme immunoassay in the beginning and at the end of the treatment period. The study has demonstrated that 56.2% of the healthy residents of the trans-Baikal region had the C/T Il-1b (C3953T) genotype. 79.1% of the patients presenting with the carious carious-destructive form of chronic suppurative otitis media were the heterozygous carriers of the T511C gene of 1-beta interleukin and had the maximally high concentrations of this interleukin in the blood serum. A rise in the production of the pro-inflammatory mediator (IL-6) was found to be related to the severity of the inflammatory process in the middle ear. The TNF-alpha content in the patients with CSOM during the active period of the disease proved to increase by a factor of 6 in comparison with that in the subjects of the control group irrespective of the type of mutation.

  15. Low-dose gamma-rays and simulated solar particle event protons modify splenocyte gene and cytokine expression patterns.

    Science.gov (United States)

    Rizvi, Asma; Pecaut, Michael J; Gridley, Daila S

    2011-01-01

    The goal was to investigate the T helper (Th) response in splenocytes of mice exposed to low-dose/low-dose-rate (LDR) γ-rays, simulated solar particle event protons (sSPE), or combination of both. C57BL/6 mice were exposed to LDR γ-radiation ((57)Co) to a total dose of 0.05 Gray (Gy) at 0.024 cGy/h, either with or without subsequent exposure to 2 Gy sSPE protons. Expression of genes related to Th cells was evaluated immediately after exposure (day 0). On day 21, intra- and extracellular cytokine production was assessed after activation with anti-CD3 monoclonal antibodies (mAb) or phorbol 12-myristate 13-acetate/ionophore (PMA/I). Five genes were significantly modulated on day 0 in one or more of the irradiated groups compared to controls (p < 0.05): Ccl11, Ccr5, Cd80, Inha, and Il9. On day 21, numbers of cells positive for interferon-γ were high in the LDR + sSPE group versus 0 Gy and LDR γ-rays (p < 0.05), but there was no difference in IL-2 and TNF-α. Levels of secreted cytokines after anti-CD3 mAb activation were high for 5 (MIP-1α, GM-CSF, IFN-γ, TNF-α, IL-13) and low for 2 (IL-7, IL-9) in all irradiated groups. Priming with LDR photons had a significant effect on IFN-γ and IL-17 compared to sSPE protons alone; IL-2 was low only in the LDR + sSPE group. The cytokine patterns after anti-PMA/I activation were different compared to anti-CD3 mAb and with fewer differences among groups. The data show that total-body exposure to space-relevant radiation has profound effects on Th cell status and that priming with LDR γ-rays can in some cases modulate the response to sSPE.

  16. Comparative genomic analysis reveals independent expansion of a lineage-specific gene family in vertebrates: The class II cytokine receptors and their ligands in mammals and fish

    Directory of Open Access Journals (Sweden)

    Mogensen Knud

    2003-07-01

    Full Text Available Abstract Background The high degree of sequence conservation between coding regions in fish and mammals can be exploited to identify genes in mammalian genomes by comparison with the sequence of similar genes in fish. Conversely, experimentally characterized mammalian genes may be used to annotate fish genomes. However, gene families that escape this principle include the rapidly diverging cytokines that regulate the immune system, and their receptors. A classic example is the class II helical cytokines (HCII including type I, type II and lambda interferons, IL10 related cytokines (IL10, IL19, IL20, IL22, IL24 and IL26 and their receptors (HCRII. Despite the report of a near complete pufferfish (Takifugu rubripes genome sequence, these genes remain undescribed in fish. Results We have used an original strategy based both on conserved amino acid sequence and gene structure to identify HCII and HCRII in the genome of another pufferfish, Tetraodon nigroviridis that is amenable to laboratory experiments. The 15 genes that were identified are highly divergent and include a single interferon molecule, three IL10 related cytokines and their potential receptors together with two Tissue Factor (TF. Some of these genes form tandem clusters on the Tetraodon genome. Their expression pattern was determined in different tissues. Most importantly, Tetraodon interferon was identified and we show that the recombinant protein can induce antiviral MX gene expression in Tetraodon primary kidney cells. Similar results were obtained in Zebrafish which has 7 MX genes. Conclusion We propose a scheme for the evolution of HCII and their receptors during the radiation of bony vertebrates and suggest that the diversification that played an important role in the fine-tuning of the ancestral mechanism for host defense against infections probably followed different pathways in amniotes and fish.

  17. Gene expression profiles of inducible nitric oxide synthase and cytokines in Leishmania major-infected macrophage-like RAW 264.7 cells treated with gallic acid

    NARCIS (Netherlands)

    Radtke, O.A.; Kiderlen, A.F.; Kayser, Oliver; Kolodziej, H

    2004-01-01

    The effects of gallic acid on the gene expressions of inducible nitric oxide synthase (iNOS) and the cytokines interleukin (IL)-1, IL-10, IL-12, IL-18, TNF-alpha, and interferon (IFN)-gamma were investigated by reverse-transcription polymerase chain reaction (RT-PCR). The experiments were performed

  18. Risk of cervical cancer associated with allergies and polymorphisms in genes in the chromosome 5 cytokine cluster.

    Science.gov (United States)

    Johnson, Lisa G; Schwartz, Stephen M; Malkki, Mari; Du, Qin; Petersdorf, Effie W; Galloway, Denise A; Madeleine, Margaret M

    2011-01-01

    Human papillomavirus is the acknowledged cause of cervical cancer. We hypothesized that allergies, characterized by hyperimmune reaction to common allergens and which have been associated with various cancers, may be related to cervical cancer, and that genetic variation in cytokine genes related to allergies might impact cervical cancer risk. We investigated the risk of invasive squamous cell cervical cancer (SCC) associated with self-reported allergies and with variation in allergy-related cytokine genes using data from a case-control study (561 cases, 1,258 controls) conducted in Washington State. Logistic regression models yielded odds ratios (OR) and 95% CI. Pollen allergy, the most commonly reported allergy, was associated with reduced SCC risk (OR: 0.6; 95% CI: 0.5-0.8). Of 60 tagging single-nucleotide polymorphisms covering eight genes (CSF2, IL3, IL4, IL13, CSF2RB, IL4R, IL13RA1, IL13RA2), several were related to pollen allergies among controls: IL4R rs3024647 (dominant OR: 1.5; 95% CI: 1.0-2.3; P = 0.04), CSF2RB rs16997517 (dominant OR: 2.2; 95% CI: 1.0-4.7; P = 0.04), and IL13 rs1800925 (per-allele OR: 1.7; 95% CI: 1.3-2.4; P = 0.0007). Two variants were inversely associated with SCC risk: IL4R rs3024656 (per-allele OR: 0.8; 95% CI: 0.6-1.0; P = 0.03) and CSF2RB rs16997517 (dominant OR: 0.4; 95% CI: 0.2-0.9; P = 0.04). Pollen allergies were related to reduced SCC risk. CSF2RB rs16997517 was directly related to pollen allergies in controls and to reduced SCC risk. If other studies confirm these results, the mechanism behind allergy-associated immune response associated with SCC risk may be worth exploring in the context of therapeutic or prophylactic vaccines. ©2011 AACR.

  19. The role of single nucleotide polymorphisms of cytokine genes in viral infections

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    Ćupić Maja

    2014-01-01

    Full Text Available Gene polymorphisms result from evolutionary processes representing mutations that survive in the population with a frequency higher than 1%. The most investigated type of gene polymorphisms are single nucleotide polymorphisms (SNPs. The SNPs of IL-12B (rs 3212227 A/C among a population of kidney graft CMV-seropositive recipients have an impact on a clinical events in cytomegalovirus (CMV disease. Constitutive -308 G/A TNF-α polymorphism (rs1800629 is related to the susceptibility of HR-HPV-associated cervical dysplasia and cancer. SNP located 3 kb upstream of the IL- 28B gene (rs12979860 seems to be the strongest host genetic predictor of sustained virologic response (SVR in hepatitis C genotype 1 patients. It is very important to identify viral and host genetic markers that may facilitate the risk of developing viral disease or some viral-associated cancers. In addition, these markers could be useful in the choice of effective treatments and preventive strategies against virally induced infection. [Projekat Ministarstva nauke Republike Srbije, br. 175073 i br. 175038

  20. The anorexigenic cytokine ciliary neurotrophic factor stimulates POMC gene expression via receptors localized in the nucleus of arcuate neurons.

    Science.gov (United States)

    Couvreur, Odile; Aubourg, Alain; Crépin, Delphine; Degrouard, Jéril; Gertler, Arieh; Taouis, Mohammed; Vacher, Claire-Marie

    2012-02-15

    Ciliary neurotrophic factor (CNTF) is a neural cytokine that reduces appetite and body weight when administrated to rodents or humans. We have demonstrated recently that the level of CNTF in the arcuate nucleus (ARC), a key hypothalamic region involved in food intake regulation, is positively correlated with protection against diet-induced obesity. However, the comprehension of the physiological significance of neural CNTF action was still incomplete because CNTF lacks a signal peptide and thus may not be secreted by the classical exocytosis pathways. Knowing that CNTF distribution shares similarities with that of its receptor subunits in the rat ARC, we hypothesized that CNTF could exert a direct intracrine effect in ARC cells. Here, we demonstrate that CNTF, together with its receptor subunits, translocates to the cell nucleus of anorexigenic POMC neurons in the rat ARC. Furthermore, the stimulation of hypothalamic nuclear fractions with CNTF induces the phosphorylation of several signaling proteins, including Akt, as well as the transcription of the POMC gene. These data strongly suggest that intracellular CNTF may directly modulate POMC gene expression via the activation of receptors localized in the cell nucleus, providing a novel plausible mechanism of CNTF action in regulating energy homeostasis.

  1. The Relationship between the Antitumor Effect of the IL-12 Gene Therapy and the Expression of Th1 Cytokines in an HPV16-Positive Murine Tumor Model

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    Flor García Paz

    2014-01-01

    Full Text Available Objective. The goal of the present study was to investigate the effect of IL-12 expressed in plasmid on the Th1 cytokine profile in an experimental HPV16-positive murine tumor model and the association with the IL-12’s antitumor effect. Methods. Mice were injected with BMK-16/myc cells to establish HPV16-positive tumor and then pNGVL3-mIL-12 plasmid; pcDNA3 plasmid or PBS was injected directly into tumor site. The antitumor effect of the treatment was evaluated and the cytokines expression profile in each tumor tissue was analyzed. Results. Treatment with pNGVL3-mIL-12 plasmid had a significant antitumor effect, and a Th2-Th3-type cytokines prolife was detected in the murine tumor model with expression of the cytokines IL-10, IL-4, and TGF-β1. However, after the tumor was treated with three intratumoral injections of plasmid containing IL-12 cDNA, it showed a cytokine profile associated with Th1 with expression of IL-2, IL-12, and IFN-γ cytokines and reduced expression of IL-10, IL-4, and TGF-β1. Conclusions. The treatment with the IL-12 gene in the experimental HPV16-positive tumor model promoted the activation of the cellular immune response via expression of a Th1-type cytokine profile and was associated with the inhibition of tumor growth. Thus, IL-12 treatment represents a novel approach for gene therapy against cervical cancer.

  2. Hemorrhagic Shock-Induced Vascular Hyporeactivity in the Rat: Relationship to Gene Expression of Nitric Oxide Synthase, Endothelin-1, and Select Cytokines in Corresponding Organs

    Science.gov (United States)

    2005-01-01

    Parvathaneni, L. S., Bourlier, V., Sauter, C., Laubach, V. E., and Cobb, J. P. iNOS gene expression modu- lates microvascular responsiveness in endotoxin...Burtrum, D., and Silerstein, F. S. Cerebral hypoxia-ischemia stimulates cytokine gene expression in peri- natal rats. Stroke 26: 1093, 1995. 22...Mattson, D. L., and Wu, F. Nitric oxide synthase activity and isoforms in rat renal vasculature. Hypertension 35: 337, 2000. 23. Thiemermann, C., Szabó, C

  3. Terapia génica con citocinas contra cáncer cervicouterino Gene therapy with cytokines against cervical cancer

    Directory of Open Access Journals (Sweden)

    Víctor Hugo Bermúdez-Morales

    2005-12-01

    Full Text Available La terapia génica es una excelente alternativa para el tratamiento de muchas enfermedades. La capacidad para manipular el DNA ha permitido dirigir la terapia génica para corregir la función de un gen alterado, aumentar la expresión de un gen o activar la respuesta inmune. Así, se puede proponer el uso del DNA como un medicamento capaz de controlar, corregir o curar una enfermedad. La terapia génica contra cáncer tiene un potencial enorme, y en la última década se han obtenido resultados muy alentadores del uso del DNA para controlar diversas neoplasias en modelos animales, lo cual ha permitido su aplicación en protocolos experimentales en humanos. Esta revisión concentra una reseña de los fundamentos de la terapia génica y su aplicación en cáncer cervical, desde el punto de vista de las alteraciones de la respuesta inmune enfocadas al microambiente tumoral y el uso de las citocinas como moduladores de la respuesta inmune.Gene therapy is an excellent alternative for treatment of many diseases. Capacity to manipulate the DNA has allowed direct the gene therapy to correct the function of an altered gene, to increase the expression of a gene and to favour the activation of the immune response. This way, it can intend the use of the DNA like medication able to control, to correct or to cure many diseases. Gene therapy against cancer has an enormous potential, and actually the use of the DNA has increased to control diverse cancer in animal models, with very encouraging results that have allowed its applications in experimental protocols in human. This work concentrates a review of the foundations of the gene therapy and its application on cervical cancer, from the point of view of the alterations of the immune system focused on the tumour micro-environment, and the use of the cytokines as immunomodulators.

  4. Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-kappaB activation

    DEFF Research Database (Denmark)

    Ortis, Fernanda; Cardozo, Alessandra K; Crispim, Daisy

    2006-01-01

    Cytokines, such as IL-1beta and TNF-alpha, contribute to pancreatic beta-cell death in type 1 diabetes mellitus. The transcription factor nuclear factor-kappaB (NF-kappaB) mediates cytokine-induced beta-cell apoptosis. Paradoxically, NF-kappaB has mostly antiapoptotic effects in other cell types......-kappaB activation in insulin-producing cells is more rapid, marked, and sustained than in fibroblasts, which correlates with a more pronounced activation of downstream genes and a proapoptotic outcome....

  5. Inflammatory cytokine gene polymorphisms increase the risk of atrophic gastritis and intestinal metaplasia.

    Science.gov (United States)

    Li, Zhong-Wu; Wu, Ying; Sun, Yu; Liu, Lu-Ying; Tian, Meng-Meng; Feng, Guo-Shuang; You, Wei-Cheng; Li, Ji-You

    2010-04-14

    To investigate the effects of interleukin-8 (IL-8), macrophage migration inhibitory factor (MIF) gene polymorphisms, Helicobacter pylori (H. pylori) infection, on the risk of developing severe chronic atrophic gastritis (SCAG) and intestinal metaplasia (IM). A total of 372 cases were selected from a cohort study in Linqu County, a high risk area for gastric cancer (GC) in northern China. To obtain a sufficient group size, patients with normal or superficial gastritis were included. Based on an average follow-up period of 56 mo, the 372 cases were divided into no progression group (no histological progression from normal or superficial gastritis, n = 137), group I (progressed from normal or superficial gastritis to SCAG, n = 134) and group II (progressed from normal or superficial gastritis to IM, n = 101). IL-8, MIF gene polymorphisms were detected by polymerase chain reaction-based denaturing high-performance liquid chromatography analysis and DNA sequencing. An increased risk of SCAG was found in subjects with IL-8-251 AA genotype [odds ratio (OR) = 2.62, 95% CI: 1.23-5.72] or IL-8-251 A allele carriers (AA + AT) (OR = 1.81, 95% CI: 1.06-3.09). An elevated risk of IM was found in subjects with IL-8-251 AT genotype (OR = 2.27, 95% CI: 1.25-4.14) or IL-8-251 A allele carriers (OR = 2.07, 95% CI: 1.16-3.69). An increased risk of SCAG was found in subjects with MIF-173 GC genotype (OR = 2.36, 95% CI: 1.38-4.02) or MIF-173 C allele carriers (GC + CC) (OR = 2.07, 95% CI: 1.21-3.55). An elevated risk of IM was found in subjects with MIF-173 CC genotype (OR = 2.27, 95% CI: 1.16-4.46) or MIF-173 C allele carriers (OR = 3.84, 95% CI: 1.58-9.34). The risk of SCAG and IM was more evident in subjects carrying IL-8-251 A allele (OR = 6.70, 95% CI: 1.29-9.78) or MIF-173 C allele (OR = 6.54, 95% CI: 2.97-14.20) and positive for H. pylori infection. IL-8-251 and MIF-173 gene polymorphisms are significantly associated with the risk of SCAG and IM in a population with a high risk

  6. Dataset of proinflammatory cytokine and cytokine receptor gene expression in rainbow trout (Oncorhynchus mykiss) measured using a novel GeXP multiplex, RT-PCR assay

    Science.gov (United States)

    A GeXP multiplex, RT-PCR assay was developed and optimized that simultaneously measures expression of a suite of immune-relevant genes in rainbow trout (Oncorhynchus mykiss), concentrating on tumor necrosis factor and interleukin-1 ligand/receptor systems and acute phase response genes. The dataset ...

  7. Inflammation-related cytokine gene polymorphisms in Behçet’s disease

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    Al-Okaily F

    2015-09-01

    Full Text Available Fahda Al-Okaily,1 Misbahul Arfin,2 Seham Al-Rashidi,1 Maysoon Al-Balawi,1 Abdulrahman Al-Asmari2 1Department of Rheumatology, 2Division of Molecular Biology and Genetics, Research Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia Abstract: Behçet’s disease (BD is a complex, multisystemic inflammatory disorder of unclear etiology. Single nucleotide polymorphisms in tumor necrosis factor (TNF and interleukin (IL-10 genes have been implicated in susceptibility to BD with inconsistent results in several ethnic populations. The aim of this case-control study was to evaluate the association of TNF-α (−308G/A, TNF-β (+252A/G, and IL-10 (−1082G/A, −819C/T, and −592 C/A polymorphisms with susceptibility of BD in Saudi patients. Molecular genotyping of TNF-α, TNF-β, and IL-10 gene polymorphisms was performed to analyze the alleles and genotypes distribution in 272 Saudi subjects, including BD patients (61 and healthy controls (211. The frequencies of allele A and genotype GA of TNF-α (−308G/A were significantly higher, whereas those of allele G and genotypes GG were significantly lower in BD patients than controls, indicating that A allele and GA genotype are susceptible, while G allele and GG genotype may be refractory to BD. The distribution of frequencies of alleles and genotype of TNF-β (+252A/G promoter polymorphism was not significantly different between BD patients and healthy controls. Genotypes 1082GG, −819TT, and 592AA of IL-10 polymorphisms are significantly associated with susceptibility risk of BD, while genotypes 1082AA, 1082GA, 819CC, 819CT, 592CC, and 592CA are resistant to BD. This study indicates that TNF-α (−308G/A and IL-10 (−1082G/A, −819C/T, and −592C/A polymorphisms are associated with risk of BD susceptibility in Saudi patients. However, larger scale studies in Saudi population as well as in other ethnicities are needed to confirm this association. Keywords: tumor necrosis factor

  8. Proliferation, migration, and expression of oral-mucosal-healing-related genes by oral fibroblasts receiving low-level laser therapy after inflammatory cytokines challenge.

    Science.gov (United States)

    Basso, Fernanda G; Soares, Diana G; Pansani, Taisa N; Cardoso, Lais M; Scheffel, Débora L; de Souza Costa, Carlos Alberto; Hebling, Josimeri

    2016-12-01

    Increased expression of inflammatory cytokines in the oral cavity has been related to the etiopathogenesis of oral mucositis and to delayed oral mucosal repair. Low-level laser therapy (LLLT) stimulates proliferation and migration of gingival fibroblasts, but the effects of specific inflammatory cytokines on oral mucosal cells and the modulation of these effects by LLLT have not been fully investigated. Therefore, this study investigated the effects of LLLT on oral fibroblasts after being challenged by oral-mucositis-related inflammatory cytokines. Human gingival fibroblasts were seeded in plain culture medium (DMEM) containing 10% fetal bovine serum (FBS) for 24 hours. Then, cells were kept in contact with inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8) in serum-free DMEM for 24 hours. After this period, cells were subjected to LLLT with a diode laser device (LaserTABLE, InGaAsP, 780 nm, 25 mW) delivering energy doses from 0.5 to 3 J/cm 2 . Irradiation was repeated for 3 consecutive days. Twenty-four hours after the last irradiation, cell migration (wound-healing and transwell migration assays), cell proliferation (BrdU), gene expression of COL-I and growth factors (real-time PCR), and synthesis of COL-I (Sirius Red assay) and VEGF (ELISA) were assessed. Data were subjected to two-way ANOVA and Tukey's tests or Kruskall-Walis and Mann-Whitney tests (P cytokines decreased the migration capacity of gingival fibroblasts. However, a statistically significant difference was observed only for IL-6, detected by transwell assay, where 30% less cells migrated through the pores (P cytokines, while growth factors and COL-I expression (approximately 80%; P cytokines. The opposite was seen for total collagen synthesis. LLLT promoted an acceleration of fibroblast migration (30%; P cytokines. Gene expression of VEGF (approximately 30%; P cytokines, especially IL-6 and IL-8 on gingival fibroblast functions directly related to the wound-healing process

  9. Muscle injury in rats induces upregulation of inflammatory cytokines in injured muscle and calcitonin gene-related peptide in dorsal root ganglia innervating the injured muscle.

    Science.gov (United States)

    Sakuma, Yoshihiro; Miyagi, Masayuki; Inoue, Gen; Ishikawa, Tetsuhiro; Kamoda, Hiroto; Yamauchi, Kazuyo; Orita, Sumihisa; Suzuki, Miyako; Oikawa, Yasuhiro; Inage, Kazuhide; Kubota, Go; Sainoh, Takeshi; Sato, Jun; Takahashi, Kazuhisa; Ohtori, Seiji

    2016-10-01

    In this study we evaluated the relationships among the behavioral changes after muscle injury, histological changes, changes in inflammatory cytokines in the injured muscle, and changes in the sensory nervous system innervating the muscle in rats. We established a model of muscle injury in rats using a dropped weight. Behavior was assessed using the CatWalk system. Subsequently, bilateral gastrocnemius muscles and dorsal root ganglia (DRGs) were resected. Muscles were stained with hematoxylin and eosin, and inflammatory cytokines in injured muscles were assayed. DRGs were immunostained for calcitonin gene-related peptide (CGRP). Changes of behavior and upregulation of inflammatory cytokines in injured muscles subsided within 2 days of injury. Repaired tissue was observed 3 weeks after injury. However, upregulation of CGRP in DRG neurons continued for 2 weeks after injury. These findings may explain in part the pathological mechanism of persistent muscle pain. Muscle Nerve 54: 776-782, 2016. © 2016 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.

  10. Macrophage inhibitory cytokine-1 (MIC-1/GDF15 gene deletion promotes cancer growth in TRAMP prostate cancer prone mice.

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    Yasmin Husaini

    Full Text Available The divergent TGF-β superfamily member, macrophage inhibitory cytokine-1 (MIC-1/GDF15, is overexpressed by most cancers, including prostate cancer (PCa. Whilst its circulating levels are linked to cancer outcome, the role MIC-1/GDF15 plays in cancer development and progression is incompletely understood. To investigate its effect on PCa development and spread, we have used TRAMP prostate cancer prone mice bearing a germline deletion of MIC-1/GDF15 (TRAMPMIC-/-. On average TRAMPMIC-/- mice died about 5 weeks earlier and had larger prostatic tumors compared with TRAMP mice that were wild type for MIC-1/GDF15 (TRAMPMIC+/+. Additionally, at the time of death or ethical end point, even when adjusted for lifespan, there were no significant differences in the number of mice with metastases between the TRAMPMIC+/+ and TRAMPMIC-/- groups. However, consistent with our previous data, more than twice as many TRAMP mice overexpressing MIC-1/GDF15 (TRAMPfmsmic-1 had metastases than TRAMPMIC+/+ mice (p<0.0001. We conclude that germ line gene deletion of MIC-1/GDF15 leads to increased local tumor growth resulting in decreased survival consistent with an overall protective role for MIC-1/GDF15 in early primary tumor development. However, in advancing disease, as we have previously noted, MIC-1/GDF15 overexpression may promote local invasion and metastatic spread.

  11. Barium chloride induces redox status unbalance, upregulates cytokine genes expression and confers hepatotoxicity in rats-alleviation by pomegranate peel.

    Science.gov (United States)

    Elwej, Awatef; Grojja, Yousri; Ghorbel, Imen; Boudawara, Ons; Jarraya, Raoudha; Boudawara, Tahia; Zeghal, Najiba

    2016-04-01

    The present study was performed to establish the therapeutic efficacy of pomegranate peel against barium chloride induced liver injury. Adult rats were divided into four groups of six animals each: group I, serving as controls, received distilled water; group II received by their drinking water 67 ppm of BaCl2; group III received both 67 ppm of BaCl2 by the same way than group II and 5 % of pomegranate peel (PP) via diet; group IV received 5 % of PP. Analysis by HPLC/MS of PP showed its rich composition in flavonoids such as gallic acid, castalin, hyperin, quercitrin, syringic acid, and quercetin. The protective effects of pomegranate peel against hepatotoxicity induced by barium chloride were assessed using biochemical parameters and histological studies. Exposure of rats to barium caused oxidative stress in the liver as evidenced by an increase in malondialdehyde (MDA), lipid hydroperoxides (LOOHs), H2O2 and advanced oxidation protein product (AOPP) levels, and lactate dehydrogenase (LDH), gamma glutamyl transpeptidase (GGT), alanine aminotransferase (AST) and aspartate aminotransferase (ALT) activities, a decrease in catalase (CAT) and glutathione peroxidase (GPx) activities, glutathion (GSH), non-protein thiol (NPSH), vitamin C levels, and Mn-SOD gene expression. Liver total MT levels, MT-1, and MT-2 and pro-inflammatory cytokine genes expression like TNF-α, IL-1β and IL-6 were increased. Pomegranate peel, supplemented in the diet of barium-treated rats, showed an improvement of all the parameters indicated above.The present work provided ethnopharmacological relevance of pomegranate peel against the toxic effects of barium, suggesting its beneficial role as a potential antioxidant.

  12. Association of cytokine and Toll-like receptor gene polymorphisms with severe malaria in three regions of Cameroon.

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    Tobias O Apinjoh

    Full Text Available P. falciparum malaria is one of the most widespread and deadliest infectious diseases in children under five years in endemic areas. The disease has been a strong force for evolutionary selection in the human genome, and uncovering the critical human genetic factors that confer resistance to the disease would provide clues to the molecular basis of protective immunity that would be invaluable for vaccine development. We investigated the effect of single nucleotide polymorphisms (SNPs on malaria pathology in a case- control study of 1862 individuals from two major ethnic groups in three regions with intense perennial P. falciparum transmission in Cameroon. Twenty nine polymorphisms in cytokine and toll-like receptor (TLR genes as well as the sickle cell trait (HbS were assayed on the Sequenom iPLEX platform. Our results confirm the known protective effect of HbS against severe malaria and also reveal a protective effect of SNPs in interleukin-10 (IL10 cerebral malaria and hyperpyrexia. Furthermore, IL17RE rs708567 GA and hHbS rs334 AT individuals were associated with protection from uncomplicated malaria and anaemia respectively in this study. Meanwhile, individuals with the hHbS rs334 TT, IL10 rs3024500 AA, and IL17RD rs6780995 GA genotypes were more susceptible to severe malarial anaemia, cerebral malaria, and hyperpyrexia respectively. Taken together, our results suggest that polymorphisms in some immune response genes may have important implications for the susceptibility to severe malaria in Cameroonians. Moreover using uncomplicated malaria may allow us to identify novel pathways in the early development of the disease.

  13. Polymorphisms in Th1/Th2 cytokine Genes, hormone replacement therapy, and risk of non-Hodgkin lymphoma

    Directory of Open Access Journals (Sweden)

    Gongjian eZhu

    2011-07-01

    Full Text Available AbstractWe conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes modify the relationship between hormone replacement therapy (HRT and risk of non-Hodgkin lymphoma (NHL. Compared to women without a history of HRT use, women with a history of HRT use had a significantly decreased risk of NHL if they carried IFNGR2 (rs1059293 CT/TT genotypes (OR=0.5, 95%CI: 0.3-0.9, IL13 (rs20541 GG genotype (OR=0.6, 95%CI: 0.4-0.9 and IL13 (rs1295686 CC genotype (OR=0.6, 95%CI: 0.4-0.8, but not among women who carried IFNGR2 CC, IL13 AG /AA and IL13 CT/TT genotypes. A similar pattern was also observed for B-cell lymphoma but not for T-cell lymphoma. A statistically significant interaction was observed for IFNGR2 (rs1059293 Pforinteraction=0.024, IL13 (rs20541 Pforinteraction=0.005, IL13 (rs1295686 Pforinteraction=0.008 and IL15RA (rs2296135 Pforinteraction=0.049 for NHL overall; IL13 (rs20541 Pforinteraction=0.0009, IL13 (rs1295686 Pforinteraction=0.0002, and IL15RA (rs2296135 Pforinteraction=0.041 for B-cell lymphoma. The results suggest that common genetic variation in Th1/Th2 pathway genes may modify the association between HRT and NHL risk.

  14. Mutation analysis of suppressor of cytokine signalling 3, a candidate gene in Type 1 diabetes and insulin sensitivity

    DEFF Research Database (Denmark)

    Gylvin, T; Nolsøe, R; Hansen, T

    2004-01-01

    Beta cell loss in Type 1 and Type 2 diabetes mellitus may result from apoptosis and necrosis induced by inflammatory mediators. The suppressor of cytokine signalling (SOCS)-3 is a natural inhibitor of cytokine signalling and also influences insulin signalling. SOCS3 could therefore be a candidate...

  15. Growth-related gene product {alpha}: A chemotactic cytokine for neutrophils in rheumatoid arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Koch, A.E.; Pope, R.M. [Northwestern Univ. Medical School, Chicago IL (United States)]|[Veteran`s Administration Lakeside Medical Center, Chicago, IL (United States); Shah, M.R.; Hosaka, S. [Northwestern Univ. Medical School, Chicago, IL (United States)] [and others

    1995-10-01

    Leukocyte recruitment is critical in the inflammation seen in rheumatoid arthritis (RA). To determine whether the chemokine growth-related gene product {alpha} (gro{alpha}) plays a role in this process, we examined synovial tissue (ST), synovial fluid (SF), and plasma samples from 102 patients with arthritis. RA SF contained more antigenic gro{alpha} (mean 5.3 {+-} 1.9 ng/ml) than did SFs from either osteoarthritis (OA) or other forms of arthritis (mean 0.1 ng/ml) (p < 0.05). RA plasma contained more gro{alpha} (mean 4.3 {+-} 1.8 ng/ml) than normal plasma (mean 0.1 ng/ml) (p < 0.05). RA ST fibroblasts (1.2 x 10{sup 5}/cells/ml RPMI 1640/24 h) produced antigenic gro{alpha} (mean 0.2 {+-} 0.1 ng/ml), and this production was increased significantly upon incubation with TNF-{alpha} (mean 1.3 {+-} 0.3 ng/ml) or IL-1{beta} (mean 2.3 {+-} 0.6 ng/ml) (p < 0.05). Cells from RA SF also produced gro{alpha}: neutrophils (PMNs) (10{sup 7} cells/ml/24 h) produced 3.7 {+-} 0.7 ng/ml. RA SF mononuclear cells produced gro{alpha}, particularly upon incubation with LPS or PHA. Immunoreactive ST gro{alpha} was found in greater numbers of RA compared with either OA or normal lining cells, as well as in RA compared with OA subsynovial macrophages (p < 0.05). IL-8 accounted for a mean of 36% of the RA SF chemotactic activity for PMNs, while epithelial neutrophil-activating peptide-78 accounted for 34%, and gro{alpha} for 28%, of this activity. Combined neutralization of all three chemokines in RA SFs resulted in a mean decrease of 50% of the chemotactic activity for PMNs present in the RA SFs. These results indicate that gro{alpha} plays an important role in the ingress of PMNs into the RA joint. 54 refs., 6 figs., 1 tab.

  16. IL-6 and IL-18 cytokine gene variants of pulmonary tuberculosis patients with co-morbid diabetes mellitus and their household contacts in Hyderabad.

    Science.gov (United States)

    Ponnana, Meenakshi; Sivangala, Ramya; Joshi, Lavanya; Valluri, Vijayalakshmi; Gaddam, Sumanlatha

    2017-09-05

    Association of cytokine genes reflects their susceptibility towards infection and disease in household contacts (HHC) of pulmonary tuberculosis (PTB) patients. Hyperglycemia, a common factor in diabetics might influence their risk towards mycobacterium tuberculosis infection and disease development. This study determines the association of IL-6 and IL-18 cytokine gene variants of TB patients with diabetes mellitus (TBDM) and their HHC in Hyderabad. Single nucleotide polymorphisms of IL-6 (-174 G>C and -572 G>C) and IL-18 (-137 G>C and -607 C>A) cytokine genes were genotyped by Amplification Refractory Mutation System and Restriction Fragment Length polymerase chain reaction in total of 705 subjects comprising of TBDM, their HHC, PTB, DM and Healthy controls (HC). At IL-6 -174G>C variant, GG genotype, G allele in TBDM and TBDM HHC, at -572G>C variant, C allele in TBDM and GG haplotype in TBDM HHC were showing positive association, however DM have not shown any association at IL-6 polymorphic sites. With respect to the IL-18 gene polymorphisms, at -137 G>C variant, GG genotype was positively associated in PTB while at -607 C>A variant positive association was shown with AC genotype in TBDM, their HHC and DM; GACC diplotype in TBDM and GCGC in PTB. Our findings suggest that susceptible combination of IL-6 and IL-18 cytokine genes associated with disease in the HHCs highlight their risk of inclination towards the disease. Copyright © 2017. Published by Elsevier B.V.

  17. [Cytokines and osteogenesis].

    Science.gov (United States)

    Fujiwara, Makoto; Ozono, Keiichi

    2014-06-01

    Many cytokines associate with proliferation, differentiation and activation of osteoblasts which have an important role in osteogenesis. TGF-β, BMP, IGF, FGF, Hedgehog, Notch, IL and WNT signaling pathways and their inhibitors have been revealed to correlate to osteogenesis, and those gene mutations have been shown to cause various bone disorders. It has been suggested that there are common pathways or crosstalk in these cytokine signaling each other, but mechanism of their complicated regulation on osteogenesis has been unclear. It was expected that the knowledge about these cytokines will apply to clinical therapies of bone diseases.

  18. Whole genome expression profiling and screening for differentially expressed cytokine genes in human bone marrow endothelial cells treated with humoral inhibitors in liver cirrhosis.

    Science.gov (United States)

    Gao, Bo; Sun, Wang; Wang, Xianqi; Jia, Xu; Ma, Biao; Chang, Yu; Zhang, Weihui; Xue, Dongbo

    2013-11-01

    Bone marrow endothelial cells (BMECs) are important components of the hematopoietic microenvironment in bone marrow, and they can secrete several types of cytokines to regulate the functions of hematopoietic stem/progenitor cells. To date, it is unknown whether BMECs undergo functional changes and lead to hematopoietic abnormalities in cases of liver cirrhosis (LC). In the present study, whole genome microarray analysis was carried out to detect differentially expressed genes in human BMECs treated for 48 h with medium supplemented with 20% pooled sera from 26 patients with LC or 10 healthy volunteers as the control group. A total of 1,106 upregulated genes and 766 downregulated genes were identified. In Gene Ontology analysis, the most significant categories of genes were revealed. A large number of the upregulated genes were involved in processes, such as cell-cell adhesion, apoptosis and cellular response to stimuli and the downregulated genes were involved in the negative regulation of secretion, angiogenesis, blood vessel development and cell growth. Pathway analysis revealed that the upregulated genes were either cell adhesion molecules or parts of the apoptotic signaling pathway and the downregulated genes were involved in the Wnt signaling pathway and MAPK signaling pathway. These were the pathways with the highest enrichment scores. The results of apoptosis assays revealed that the humoral inhibitors in the sera of patients with LC induced the apoptosis of BMECs, which confirmed the accuracy of bioinformatic analysis. Moreover, we screened and verified 21 differentially expressed cytokine genes [transforming growth factor (TGF)B1, tumor necrosis factor (TNF)B, TNF receptor superfamily, member 11b (TNFRSF11B), TNF (ligand) superfamily, member 13b (TNFSF13B), interleukin (IL)1A, IL6, IL11, IL17C, IL24, family with sequence similarity 3, member B (FAM3B), Fas ligand (FASLG), matrix metallopeptidase (MMP)3, MMP15, vitronectin (VTN), insulin-like growth factor

  19. A retrospective study of cytokine profiles changes in mice with FVIII inhibitor development after AAV mediated gene therapy in hemophilia A mouse model.

    Science.gov (United States)

    Sun, Junjiang; Yuan, Zhenhua; Abajas, Yasmina L; Szollosi, Dorreen E; Hu, Genlin; Hua, Baolai; Xiao, Xiao; Li, Chengwen

    2017-09-19

    The development of inhibitory autoantibodies to the infused clotting factor VIII is a major complication for severe hemophilia A management. Novel therapy options for hemophilia have significantly progressed in the last decade and a gene therapy cure for hemophilia is translating into reality. However, mechanistic studies of FVIII autoantibodies (FVIII inhibitors) have lagged behind and remain a challenge for both protein replacement and gene therapy. FVIII inhibitor formation is assumed to be a classical T cell-dependent immune response in which cytokines/chemokines play an important role. The study of cytokine profile changes during FVIII inhibitor development may be helpful to understand the mechanism of inhibitor development and to explore potential novel approaches that will minimize the risk. After FVIII-/- mice were treated with intravenous administration of an AAV8 vector encoding human FVIII, FVIII expression peaked at week 2 (W2), and FVIII inhibitor was thoroughly developed at week 8 (W8). W8 plasma that showed positive FVIII inhibitor, and W2 samples with negative FVIII inhibitor ("Anti-FVIII(+)"), were subjected to multiplex cytokines measurement, W8 and W2 samples were both negative for FVIII inhibitor ("Anti-FVIII(-)") as the control. In comparison to mice in the "Anti-FVIII(-)" group, the mice in group of "Anti-FVIII(+)", especially at higher titers, exhibited significantly elevated pro-inflammatory cytokines of IL-1, IL-6, IL-12p40, MCP-1, MIP-1, MIP-2, and TNFα. The anti-inflammatory cytokine of TGFβ was decreased at W2 in both groups. Multivariate analysis of the risk factors for FVIII inhibitor development showed peak FVIII activity at W2, IL-6 and TNFα at W8 were positively correlated with inhibitor formation, and age starting gene therapy was negatively correlated. Collectively, the elevated monocyte derived pro-inflammatory cytokines/chemokines, together with the decreased anti-inflammatory cytokine of TGFβ at an early time point, may

  20. Effects of Curcuma comosa on the expression of atherosclerosis-related cytokine genes in rabbits fed a high-cholesterol diet.

    Science.gov (United States)

    Charoenwanthanang, Puttavee; Lawanprasert, Somsong; Phivthong-Ngam, Laddawal; Piyachaturawat, Pawinee; Sanvarinda, Yupin; Porntadavity, Sureerut

    2011-04-12

    Curcuma comosa has been known to have potential use in cardiovascular diseases, but its immunoregulatory role in atherosclerosis development and liver toxicity has not been well studied. We therefore investigated the effects of Curcuma comosa on the expression of atherosclerosis-related cytokine genes in rabbits fed a high-cholesterol diet. Twelve male New Zealand White rabbits were treated with 1.0% cholesterol for one month and were subsequently treated with 0.5% cholesterol either alone, or in combination with 5mg/kg/day of simvastatin or with 400mg/kg/day of Curcuma comosa powder for three months. The expression of IL-1, MCP-1, TNF-α, IL-10, and TGF-β in the isolated abdominal aorta and liver were determined by real-time RT-PCR. Liver toxicity was determined by hepatic enzyme activity. Curcuma comosa significantly decreased the expression of pro-inflammatory cytokines, leading to a stronger reduction in IL-1, MCP-1, and TNF-α expression compared to that was suppressed by simvastatin treatment. However, neither Curcuma comosa nor simvastatin affected the expression of anti-inflammation cytokines. In the liver, Curcuma comosa insignificantly decreased the expression of pro-inflammatory cytokines and significantly increased the expression of the anti-inflammatory cytokine IL-10 without altering the activity of hepatic enzymes. In contrast, simvastatin significantly increased the MCP-1 and TNF-α expressions and serum ALT level, without affecting the expression of anti-inflammatory cytokines. In this study, we demonstrated that Curcuma comosa exerts anti-inflammatory activity in the aorta and liver without causing liver toxicity, indicating that Curcuma comosa is a potential candidate as an alternative agent in cardiovascular disease therapy. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  1. Dataset of proinflammatory cytokine and cytokine receptor gene expression in rainbow trout (Oncorhynchus mykiss) measured using a novel GeXP multiplex, RT-PCR assay

    OpenAIRE

    Kutyrev, Ivan; Cleveland, Beth; Leeds, Timothy; Wiens, Gregory D.

    2017-01-01

    A GeXP multiplex, RT-PCR assay was developed and optimized that simultaneously measures expression of a suite of immune-relevant genes in rainbow trout (Oncorhynchus mykiss), concentrating on tumor necrosis factor and interleukin-1 ligand/receptor systems and acute phase response genes. The dataset includes expression values for drpt, il11a, il1b1, il1b2, il1b3, il1r-like-1(e3-5), il1r-like-1(e9-11), il1r1-like-a, il1r1-like-b, il1r2, saa, tnfa1, tnfa2, tnfa3, tnfrsf1a, tnfrsf1a-like-a, tnfrs...

  2. Transcription Factors Oct-1 and GATA-3 Cooperatively Regulate Th2 Cytokine Gene Expression via the RHS5 within the Th2 Locus Control Region

    Science.gov (United States)

    Kim, Kiwan; Kim, Najung; Lee, Gap Ryol

    2016-01-01

    The T helper type 2 (Th2) locus control region (LCR) regulates Th2 cell differentiation. Several transcription factors bind to the LCR to modulate the expression of Th2 cytokine genes, but the molecular mechanisms behind Th2 cytokine gene regulation are incompletely understood. Here, we used database analysis and an oligonucleotide competition/electrophoretic mobility shift assays to search for transcription factors binding to RHS5, a DNase I hypersensitive site (DHS) within the Th2 LCR. Consequently, we demonstrated that GATA-binding protein-3 (GATA-3), E26 transformation-specific protein 1 (Ets-1), octamer transcription factor-1 (Oct-1), and Oct-2 selectively associate with RHS5. Furthermore, chromatin immunoprecipitation and luciferase reporter assays showed that Oct-1 and Oct-2 bound within the Il4 promoter region and the Th2 LCR, and that Oct-1 and GATA-3 or Oct-2 synergistically triggered the transactivational activity of the Il4 promoter through RHS5. These results suggest that Oct-1 and GATA-3/Oct-2 direct Th2 cytokine gene expression in a cooperative manner. PMID:26840450

  3. The association between cytokine gene polymorphisms and graft rejection in liver transplantation: a systematic review and meta-analysis.

    Science.gov (United States)

    Rattanasiri, Sasivimol; McDaniel, D Olga; McEvoy, Mark; Anothaisintawee, Thunyarat; Sobhonslidsuk, Abhasnee; Attia, John; Thakkinstian, Ammarin

    2013-01-01

    We investigated the contribution of polymorphisms in cytokine genes (TNFa-308, IL10-1082 and -592, TGFb1-c10 and c25, and IFNg+874) on the risk of graft rejection in liver transplantation. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. In total, 12 studies were eligible and included in the study. Data extraction and assessments for risk of bias were independently performed by two reviewers. Data for allele frequencies, allelic, and genotypic effects were pooled. Heterogeneity and publication bias were assessed. Pooled minor allele frequencies for TNFa-308, IL10-1082, TGFb1-c10, TGFb1-c25, IFNg+874, and IL10-592 were 0.140 (95% CI: 0.083, 0.198), 0.432 (95% CI: 0.392, 0.472), 0.387 (95% CI: 0.307, 0.467), 0.090 (95% CI: 0.056, 0.123), 0.460 (95% CI: 0.392, 0.528), and 0.224 (95% CI: 0.178, 0.269), respectively. OnlyTNFa-308 and IL10-1082 polymorphisms were significantly associated with graft rejection. Patients who carried minor homozygous genotypes for these two polymorphisms were at 3.5 and 1.69 times higher risk of graft rejections than patients who carried major homozygous genotypes. The estimated lambdas were 0.41 and 0.47, suggesting an additive mode of effect was most likely. However, we could not detect the associations of TGFb1at c10 and c25, INFg+874, and IL10-592 polymorphisms and graft rejection. In summary, our systematic review has demonstrated that TNFa-308 and IL10-1082 are potential risk factors of poor outcomes in liver transplantation. Future updated meta-analysis studies to confirm the power of these genotypes in association with allograft rejection are needed. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Extensive changes in innate immune gene expression in obese Göttingen minipigs do not lead to changes in concentrations of circulating cytokines and acute phase proteins

    DEFF Research Database (Denmark)

    Højbøge, Tina Rødgaard; Skovgaard, Kerstin; Moesgaard, S. G.

    2014-01-01

    was significantly different in obese pigs (three up-regulated, six down-regulated). Of 33 genes in adipose tissues, obesity was associated with changed expression of 12 genes in the visceral adipose tissue (VAT) (three up-regulated), 11 in the abdominal retroperitoneal adipose tissue (RPAT) (seven of these up...... between adipose tissues and a decreased tissue-specific expression of cytokines and chemokines. In contrast to obese humans, no changes in serum concentrations of haptoglobin, C-reactive protein, serum amyloid A, tumor necrosis factor-α and interleukin 6 were found in obese Göttingen minipigs....

  5. An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes.

    Science.gov (United States)

    Sharma, Poonam R; Mackey, Aaron J; Dejene, Eden A; Ramadan, James W; Langefeld, Carl D; Palmer, Nicholette D; Taylor, Kent D; Wagenknecht, Lynne E; Watanabe, Richard M; Rich, Stephen S; Nunemaker, Craig S

    2015-09-01

    Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a contributor to T2D risk. Chronic low-grade inflammation resulting from obesity is a risk factor for T2D and a possible trigger of β-cell failure. In this study, microarray data were collected from mouse islets after overnight treatment with cytokines at concentrations consistent with the chronic low-grade inflammation in T2D. Genes with a cytokine-induced change of >2-fold were then examined for associations between single nucleotide polymorphisms and the acute insulin response to glucose (AIRg) using data from the Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium. Significant evidence of association was found between AIRg and single nucleotide polymorphisms in Arap3 (5q31.3), F13a1 (6p25.3), Klhl6 (3q27.1), Nid1 (1q42.3), Pamr1 (11p13), Ripk2 (8q21.3), and Steap4 (7q21.12). To assess the potential relevance to islet function, mouse islets were exposed to conditions modeling low-grade inflammation, mitochondrial stress, endoplasmic reticulum (ER) stress, glucotoxicity, and lipotoxicity. RT-PCR revealed that one or more forms of stress significantly altered expression levels of all genes except Arap3. Thapsigargin-induced ER stress up-regulated both Pamr1 and Klhl6. Three genes confirmed microarray predictions of significant cytokine sensitivity: F13a1 was down-regulated 3.3-fold by cytokines, Ripk2 was up-regulated 1.5- to 3-fold by all stressors, and Steap4 was profoundly cytokine sensitive (167-fold up-regulation). Three genes were thus closely associated with low-grade inflammation in murine islets and also with a marker for islet function (AIRg) in a diabetes-prone human population. This islet-targeted genome-wide association scan identified several previously unrecognized candidate genes related to islet dysfunction during the development of T2D.

  6. The influence of methotrexate on the gene expression of the pro-inflammatory cytokine IL-12A in the therapy of rheumatoid arthritis.

    Science.gov (United States)

    Hobl, Eva-Luise; Mader, Robert M; Erlacher, Ludwig; Duhm, Bernhard; Mustak, Monika; Bröll, Hans; Högger, Petra; Kalipciyan, Maria; Jilma, Bernd

    2011-01-01

    Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis (RA). Among its anti-proliferative activity, the anti-inflammatory mechanisms of MTX seem to play a major role in the treatment of RA. MTX reduces the production of pro-inflammatory cytokines such as interleukin (IL)-1, IL-2, IL-6 and interferon (INF)-γ, while the gene expression of anti-inflammatory Th2 cytokines like IL-4 and IL-10 is increased - altogether resulting in the anti-inflammatory effect. As little is known about the impact of MTX on other cytokines involved in the pathogenesis of RA, the present trial investigated the effect of MTX on IL-12A and IL-18 gene expression by peripheral blood mononuclear cells (PBMCs). For comparison, the effect on IL-6 and tumour necrosis factor (TNF) was analysed. Using real-time PCR, mRNA concentrations of pro-inflammatory cytokines were determined in PBMCs from 17 patients before and during MTX therapy. Furthermore, gene expression was correlated with clinical and pharmacokinetic parameters such as methotrexate polyglutamate concentrations (Spearman's correlation coefficient). To eliminate concomitant corticosteroids as confounding factor, a subgroup analysis for methotrexate without corticosteroids was performed in 6 patients. MTX statistically significantly reduced the mRNA expression of IL-12A by PBMCs in rheumatoid arthritis patients (Wilcoxon-test for paired samples, p<0.046). Consistent with other reports, IL-6 was reduced under MTX treatment. Although the combination of MTX and corticosteroids significantly reduced the gene expression of IL-18, this key molecule was unaffected by MTX without corticosteroids. Our results were further supported by a negative correlation of methotrexate polyglutamate concentrations and the mRNA expression of the pro-inflammatory cytokines IL-6 and IL-12A. We describe a novel effect of MTX reducing the gene expression of IL-12A independently of corticosteroid application in patients. This impact was further

  7. Type of Renal Replacement Therapy (Hemodialysis versus Peritoneal Dialysis) Does Not Affect Cytokine Gene Expression or Clinical Parameters of Renal Transplant Candidates.

    Science.gov (United States)

    Kamińska, Dorota; Kościelska-Kasprzak, Katarzyna; Chudoba, Paweł; Mazanowska, Oktawia; Banasik, Mirosław; Żabinska, Marcelina; Boratyńska, Maria; Lepiesza, Agnieszka; Korta, Krzysztof; Gomółkiewicz, Agnieszka; Dzięgiel, Piotr; Klinger, Marian

    2015-01-01

    Patients with renal failure suffer from immune disturbances, caused by uremic toxins and influenced by dialysis treatment. The aim of the present study was to reveal whether type of dialysis modality (hemodialysis, HD, versus peritoneal dialysis, PD) differentially affects the immunocompetence, particularly the expression of genes involved in the immune response. 87 renal transplant candidates (66 HD, 21 PD) were included in the study. The peripheral blood RNA samples were obtained with the PAXgene Blood system just before transplantation. The gene expression of CASP3, FAS, TP53, FOXP3, IFNG, IL2, IL6, IL8, IL10, IL17, IL18, LCN2, TGFB1, and TNF was assessed with real-time PCR on custom-designed low density arrays (TaqMan). Gene expression data were analyzed in relation to pretransplant clinical parameters. The mean expression of examined genes showed no significant differences between PD and HD with the exception of FAS, expression of which was 30% higher in PD patients compared to the HD group. There was nonsignificantly higher expression of proinflammatory cytokines in the PD group. The clinical inflammatory parameters (CRP, albumin, cholesterol, and hemoglobin levels) did not differ between the groups. Type of renal replacement therapy exerts no differential effect on cytokine gene expression or inflammatory clinical parameters.

  8. Post-operative infection and sepsis in humans is associated with deficient gene expression of γc cytokines and their apoptosis mediators.

    Science.gov (United States)

    White, Mary; Mahon, Vivienne; Grealy, Robert; Doherty, Derek G; Stordeur, Patrick; Kelleher, Dermot P; McManus, Ross; Ryan, Thomas

    2011-06-28

    Lymphocyte homeostasis is dependent on the γc cytokines. We hypothesised that sepsis in humans is associated with differential gene expression of the γc cytokines and their associated apoptosis mediators. The study population consisted of a total of 60 patients with severe sepsis, 15 with gram negative bacteraemia, 10 healthy controls and 60 patients undergoing elective lung resection surgery. Pneumonia was diagnosed by CDC NNIC criteria. Gene expression in peripheral blood leukocytes (PBLs) of interleukin (IL)-2, 7, 15 and interferon (IFN)-γ, Bax, Bim, Bcl-2 was determined by qRT-PCR and IL-2 and IL-7 serum protein levels by ELISA. Gene expression of IL-2, 7 and IFN-γ was measured in peripheral blood leukocytes (PBL), cultured in the presence of lipopolysaccharide (LPS) and CD3 binding antibody (CD3ab) IL-2 gene expression was lower in the bacteraemia group compared with controls, and lower still in the sepsis group (P IL-7 gene expression was similar in controls and bacteraemia, but lower in sepsis (P sepsis compared to bacteraemic and healthy controls. Bax gene expression was similar in the three groups.In lung resection surgery patients, post-operative pneumonia was associated with a perioperative decrease in IL-2 mRNA (P IL-7 mRNA (P = 0.003). IL-2 protein levels were reduced in sepsis and bacteraemia compared to controls (P = 0.02) but similar in pneumonia and non-pneumonia groups. IL-7 protein levels were similar in all groups.In cultured PBLs, IFN-γ gene expression was decreased in response to LPS and increased in response to CD3ab with sepsis: IL-7 gene expression increased in response to LPS in controls and to CD3ab with sepsis; Bcl-2 gene expression decreased in response to combined CD3ab and IL-2 with sepsis. Patients with infection and sepsis have deficient IL-2 and IL-7 gene expression in PBLs. Aberrant cytokine gene expression may precede the onset of infection.

  9. Binding of superantigen toxins into the CD28 homodimer interface is essential for induction of cytokine genes that mediate lethal shock.

    Directory of Open Access Journals (Sweden)

    Gila Arad

    2011-09-01

    Full Text Available Bacterial superantigens, a diverse family of toxins, induce an inflammatory cytokine storm that can lead to lethal shock. CD28 is a homodimer expressed on T cells that functions as the principal costimulatory ligand in the immune response through an interaction with its B7 coligands, yet we show here that to elicit inflammatory cytokine gene expression and toxicity, superantigens must bind directly into the dimer interface of CD28. Preventing access of the superantigen to CD28 suffices to block its lethality. Mice were protected from lethal superantigen challenge by short peptide mimetics of the CD28 dimer interface and by peptides selected to compete with the superantigen for its binding site in CD28. Superantigens use a conserved β-strand/hinge/α-helix domain of hitherto unknown function to engage CD28. Mutation of this superantigen domain abolished inflammatory cytokine gene induction and lethality. Structural analysis showed that when a superantigen binds to the T cell receptor on the T cell and major histocompatibility class II molecule on the antigen-presenting cell, CD28 can be accommodated readily as third superantigen receptor in the quaternary complex, with the CD28 dimer interface oriented towards the β-strand/hinge/α-helix domain in the superantigen. Our findings identify the CD28 homodimer interface as a critical receptor target for superantigens. The novel role of CD28 as receptor for a class of microbial pathogens, the superantigen toxins, broadens the scope of pathogen recognition mechanisms.

  10. Interaction between cytokine gene polymorphisms and the effect of physical exercise on clinical and inflammatory parameters in older women: study protocol for a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Pereira Daniele S

    2012-08-01

    Full Text Available Abstract Background Aging is associated with chronic low-grade inflammatory activity with an elevation of cytokine levels. An association between regular physical activity and reduction of blood levels of anti-inflammatory cytokines is demonstrated in the literature pointing to an anti-inflammatory effect related to exercise. However, there is no consensus regarding which type of exercise and which parameters are the most appropriate to influence inflammatory markers. Evidence indicates that the single nucleotide polymorphism (SNP can influence the synthesis of those cytokines affecting their production. Methods/Design The design of this study is a randomized controlled trial. The aim of this study is to investigate the interaction between the cytokine genes SNP and the effect of physical activity on older women. The main outcomes are: serum levels of sTNFR-1, sTNFR-2, interleukin (IL-6, IL-10, measured by the ELISA method; genotyping of tumor necrosis factor- (TNF-alpha (rs1800629, IL6 (rs1800795, IL10 (rs1800896 by the TaqMan Method (Applied Biosystems, Foster City, CA, USA; and physical performance assessed by Timed Up and Go and 10-Meter Walk Tests. Secondary outcomes include: Geriatric Depression Scale, Perceived Stress Scaleand aerobic capacity, assessed by the six-minute walk; and lower limb muscle strength, using an isokinetic dinamometer (Biodex Medical Systems, Inc., Shirley, NY,USA. Both exercise protocols will be performed three times a week for 10 weeks, 30 sessions in total. Discussion Investigating the interaction between genetic factors and exercise effects of both protocols of exercise on the levels of inflammatory cytokine levels can contribute to guide clinical practice related to treatment and prevention of functional changes due to chronic inflammatory activity in older adults. This approach could develop new perspectives on preventive and treatment proposals in physical therapy and in the management of the older patient

  11. Hepatitis C virus NS2 and NS3/4A proteins are potent inhibitors of host cell cytokine/chemokine gene expression

    Directory of Open Access Journals (Sweden)

    Hiscott John

    2006-09-01

    Full Text Available Abstract Background Hepatitis C virus (HCV encodes several proteins that interfere with the host cell antiviral response. Previously, the serine protease NS3/4A was shown to inhibit IFN-β gene expression by blocking dsRNA-activated retinoic acid-inducible gene I (RIG-I and Toll-like receptor 3 (TLR3-mediated signaling pathways. Results In the present work, we systematically studied the effect of all HCV proteins on IFN gene expression. NS2 and NS3/4A inhibited IFN gene activation. NS3/4A inhibited the Sendai virus-induced expression of multiple IFN (IFN-α, IFN-β and IFN-λ1/IL-29 and chemokine (CCL5, CXCL8 and CXCL10 gene promoters. NS2 and NS3/4A, but not its proteolytically inactive form NS3/4A-S139A, were found to inhibit promoter activity induced by RIG-I or its adaptor protein Cardif (or IPS-1/MAVS/VISA. Both endogenous and transfected Cardif were proteolytically cleaved by NS3/4A but not by NS2 indicating different mechanisms of inhibition of host cell cytokine production by these HCV encoded proteases. Cardif also strongly colocalized with NS3/4A at the mitochondrial membrane, implicating the mitochondrial membrane as the site for proteolytic cleavage. In many experimental systems, IFN priming dramatically enhances RNA virus-induced IFN gene expression; pretreatment of HEK293 cells with IFN-α strongly enhanced RIG-I expression, but failed to protect Cardif from NS3/4A-mediated cleavage and failed to restore Sendai virus-induced IFN-β gene expression. Conclusion HCV NS2 and NS3/4A proteins were identified as potent inhibitors of cytokine gene expression suggesting an important role for HCV proteases in counteracting host cell antiviral response.

  12. Impact of thyme powder (Thymus vulgaris L.) supplementation on gene expression profiles of cytokines and economic efficiency of broiler diets.

    Science.gov (United States)

    Hassan, Fardos A M; Awad, Ashraf

    2017-06-01

    This study was conducted in an attempt to evaluate the impact of thyme powder supplementation on broiler diets with respect to cytokine and mucin2 gene expressions. It was also our aim to evaluate the growth performance, blood biochemical and hematological profiles, and economic efficiency of the diet. A total of 120 1-day old chicks (Cobb 500) were divided into four groups on the basis of the diet. One group received a basal diet (control) while the others received a basal diet supplemented with 2, 5, or 8 g/kg of thyme powder. At 42 days of age, the chickens were weighed and euthanized, and then blood and tissue samples were collected for the purpose of analysis. Results obtained clearly indicated that thyme supplementation of the diet, especially at 5 g/kg, resulted in a significant increase in body weight and caused the increased body weight gain and feed intake (P ˂ 0.05) as well as augmented WBC and lymphocyte count and IgG and NO levels (P ˂ 0.001). The economic evaluation showed that birds fed on 8 g/kg thyme yielded the lowest net revenue and highest feed cost to produce 1 kg of live weight compared to the other treatments, while birds fed on 2 and 5 g/kg thyme did not differ significantly from values obtained for the controls. The lipid profile of the broilers was affected by thyme supplementation at 2 and 5 g/kg as represented by a significant decrease in serum cholesterol levels as well as low density lipoprotein levels, which is known to be associated with a corresponding increase in high-density lipoprotein (P ˂ 0.001). Furthermore, supplementation of thyme downregulated the pro-inflammatory mediators and increased the expression of mucin2 mRNA in the jejunum of chickens. It can be concluded that thyme supplementation in the diet of broilers at 5 g/kg has the potential to favorably influence productive performance via an improvement in the immune status of the broiler.

  13. Triggering receptor expressed on myeloid cells 1 (TREM-1) and cytokine gene variants in complicated and uncomplicated malaria.

    Science.gov (United States)

    Adukpo, Selorme; Gyan, Ben A; Ofori, Michael F; Dodoo, Daniel; Velavan, Thirumalaisamy P; Meyer, Christian G

    2016-12-01

    Malaria elicits inflammatory responses, which, if not well regulated, may exert detrimental effects. When activated, triggering receptor expressed on myeloid cells 1 (TREM-1) enhances inflammatory responses by increasing secretion of IL-8 and other Th1 cytokines. In contrast, TREM-like transcript 1 (TREML-1) promotes anti-inflammatory responses by binding to TREM-1 ligands and competing with TREM-1, thus antagonizing TREM-1 activation to reduce inflammation. Endothelial protein C receptor (EPCR) also mediates anti-inflammatory responses by activating endothelial protein C (PC). Upon microbial stimulation, soluble forms of TREM-1 (sTREM-1) and soluble EPCR (sEPCR) are released. Their plasma levels reflect the degree of inflammation and the severity of infection. In a cross-sectional study comparing patients with severe with uncomplicated malaria, sTREM-1, soluble TREML-1 (sTREML-1) and sEPCR plasma levels as well as plasma levels of sEPCR derived from convalescent patients were quantified. Samples were collected on admittance of paediatric patients infected with Plasmodium falciparum to hospitals in Accra, Ghana. Distinct genetic regions of the genes encoding TREM-1, EPCR, interleukin (IL)-8 and IL-18 encompassing known genetic polymorphisms that influence plasma levels underwent DNA sequencing. Higher sTREM-1 levels were observed among children suffering from severe malaria compared to those with uncomplicated malaria (P = 0.049). Low TREM-1 to TREML-1 ratios were associated with uncomplicated malaria (P = 0.033). The TREM1 rs2234237T variant causing the amino acid exchange Thr25Ser, which has been associated with higher TREM-1 plasma levels, was significantly more frequent among patients with severe malaria than in those with uncomplicated malaria (P = 0.036). Low levels of sEPCR were observed in severe and uncomplicated malaria, while variant genotypes of IL8, IL18 and EPCR did not show any association. Higher plasma levels of sTREM-1 alone or relative to s

  14. Importância de polimorfismos de genes reguladores de citocinas em transplantes de células progenitoras hematopoiéticas Importance of regulatory cytokine gene polymorphisms in hematopoietic stem cell transplantation

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    Jeane Eliete Laguila Visentainer

    2008-12-01

    Full Text Available A compatibilidade genética HLA entre doador e receptor é um fator importante para o sucesso do transplante de células progenitoras hematopoiéticas (TCPH. No entanto, outros genes não-HLA estão sendo investigados em relação ao seu papel na incidência e gravidade da doença do enxerto contra o hospedeiro e na sobrevida, por modularem a intensidade da inflamação e os danos teciduais. Estes genes, não-HLA, incluem os genes de citocinas com polimorfismos dentro das seqüências 5' ou 3' regulatórias dos genes. Os polimorfismos ou microssatélites podem alterar a ligação dos fatores de transcrição aos sítios dentro dos genes promotores e a quantidade de citocina produzida. Este estudo revisa o papel potencial destes polimorfismos genéticos relativos às citocinas em prever o curso do TCPH.HLA genetic matching of donor and recipient is an important requirement for optimizing outcome following hematopoietic stem cell transplantation (HSCT. However, other non-HLA genes are being investigated for their role in graft-versus-host disease incidence and severity and in survival, by modulating the intensity of inflammation and tissue injury. These non-HLA-encoded genes include cytokine genes with polymorphisms within the 5' or 3' regulatory sequences of the genes. The polymorphisms or microsatellites may alter the transcription factor binding sites within the gene promoters and the amount of cytokine produced. This chapter summarizes the potential role of these genetic polymorphisms regarding the cytokines in predicting outcome of HSCT.

  15. Cytokine and acute phase protein gene expression in liver biopsies from dairy cows with a lipopolysaccharide - induced mastitis

    DEFF Research Database (Denmark)

    Vels, J; Røntved, Christine M.; Bjerring, Martin

    2009-01-01

    A minimally invasive liver biopsy technique was tested for its applicability to study the hepatic acute phase response (APR) in dairy cows with Escherichia coli lipopolysaccharide (LPS)-induced mastitis. The hepatic mRNA expression profiles of the inflammatory cytokines, tumor necrosis factor (TNF......, a minimally invasive liver biopsy technique can be used for studying the hepatic APR in diseased cattle. Lipopolysaccharide-induced mastitis resulted in a time-dependent production of inflammatory cytokines and SAA and Hp in the liver of dairy cows....

  16. T helper-2 cytokine/regulatory T-cell gene polymorphisms and their relation with risk of psoriasis in a South Indian Tamil cohort.

    Science.gov (United States)

    Indhumathi, Sundar; Rajappa, Medha; Chandrashekar, Laxmisha; Ananthanarayanan, Palghat Hariharan; Thappa, Devinder Mohan; Negi, Vir Singh

    2017-02-01

    Psoriasis is known to be associated with an up-regulation of T-helper (Th)-1 & Th-17 cytokines and a relative down-regulation of Th-2 and T-regulatory (T-reg) cytokines. Certain allelic variants of these cytokine genes may alter Th1/Th17 and Th2/T-reg balance and may be associated with the risk of psoriasis. Hence we aimed to determine the association of IL-4 (rs2243250), IL-10 (rs1800871 and rs1800896) and FOXP3 (rs3761548) gene polymorphisms with risk of psoriasis in South Indian Tamils. A total of 360 cases of psoriasis and 360 healthy controls were recruited. The polymorphism in IL-4 (rs2243250) & IL-10 (rs1800871) were typed by ARMS-PCR and IL-10 (rs1800896) & FOXP3 (rs3761548) were typed by TaqMan 5'allele discrimination assay. We observed that IL-4 (rs2243250) had a reduced risk of psoriasis, while the IL-10 (rs1800871) conferred an increased susceptibility to psoriasis, as compared with controls. However, IL-10 (rs1800896) and FOXP3 (rs3761548) gene polymorphisms were not associated with psoriasis risk. The plasma IL-4 levels was not different between the cases and controls, however the heterozygous CT genotype demonstrated significant high IL-4 levels. Plasma IL-10 levels were significantly increased in cases compared to controls, however none of the genotypes were associated with the plasma IL-10 levels. Our results suggest that IL-4 (rs2243250) polymorphism is protective against psoriasis, while IL-10 (rs1800871) polymorphism confers increased risk of psoriasis in South Indian Tamils. Detection of these genetic variants as predictive risk factors may lead to the selection of patient-tailored therapy to maximize the effectiveness of therapy. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  17. Polymorphisms in genes TLR1, 2 and 4 are associated with differential cytokine and chemokine serum production in patients with leprosy.

    Science.gov (United States)

    Santana, Nadja de Lima; Rêgo, Jamile Leão; Oliveira, Joyce Moura; Almeida, Lucas Frederico de; Braz, Marcos; Machado, Lídia Maria Medeiros; Machado, Paulo Roberto Lima; Castellucci, Léa Cristina

    2017-04-01

    Leprosy or hansen's disease is a spectral disease whose clinical forms mostly depends on host's immune and genetic factors. Different Toll-like receptors (TLR) variants have been described associated with leprosy, but with some lack of replication across different populations. To evaluate the role of polymorphisms in genes TLR1, TLR2 and TLR4 and susceptibility to leprosy in a genetic case control study; to verify the association between genotypes of these markers and the immunological profile in the serum of patients with leprosy. Pre-designed TaqMan® assays were used to genotype markers at TLR1 (rs4833095, rs5743551), TLR2 (rs7656411, rs3804099) and TLR4 (rs1927914, rs1927911). A panel of cytokines and chemokines was accessed by enzime-linked immunosorbent assay (ELISA) test in the serum of a subgroup of patients with and without leprosy reactions. Our results show an association between the T allele of rs3804099 at the TLR2 gene and increased risk for leprosy per se [Odds ratio (OR) = 1.296, p = 0,022]. In addition, evaluating the association between different genotypes of the TLR1, 2 and 4 markers and cytokine/chemokine serological levels, IL-17 appears as an immunological marker regulated by the polymorphism of the three TLR genes evaluated, whereas different TLR1 genotypes were associated with differential production of IL-12p40 and MCP-1(CCL2). Furthermore, other relevant serum markers such as CXCL-10 and IL-6 seemed to be regulated by TLR2 variants and IL-1β was related to TLR4 genotypes. All together our data points that the tested TLR markers may have a regulatory role in the immunity against Mycobacterium leprae, by driving the host's production of key cytokines and chemokines involved in the pathogenesis of this disease.

  18. Polymorphisms in genes TLR1, 2 and 4 are associated with differential cytokine and chemokine serum production in patients with leprosy

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    Nadja de Lima Santana

    Full Text Available BACKGROUND Leprosy or hansen’s disease is a spectral disease whose clinical forms mostly depends on host’s immune and genetic factors. Different Toll-like receptors (TLR variants have been described associated with leprosy, but with some lack of replication across different populations. OBJECTIVES To evaluate the role of polymorphisms in genes TLR1, TLR2 and TLR4 and susceptibility to leprosy in a genetic case control study; to verify the association between genotypes of these markers and the immunological profile in the serum of patients with leprosy. METHODS Pre-designed TaqMan® assays were used to genotype markers at TLR1 (rs4833095, rs5743551, TLR2 (rs7656411, rs3804099 and TLR4 (rs1927914, rs1927911. A panel of cytokines and chemokines was accessed by enzime-linked immunosorbent assay (ELISA test in the serum of a subgroup of patients with and without leprosy reactions. FINDINGS Our results show an association between the T allele of rs3804099 at the TLR2 gene and increased risk for leprosy per se [Odds ratio (OR = 1.296, p = 0,022]. In addition, evaluating the association between different genotypes of the TLR1, 2 and 4 markers and cytokine/chemokine serological levels, IL-17 appears as an immunological marker regulated by the polymorphism of the three TLR genes evaluated, whereas different TLR1 genotypes were associated with differential production of IL-12p40 and MCP-1(CCL2. Furthermore, other relevant serum markers such as CXCL-10 and IL-6 seemed to be regulated by TLR2 variants and IL-1β was related to TLR4 genotypes. MAIN CONCLUSIONS All together our data points that the tested TLR markers may have a regulatory role in the immunity against Mycobacterium leprae, by driving the host’s production of key cytokines and chemokines involved in the pathogenesis of this disease.

  19. Effect of Amaranthus on Advanced Glycation End-Products Induced Cytotoxicity and Proinflammatory Cytokine Gene Expression in SH-SY5Y Cells

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    Warisa Amornrit

    2015-09-01

    Full Text Available Amaranthus plants, or spinach, are used extensively as a vegetable and are known to possess medicinal properties. Neuroinflammation and oxidative stress play a major role in the pathogenesis of many neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Advanced glycation end-products (AGEs cause cell toxicity in the human neuronal cell line, SH-SY5Y, through an increase in oxidative stress, as shown by reducing cell viability and increasing cell toxicity in a dose-dependent manner. We found that preincubation of SH-SY5Y cells with either petroleum ether, dichloromethane or methanol extracts of A. lividus and A. tricolor dose-dependently attenuated the neuron toxicity caused by AGEs treatment. Moreover, the results showed that A. lividus and A. tricolor extracts significantly downregulated the gene expression of the pro-inflammatory cytokines, TNF-α, IL-1 and IL-6 genes in AGEs-induced cells. We concluded that A. lividus and A. tricolor extracts not only have a neuroprotective effect against AGEs toxicity, but also have anti-inflammatory activity by reducing pro-inflammatory cytokine gene expression. This suggests that Amaranthus may be useful for treating chronic inflammation associated with neurodegenerative disorders.

  20. Interactive roles of NPR1 gene-dosage and salt diets on cardiac angiotensin II, aldosterone and pro-inflammatory cytokines levels inmutantmice

    Science.gov (United States)

    Zhao, Di; Das, Subhankar; Pandey, Kailash N.

    2015-01-01

    Objective The objective of the present study was to elucidate the interactive roles of guanylyl cyclase/natriuretic peptide receptor-A (NPRA) gene (Npr1) and salt diets on cardiac angiotensin II (ANG II), aldosterone and proinflammatory cytokines levels in Npr1 gene-targeted (1-copy, 2-copy, 3-copy, 4-copy) mice. Methods Npr1 genotypes included 1-copy gene-disrupted heterozygous (+/−), 2-copy wild-type (+/+), 3-copy gene-duplicated heterozygous (++/+) and 4-copy gene-duplicated homozygous (++/++) mice. Animals were fed low, normal and high-salt diets. Plasma and cardiac levels of ANG II, aldosterone and pro-inflammatory cytokines were determined. Results With a high-salt diet, cardiac ANG II levels were increased (+) in 1-copy mice (13.7 ± 2.8 fmol/mg protein, 111%) compared with 2-copy mice (6.5 ± 0.6), but decreased (−) in 4-copy (4.0 ± 0.5, 38%) mice. Cardiac aldosterone levels were increased (+) in 1-copy mice (80 ± 4 fmol/mg protein, 79%) compared with 2-copy mice (38 ± 3). Plasma tumour necrosis factor alpha was increased (+) in 1-copy mice (30.27 ± 2.32 pg/ml, 38%), compared with 2-copy mice (19.36 ± 2.49, 24%), but decreased (−) in 3-copy (11.59 ± 1.51, 12%) and 4-copy (7.13 ± 0.52, 22%) mice. Plasma interleukin (IL)-6 and IL-1α levels were also significantly increased (+) in 1-copy compared with 2-copy mice but decreased (−) in 3-copy and 4-copy mice. Conclusion These results demonstrate that a high-salt diet aggravates cardiac ANG II, aldosterone and proinflammatory cytokine levels in Npr1 gene-disrupted 1-copy mice, whereas, in Npr1 gene-duplicated (3-copy and 4-copy) mice, high salt did not render such elevation, suggesting the potential roles of Npr1 against salt loading. PMID:23188418

  1. Effect of Gene Polymorphism of Inflammatory Cytokines on Postoperative Prognosis of Patients with Coronary Heart Disease: A Study on Translational Medicine

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    Bing-bing SUN

    2016-03-01

    Full Text Available To explore the effect of gene polymorphism of inflammatory cytokines on the prognosis of patients with coronary atherosclerotic heart disease (coronary heart disease, CHD after surgical treatment, and to provide individualized therapeutic evidence for CHD at gene level so as to promote the translational application of research achievements in CHD genetics. Methods: A total of 120 patients with CHD underwent off-pump coronary artery bypass grafting (OPCABG. The whole blood was drawn before surgery, and gene polymorphism of inflammatory cytokines was detected using polymerase chain reaction (PCR and gene sequencing. The plasma was respectively taken before and 4 h, 24 h and 72 h after surgery. The levels of inflammatory cytokines were all detected using Liquichip system. Results: The levels of plasma interleukin (IL-6, IL-8 and IL-10 increased after surgery and reached the peak 4 h after surgery. The levels of IL-8 and IL-10 decreased to the preoperative within 72 h after surgery, but that of IL-6 was still higher than surgery before. The level of tumor necrosis factor-α (TNF-α began to decrease 4 h after surgery, but increased to the preoperative 72 h after surgery. There were 4 cases of GC and 116 cases of GG in IL-6 genotypes, 12 cases of AA, 67 cases of AT and 41 cases of TT in IL-8 genotypes, 4 cases of GG, 21 cases of AG and 95 cases of AA in IL-10 genotypes as well as 19 cases of AG and 101 cases of GG in TNF-α genotypes. 4 h after surgery, the levels of IL-6 in patients with IL-6-174GG genotype, IL-8 in patients with IL-8-251AA genotype and IL-10 in patients with IL-10-1082AA genotype were all significantly higher than those with other genotypes at the same time. No difference was statistically significant among different genotypes at other time points regarding the levels of inflammatory cytokines. The results of Logistic regression analysis indicated that the risk of postoperative ventilator-applied time >1 d and hospital stays >14 d

  2. PAH- and PCB-induced Alterations of Protein Tyrosine Kinase and Cytokine Gene Transcription in Harbor Seal (Phoca Vitulina PBMC

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    Jennifer C. C. Neale

    2005-01-01

    Full Text Available Mechanisms underlying in vitro immunomodulatory effects of polycyclic aromatic hydrocarbons (PAHs and polychlorinated biphenyls (PCBs were investigated in harbor seal peripheral leukocytes, via real-time PCR. We examined the relative genetic expression of the protein tyrosine kinases (PTKs Fyn and Itk, which play a critical role in T cell activation, and IL-2, a cytokine of central importance in initiating adaptive immune responses. IL-1, the macrophage-derived pro-inflammatory cytokine of innate immunity, was also included as a measure of macrophage function. Harbor seal PBMC were exposed to the prototypic immunotoxic PAH benzo[a]pyrene (BaP, 3,3',4,4',5,5'-hexachlorobiphenyl (CB-169, a model immunotoxic PCB, or DMSO (vehicle control. Exposure of Con A-stimulated harbor seal PBMC to both BaP and CB-169 produced significantly altered expression in all four targets relative to vehicle controls. The PTKs Fyn and Itk were both up-regulated following exposure to BaP and CB-169. In contrast, transcripts for IL-2 and IL-1 were decreased relative to controls by both treatments. Our findings are consistent with those of previous researchers working with human and rodent systems and support a hypothesis of contaminant-altered lymphocyte function mediated (at least in part by disruption of T cell receptor (TCR signaling and cytokine production.

  3. Regulation of tissue inhibitor of metalloproteinases-1 gene expression by cytokines and dexamethasone in rat hepatocyte primary cultures.

    Science.gov (United States)

    Roeb, E; Graeve, L; Hoffmann, R; Decker, K; Edwards, D R; Heinrich, P C

    1993-12-01

    The steady-state levels of extracellular matrix proteins are regulated by the rates of their synthesis and degradation. Metalloproteinases and their specific inhibitors, tissue inhibitor of metalloproteinases-1 and -2 are believed to play a crucial role in extracellular matrix protein degradation. Here we show that the tissue inhibitor of metalloproteinases-1 is expressed in rat hepatocytes in primary culture and regulated by inflammatory cytokines. Rat hepatocytes constitutively express mRNA of tissue inhibitors of metalloproteinases-1 at a low level. Incubation with conditioned medium from lipopolysaccharide-stimulated human monocytes led to a dramatic induction of mRNA of tissue inhibitors of metalloproteinases-1. The inflammatory cytokines interleukin-1 beta, interleukin-6, interleukin-11, leukemia inhibitory factor and ciliary neurotrophic factor were also capable of stimulating expression of mRNA of tissue inhibitors of metalloproteinases-1. Among these cytokines interleukin-6 was the most potent stimulator. The combination of interleukin-1 beta, interleukin-6 and interleukin-11 synergistically up-regulated mRNA of tissue inhibitors of metalloproteinases-1. The synthetic glucocorticoid dexamethasone dose dependently inhibited constitutive and interleukin-6-induced expression of tissue inhibitors of metalloproteinases-1. A possible involvement of tissue inhibitor of metalloproteinases-1 in the pathogenesis of liver fibrosis and cirrhosis is discussed.

  4. Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for molecules associated with metabolism, signaling and regulation in central nervous system mixed glial cell cultures

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    Studzinski Diane

    2009-01-01

    Full Text Available Abstract Background Cytokines secreted by immune cells and activated glia play central roles in both the pathogenesis of and protection from damage to the central nervous system (CNS in multiple sclerosis (MS. Methods We have used gene array analysis to identify the initial direct effects of cytokines on CNS glia by comparing changes in early gene expression in CNS glial cultures treated for 6 hours with cytokines typical of those secreted by Th1 and Th2 lymphocytes and monocyte/macrophages (M/M. Results In two previous papers, we summarized effects of these cytokines on immune-related molecules, and on neural and glial related proteins, including neurotrophins, growth factors and structural proteins. In this paper, we present the effects of the cytokines on molecules involved in metabolism, signaling and regulatory mechanisms in CNS glia. Many of the changes in gene expression were similar to those seen in ischemic preconditioning and in early inflammatory lesions in experimental autoimmune encephalomyelitis (EAE, related to ion homeostasis, mitochondrial function, neurotransmission, vitamin D metabolism and a variety of transcription factors and signaling pathways. Among the most prominent changes, all three cytokine mixtures markedly downregulated the dopamine D3 receptor, while Th1 and Th2 cytokines downregulated neuropeptide Y receptor 5. An unexpected finding was the large number of changes related to lipid metabolism, including several suggesting a switch from diacylglycerol to phosphatidyl inositol mediated signaling pathways. Using QRT-PCR we validated the results for regulation of genes for iNOS, arginase and P glycoprotein/multi-drug resistance protein 1 (MDR1 seen at 6 hours with microarray. Conclusion Each of the three cytokine mixtures differentially regulated gene expression related to metabolism and signaling that may play roles in the pathogenesis of MS, most notably with regard to mitochondrial function and neurotransmitter

  5. Calyptranthes grandifolia O.Berg (Myrtaceae) ethanolic extract inhibits TNF-α gene expression and cytokine release in vitro.

    Science.gov (United States)

    Dexheimer, Geórgia Muccillo; Becker Delving, Luciana Knabben de Oliveira; de Oliveira, Henrique Sulzbach; Biolchi, Vanderlei; Goettert, Márcia Inês; Pozzobon, Adriane

    2017-05-01

    Anti-tumor therapies based on anti-inflammatory effects have been considered in cancer treatment. Survival, proliferation and, resultantly, invasion and metastasis of tumor cells are regulated by local inflammatory mediators. Primary inflammatory cytokines, such as tumor necrosis factor (TNF), are targets for anticancer therapy. Several anti‑inflammatory agents isolated from natural products are becoming important chemopreventive and therapeutic agents for cancer. The present study aimed to investigate the expression of TNF‑α, nuclear factor‑κΒ (NF‑κΒ) and p38α mitogen-activated protein kinase (p38α) genes, associated with proliferation and inflammation in the Caco‑2 cell line treated with ethanolic and hexanic extracts of Calyptranthes grandifolia O.Berg (Myrtaceae). Caco‑2 cells were cultured and treated with plant extract at different concentrations (25, 50, 100 and 200 µg/ml) and stimulated with lipopolysaccharide (LPS). For gene expression, analysis was performed by total RNA extraction followed by synthesis of complementary DNA and analysis by quantitative polymerase chain reaction. The release of TNF‑α cytokine was evaluated by ELISA in RAW 264.7 murine macrophages activated by LPS. Among the evaluated genes, there was a decrease in TNF-α expression at 100 and 200 µg/ml concentrations only with the ethanolic extract (P<0.025). The p38α gene exhibited a tendency to increase expression only when treated with ethanolic extract and the NF‑κΒ gene did not significantly differ compared with the positive control when treated with either analyzed extract. The inhibition of TNF-α cytokine in the RAW 264.7 cell line was significant (P<0.05) in ethanolic extract at 200 µg/ml compared with the positive control (LPS 1 µg/ml). In conclusion, the ethanolic extract may exhibit an anti‑inflammatory activity by inhibiting TNF‑α. However, further studies are required to confirm its potential anti-inflammatory effects.

  6. The Comparison of TH1 and TH2 Cytokines Gene Expression in Allergic and Non-Allergic Patients With Nasal Polyps By PCR

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    Javadinia Sh

    2011-12-01

    Full Text Available Background: Too many studies are in the process of determining the probable role of immune system in the etiopathogenesis of nasal polyposis. This study was designed to identify the probable participation of Th1, Th2 lymphocytes in the induction and progression of nasal polyposis.Methods: Seventy-five patients, 42 male and 33 female, with nasal polyposis were examined for total serum IgE, specific serum IgE and reaction to skin test for differentiating allergic from non-allergic participants in Rasoul Akram Hospital during 2010. To determine the possible correlation of allergic reactions in the upper respiratory tract and nasal polyposis, cytokine gene expression was evaluated on the extracted RNA by RT-PCR. The data were analyzed by using c2, independent t-test, correlation and Receiver operating characteristic (ROC curve.Results: The mean age of participants was 38 years (18-81 years. IFN-γ and IL-4 gene expressions were more prevalent in allergic than non-allergic individuals (IFN-γ: 39.5% vs. 14.2%, P=0.3 and IL-4: 44.7% vs. 18.9%, P=0.02, respectively. IL-10 and IL-12 (P35 and P40 fractions genes were not significantly different between the two groups. IL-10 and IL-12 (P35, P40 genes did not differ significantly either.Conclusion: This research suggests that overproduction of cytokines and an imbalance of Th1 and Th2 cell production may play an important role in the pathophysiology of allergic or non-allergic nasal polyp formation. Thus, although nasal polyposis is a multifactorial disease with several different etiological factors, chronic persistent inflammation is undoubtedly a major factor irrespective of the etiology.

  7. Cytokine-dependent and–independent gene expression changes and cell cycle block revealed in Trypanosoma cruzi-infected host cells by comparative mRNA profiling

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    Burleigh Barbara A

    2009-05-01

    Full Text Available Abstract Background The requirements for growth and survival of the intracellular pathogen Trypanosoma cruzi within mammalian host cells are poorly understood. Transcriptional profiling of the host cell response to infection serves as a rapid read-out for perturbation of host physiology that, in part, reflects adaptation to the infective process. Using Affymetrix oligonucleotide array analysis we identified common and disparate host cell responses triggered by T. cruzi infection of phenotypically diverse human cell types. Results We report significant changes in transcript abundance in T. cruzi-infected fibroblasts, endothelial cells and smooth muscle cells (2852, 2155 and 531 genes respectively; fold-change ≥ 2, p-value T. cruzi-infected fibroblasts and endothelial cells transwell plates were used to distinguish cytokine-dependent and -independent gene expression profiles. This approach revealed the induction of metabolic and signaling pathways involved in cell proliferation, amino acid catabolism and response to wounding as common themes in T. cruzi-infected cells. In addition, the downregulation of genes involved in mitotic cell cycle and cell division predicted that T. cruzi infection may impede host cell cycle progression. The observation of impaired cytokinesis in T. cruzi-infected cells, following nuclear replication, confirmed this prediction. Conclusion Metabolic pathways and cellular processes were identified as significantly altered at the transcriptional level in response to T. cruzi infection in a cytokine-independent manner. Several of these alterations are supported by previous studies of T. cruzi metabolic requirements or effects on the host. However, our methods also revealed a T. cruzi-dependent block in the host cell cycle, at the level of cytokinesis, previously unrecognized for this pathogen-host cell interaction.

  8. Influence of single nucleotide polymorphisms of cytokine genes on anti-HBs antibody production after hepatitis B vaccination in a Japanese young adult population.

    Science.gov (United States)

    Yukimasa, Nobuyasu; Sato, Shoichi; Oboshi, Wataru; Watanabe, Toru; Uzawa, Ryuichi

    2016-01-01

    Hepatitis B (HB) vaccination is one of the most efficient tools to prevent the transmission of the virus. Considerable variability exists in HB vaccine responses, with 5-10% of healthy Japanese adults demonstrating no response following a standard vaccination. Recently, polymorphisms of immune-regulatory genes, such as cytokine genes, have been reported to influence the immune response to HB vaccine. The aim of this study was to investigate the underlying mechanisms of the genetic association between several cytokine gene polymorphisms and the immune response to HB vaccination in a Japanese population. One hundred and twenty three vaccinated young adults were classified according to the level of antibody-titer (anti-HBs). Single nucleotide polymorphism typing for IFN-γ (+874, 3'-UTR), IL-10 (-591, -819, -1082), and TNF-α (-308, -857), was accomplished using the PCR-RFLP or SSP-PCR method. The TNF-α (-857) CC type and the IL-10 (-1082) AG type were present more frequently in the low titer group than in the high titer group. The TNF-α (-857) CC type was found to be significantly associated with low response of serum anti-HBs. The anti-HBs antibody was not readily produced in the IL-10 (-1082) AG and TNF-α (-857) CC haplotype. Conversely, the antibody was readily produced in the IL-10 (-1082) AA and TNF-α (-857) CC haplotype, and the IL-10 (-1082) AA and TNF-α (-857) CT haplotype, suggesting a high likelihood of the IL-10 (-1082) AG type to be included in the low anti-HBs group, and high anti-HBs antibody production in those with the TNF-α (-857) CT type. These SNPs may produce ethnically-specific differences in the immune response to HB vaccine in the Japanese population. J. Med. Invest. 63: 256-261, August, 2016.

  9. Gene disruption study reveals a non-redundant role for TRIM21/Ro52 in NF-κB-dependent cytokine expression in fibroblasts1

    Science.gov (United States)

    Yoshimi, Ryusuke; Chang, Tsung-Hsien; Wang, Hongsheng; Atsumi, Toru; Morse, Herbert C.; Ozato, Keiko

    2009-01-01

    The tripartite motif (TRIM) family member, TRIM21, is an E3 ubiquitin ligase for IRF3 and IRF8 that functions in both innate and acquired immunity. It is also an autoantigen known as Ro52/SS-A. The function of TRIM21 in vivo, however, has remained elusive. We generated Trim21−/− mice with the Trim21 gene replaced by an EGFP reporter. EGFP expression analyses showed that Trim21 was widely expressed in many tissues, with the highest levels in immune cells. Studies of Trim21−/− embryonic fibroblasts demonstrated that TLR-mediated induction of proinflammatory cytokines, including IL-1β, IL-6, TNFα and CXCL10, was consistently upregulated relative to wild-type cells. Reporter analyses demonstrated that TLR-mediated NF-κB activation was higher in Trim21−/− cells than in wild-type cells, likely accounting for their enhanced cytokine expression. In contrast, functional analyses of immune cells from Trim21−/− mice revealed no abnormalities in their composition or function, even though ubiquitylation of IRF3 and IRF8 was impaired. These results suggested possible redundancies in activities mediated by TRIM21. In keeping with this concept, we found that a number of TRIM family members were upregulated in Trim21−/− cells. Taken together, these findings demonstrate that TRIM21 plays a previously unrecognized role in the negative regulation of NF-κB-dependent proinflammatory cytokine responses, and suggest that multiple TRIM proteins contribute to the maintenance of functional equilibrium in inflammatory responses, in part through functional redundancy. PMID:19494276

  10. Identification of marker genes for pars tuberalis morphogenesis in chick embryo: expression of Cytokine-like 1 and Gap junction protein alpha 5 in pars tuberalis.

    Science.gov (United States)

    Aizawa, Sayaka; Higaki, Yuriko; Dudaui, Amrita; Nagasaka, Mai; Takahashi, Sumio; Sakata, Ichiro; Sakai, Takafumi

    2016-12-01

    The adenohypophysis is formed from the oral ectoderm and consists of the pars distalis (PD), pars intermedia, and pars tuberalis (PT). The mechanisms of PD development have been extensively studied, and the cellular differentiation of the PD is well understood. However, the morphogenesis and differentiation of the PT are still unclear, and the genes expressed during PT development remain largely unknown. We have explored genes specifically expressed in the PT during embryonic development and analyzed their spatiotemporal expression patterns. Microarray analysis of laser-captured PT and PD tissues obtained from chick embryos on embryonic day 10 (E10.0) has shown high expression of Cytokine-like 1 (CYTL1) and Gap junction protein alpha 5 (GJA5) genes in the PT. Detailed analysis of these spatiotemporal expression patterns during chick embryo development by in situ hybridization has revealed that CYTL1 mRNA first appears in the lateral head ectoderm and ventral head ectoderm at E1.5. The expression of CYTL1 moves into Rathke's pouch at E2.5 and is then localized in the PT primordium where it is continuously expressed until E12.0. GJA5 mRNA is transiently detected in the PT primordium from E6.0 to E12.0, whereas its expression is not detected in the PD during development. Thus, these genes might be involved in the regulation mechanisms of PT development and could be useful markers for PT development.

  11. Coordinate cytokine regulatory sequences

    Science.gov (United States)

    Frazer, Kelly A.; Rubin, Edward M.; Loots, Gabriela G.

    2005-05-10

    The present invention provides CNS sequences that regulate the cytokine gene expression, expression cassettes and vectors comprising or lacking the CNS sequences, host cells and non-human transgenic animals comprising the CNS sequences or lacking the CNS sequences. The present invention also provides methods for identifying compounds that modulate the functions of CNS sequences as well as methods for diagnosing defects in the CNS sequences of patients.

  12. Genetic association of pro-inflammatory cytokine gene polymorphisms with coronary artery disease (CAD) in a North Indian population.

    Science.gov (United States)

    Mastana, Sarabjit; Prakash, Swayam; Akam, Elizabeth C; Kirby, Melissa; Lindley, Martin R; Sinha, Nakul; Agrawal, Suraksha

    2017-09-10

    Cytokines regulate the expression of inflammatory molecules which destabilize the atheromatic plaques. This study focuses on studying the association of inflammatory cytokine polymorphisms like TNF-α -308 (G/A), TNF-β +252 (A/G), IL-6 -174 (G/C) and IL-6 -597 (G/A), and IFN-ɣ +874 (T/A) with coronary artery disease (CAD) among north Indian patients. 143 CAD and 137 normal healthy controls were recruited in this study. DNA extraction was carried out by high salting out method. TNF-α -308 (G/A) (rs1800797), TNF-β +252 (A/G) (rs909253), IL-6 -174 (G/C) (rs1800795), IL6 -597 (G/A) (rs1800797), and IFN-ɣ +874 (T/A) (rs2430561) SNPs were genotyped by TaqMan®SNP genotyping assays. Different statistical analyses were performed using SPSS v 22.0 and SNPStats. p≤0.05 was considered significant. Significant risk association with CAD was found for TNF-α -308 (G/A) "A" allele (OR=5.6, CI 1.8-17.4, p=0.001) and TNF-β +252 (A/G) "G" allele (OR=3.4, CI=1.9-6.0, pCAD. TNF-α -308 (G/A), and TNF-β +252 (A/G) haplotype "GG" "AG" increased CAD risk significantly (GG haplotype, adjusted OR=2.6, CI 1.4-5.0, p=0.003 and AG haplotype OR=8.5, CI 2.2-33.35, p=0.002) after adjustments for age, sex, TC, TG, HDL, APOB, smoking and diet. The present study found significant risk association for TNF-α -308 (G/A), and TNF-β +252 (A/G) genotypes, alleles and haplotypes, with CAD in a North Indian population. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. The Modulatory Effect of Ellagic Acid and Rosmarinic Acid on Ultraviolet-B-Induced Cytokine/Chemokine Gene Expression in Skin Keratinocyte (HaCaT Cells

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    Serena Lembo

    2014-01-01

    Full Text Available Ultraviolet radiation (UV induces an increase in multiple cutaneous inflammatory mediators. Ellagic acid (EA and rosmarinic acid (RA are natural anti-inflammatory and immunomodulatory compounds found in many plants, fruits, and nuts. We assessed the ability of EA and RA to modulate IL-1β, IL-6, IL-8, IL-10, MCP-1, and TNF-α gene expression in HaCaT cells after UVB irradiation. Cells were treated with UVB (100 mJ/cm2 and simultaneously with EA (5 μM in 0.1% DMSO or RA (2.7 μM in 0.5% DMSO. Moreover, these substances were added to the UVB-irradiated cells 1 h or 6 h before harvesting, depending on the established UVB-induced cytokine expression peak. Cytokine gene expression was examined using quantitative real time polymerase chain reaction. RA produced a significant reduction in UVB-induced expression of IL-6, IL-8, MCP-1, and TNF-α when applied at the same time as irradiation. EA showed milder effects compared with RA, except for TNF-α. Both substances decreased IL-6 expression, also when applied 5 h after irradiation, and always produced a significant increase in UVB-induced IL-10 expression. Our findings suggest that EA and RA are able to prevent and/or limit the UVB-induced inflammatory cascade, through a reduction in proinflammatory mediators and the enhancement of IL-10, with its protective function.

  14. Comparison of Bacterial Burden and Cytokine Gene Expression in Golden Hamsters in Early Phase of Infection with Two Different Strains of Leptospira interrogans.

    Science.gov (United States)

    Fujita, Rie; Koizumi, Nobuo; Sugiyama, Hiromu; Tomizawa, Rina; Sato, Ryoichi; Ohnishi, Makoto

    2015-01-01

    Leptospirosis, a zoonotic infection with worldwide prevalence, is caused by pathogenic spirochaetes of Leptospira spp., and exhibits an extremely broad clinical spectrum in human patients. Although previous studies indicated that specific serovars or genotypes of Leptospira spp. were associated with severe leptospirosis or its outbreak, the mechanism underlying the difference in virulence of the various Leptospira serotypes or genotypes remains unclear. The present study addresses this question by measuring and comparing bacterial burden and cytokine gene expression in hamsters infected with strains of two L. interrogans serovars Manilae (highly virulent) and Hebdomadis (less virulent). The histopathology of kidney, liver, and lung tissues was also investigated in infected hamsters. A significantly higher bacterial burden was observed in liver tissues of hamsters infected with serovar Manilae than those infected with serovar Hebdomadis (p hamsters infected with serovar Manilae and 1,340 and 4,896, respectively, in hamsters infected with serovar Hebdomadis. The expression levels of mip1alpha in blood; tgfbeta, il1beta, mip1alpha, il10, tnfalpha and cox2 in liver; and tgfbeta, il6, tnfalpha and cox2 in lung tissue were significantly higher in hamsters infected with serovar Manilae than those infected with serovar Hebdomadis (p hamsters with tnfalpha upregulation (p = 0.04). Severe distortion of tubular cell arrangement and disruption of renal tubules in kidney tissues and hemorrhage in lung tissues were observed in Manilae-infected hamsters. These results demonstrate that serovar Manilae multiplied more efficiently in liver tissues and induced significantly higher expression of genes encoding pro- and anti-inflammatory cytokines than serovar Hebdomadis even in tissues for which a significant difference in leptospiral load was not observed. In addition, our results suggest a serovar Manilae-specific mechanism responsible for inducing severe damage in kidneys and

  15. Methionine-supplemented diet affects the expression of cardiovascular disease-related genes and increases inflammatory cytokines in mice heart and liver.

    Science.gov (United States)

    Aissa, Alexandre Ferro; Amaral, Catia Lira do; Venancio, Vinicius Paula; Machado, Carla da Silva; Hernandes, Lívia Cristina; Santos, Patrick Wellington da Silva; Curi, Rui; Bianchi, Maria de Lourdes Pires; Antunes, Lusânia Maria Greggi

    2017-01-01

    Some important environmental factors that influence the development of cardiovascular diseases (CVD) include tobacco, excess alcohol, and unhealthy diet. Methionine obtained from the diet participates in the synthesis of DNA, proteins, lipids and affects homocysteine levels, which is associated with the elevated risk for CVD development. Therefore, the aim of this study was to investigate the manner in which dietary methionine might affect cellular mechanisms underlying CVD occurrence. Swiss albino mice were fed either control (0.3% DL-methionine), methionine-supplemented (2% DL-methionine), or a methionine-deprived diet (0% DL-methionine) over a 10-week period. The parameters measured included plasma homocysteine concentrations, oxidative stress by reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, levels of inflammatory cytokines IL-1ß, TNF-α, and IL-6, as well as expression of genes associated with CVD. The levels of apolipoprotein A5 (APOA5), a regulator of plasma triglycerides, were measured. The methionine-supplemented diet increased oxidative stress by lowering the GSH/GSSG ratio in heart tissues and decreased expression of the genes Apob, Ctgf, Serpinb2, Spp1, Il1b, and Sell, but elevated expression of Thbs4, Tgfb2, Ccr1, and Vegfa. Methionine-deprived diet reduced expression of Col3a1, Cdh5, Fabp3, Bax, and Hbegf and increased expression of Sell, Ccl5, Itga2, Birc3, Msr1, Bcl2a1a, Il1r2, and Selp. Methionine-deprived diet exerted pro-inflammatory consequences as evidenced by elevated levels of cytokines IL-1ß, TNF-α, and IL-6 noted in liver. Methionine-supplemented diet increased hepatic IL-6 and cardiac TNF-α. Both methionine supplementation and deprivation lowered hepatic levels of APOA5. In conclusion, data demonstrated that a methionine-supplemented diet modulated important biological processes associated with high risk of CVD development.

  16. Effects of Thyme Extract Oils (from Thymus vulgaris, Thymus zygis, and Thymus hyemalis on Cytokine Production and Gene Expression of oxLDL-Stimulated THP-1-Macrophages

    Directory of Open Access Journals (Sweden)

    A. Ocaña

    2012-01-01

    Full Text Available Properties of thyme extracts from three different species (Thymus vulgaris, Thymus zygis, and Thymus hyemalis were examined. Two oil fractions from each species were obtained by CO2 supercritical fluid extraction. Main compounds presented in the supercritical extracts of the three thyme varieties were 1,8 cineole, thymol, camphor, borneol, and carvacrol. As a cellular model of inflammation/atherogenesis, we use human macrophages derived from THP-1 monocytes and activated by oxidized LDLs. These cells were incubated with the thyme fraction oils, and the productions and gene expressions of the inflammatory mediators TNF-α, IL-1B, IL-6, and IL-10 were determined. Thyme extracts significantly reduced production and gene expression of the proinflammatory mediators TNF-α, IL-1B, and IL-6 and highly increased these parameters on the anti-inflammatory IL-10 cytokine. Changes on production and gene expressions were dose dependent and according to the thyme content of each species. Taken together, these results may suggest that thyme extracts could have anti-inflammatory effects.

  17. Effects of Thyme Extract Oils (from Thymus vulgaris, Thymus zygis, and Thymus hyemalis) on Cytokine Production and Gene Expression of oxLDL-Stimulated THP-1-Macrophages

    Science.gov (United States)

    Ocaña, A.; Reglero, G.

    2012-01-01

    Properties of thyme extracts from three different species (Thymus vulgaris, Thymus zygis, and Thymus hyemalis) were examined. Two oil fractions from each species were obtained by CO2 supercritical fluid extraction. Main compounds presented in the supercritical extracts of the three thyme varieties were 1,8 cineole, thymol, camphor, borneol, and carvacrol. As a cellular model of inflammation/atherogenesis, we use human macrophages derived from THP-1 monocytes and activated by oxidized LDLs. These cells were incubated with the thyme fraction oils, and the productions and gene expressions of the inflammatory mediators TNF-α, IL-1B, IL-6, and IL-10 were determined. Thyme extracts significantly reduced production and gene expression of the proinflammatory mediators TNF-α, IL-1B, and IL-6 and highly increased these parameters on the anti-inflammatory IL-10 cytokine. Changes on production and gene expressions were dose dependent and according to the thyme content of each species. Taken together, these results may suggest that thyme extracts could have anti-inflammatory effects. PMID:22577523

  18. Combined chromatin and expression analysis reveals specific regulatory mechanisms within cytokine genes in the macrophage early immune response.

    Directory of Open Access Journals (Sweden)

    Maria Jesus Iglesias

    Full Text Available Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS.To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches--gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII, which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF, was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines, was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40% was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at

  19. Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells.

    Science.gov (United States)

    Novo, Erica; Busletta, Chiara; Bonzo, Lorenzo Valfrè di; Povero, Davide; Paternostro, Claudia; Mareschi, Katia; Ferrero, Ivana; David, Ezio; Bertolani, Cristiana; Caligiuri, Alessandra; Cannito, Stefania; Tamagno, Elena; Compagnone, Alessandra; Colombatto, Sebastiano; Marra, Fabio; Fagioli, Franca; Pinzani, Massimo; Parola, Maurizio

    2011-05-01

    Liver fibrogenesis is sustained by myofibroblast-like cells originating from hepatic stellate cells (HSC/MFs), portal fibroblasts or bone marrow-derived cells, including mesenchymal stem cells (MSCs). Herein, we investigated the mechanistic role of intracellular generation of reactive oxygen species (ROS) and redox-sensitive signal transduction pathways in mediating chemotaxis, a critical profibrogenic response for human HSC/MFs and for MSC potentially engrafting chronically injured liver. Intracellular generation of ROS and signal transduction pathways were evaluated by integrating morphological and molecular biology techniques. Chemokinesis and chemotaxis were evaluated by wound healing assay and modified Boyden's chamber assay, respectively. Additional in vivo evidence was obtained in human specimens from HCV-related cirrhosis. Human MSCs and HSC/MFs migrate in response to a panel of polypeptide chemoattractants and extracellularly generated superoxide anion. All polypeptides induced a NADPH-oxidase-dependent intracellular rise in ROS, resulting in activation of ERK1/2 and JNK1/2. Moreover, menadione or 2,3-dimethoxy-1,4-naphthoquinone, which generate intracellular superoxide anion or hydrogen peroxide, respectively, induced ERK1/2 and JNK1/2 activation and migration. JNK1 activation was predominant for migration as shown by specific silencing. Finally, activation of ERK1/2 and JNK1/2 was found in extracts obtained from HSC/MFs during the course of an oxidative stress-mediated model of liver injury and phosphorylated JNK1/2 isoforms were detected in α-smooth muscle actin-positive myofibroblasts lining fibrotic septa in human cirrhotic livers. Intracellular generation of ROS, through activation of specific signaling pathways, is a critical event for directional migration of HSC/MFs and MSCs. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  20. Live and heat-killed Lactobacillus rhamnosus GG upregulate gene expression of pro-inflammatory cytokines in 5-fluorouracil-pretreated Caco-2 cells.

    Science.gov (United States)

    Fang, Shiuh-Bin; Shih, Hsin-Yu; Huang, Chih-Hung; Li, Li-Ting; Chen, Chia-Chun; Fang, Hsu-Wei

    2014-06-01

    This study investigates whether post-chemotherapeutic use of live and heat-killed Lactobacillus rhamnosus GG can modulate the expression of three pro-inflammatory cytokines in 5-fluorouracil (5-FU)-induced intestinal mucositis in vitro. Live L. rhamnosus GG and heat-killed L. rhamnosus GG were observed using scanning electron microscopy. To establish the duration required for optimal expression of tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), and interleukin-12 (IL-12), 5 μM of 5-FU was selected to treat 10-day-old Caco-2 cells for 4, 6, 8, and 24 h. Caco-2 cells were treated with 5-FU (5 μM) for 4 h, followed by the administration of live L. rhamnosus GG (multiplicity of infection = 25), and heat-killed L. rhamnosus GG for 2 and 4 h. Finally, total cellular RNA was isolated to quantify mRNA expression of TNF-α, MCP-1, and IL-12 using real-time PCR. The results demonstrated that heat-killed L. rhamnosus GG remained structurally intact with elongation. A biphasic upregulated expression of TNF-α, MCP-1, and IL-12 was observed in 5-FU-treated Caco-2 cells at 4 and 24 h. Compared to non-L. rhamnosus GG controls in 5-FU-pretreated Caco-2 cells, a 2-h treatment of heat-killed L. rhamnosus GG significantly upregulated the MCP-1 expression (p GG treatments lasting 4 h upregulated the TNF-α and MCP-1 expression (p GG upregulated the IL-12 expression (p GG can upregulate the gene expression of 5-FU-induced pro-inflammatory cytokines in Caco-2 cells. Human intestinal epithelium may be vulnerable to the post-chemotherapeutic use of L. rhamnosus GG in 5-FU-induced mucositis that requires further in vivo studies for clarification.

  1. Transforming growth factor beta receptor endoglin is expressed in cardiac fibroblasts and modulates profibrogenic actions of angiotensin II.

    Science.gov (United States)

    Chen, Kui; Mehta, Jawahar L; Li, Dayuan; Joseph, Lija; Joseph, Jacob

    2004-12-10

    Angiotensin II (Ang II) is a powerful mediator of adverse cardiac remodeling and fibrosis. However, the mechanisms of Ang II-induced myocardial fibrosis remain to be clarified. We postulated that Ang II alters transforming growth factor beta (TGF-beta) receptor expression, specifically that of endoglin, and thereby modulates cardiac fibroblast (CF) collagen metabolism. Experiments were conducted using CF from adult Sprague Dawley rats to determine the expression of TGF-beta1 receptors including endoglin, and the role of Ang II type 1 (AT1) and type 2 (AT2) receptors, and MAPK p42/44 in this process. The functional role of endoglin in modulating Ang II effects on matrix metalloproteinase-1 (MMP-1) and type I collagen expression was also analyzed. Endoglin gene and protein expression were consistently identified in quiescent CFs. Ang II increased the expression of endoglin mRNA and protein in a concentration and time-dependent manner, with no effect on TGF-beta receptors I and II expression. This effect was AT1 receptor mediated, because AT1 receptor antagonists valsartan, candesartan, and losartan inhibited Ang II-induced endoglin expression, whereas the AT2 receptor antagonist PD123319 had no effect. MAPKp42/44 inhibition attenuated Ang II-induced endoglin expression. Ang II-induced decrease in MMP-1 protein expression and increase in type I collagen protein expression were both blocked by a specific endoglin antibody. Hence, our results indicate that endoglin is upregulated in CFs by Ang II via the AT1 receptor and modulates profibrotic effects of Ang II. These findings provide novel insights into Ang II-induced cardiac remodeling.

  2. Analysis of transforming growth factor-beta and profibrogenic molecules in a rat cardiac allograft model treated with cyclosporine.

    Science.gov (United States)

    Khanna, Ashwani K; Hosenpud, Jessica S; Plummer, Matthew S; Hosenpud, Jeffrey D

    2002-05-27

    Long-term treatment of heart transplantation recipients with cyclosporine (CsA) results in chronic nephrotoxic effects, which frequently lead to progressive renal failure. Transforming growth factor (TGF)-beta and other fibrogenic molecules are leading candidates for these effects, because CsA is known to induce TGF-beta. In this study we compared the expression of TGF-beta, collagen, fibronectin, metalloproteinases, and tissue inhibitors of metalloproteinases in kidneys from recipients of heterotopic heart transplants treated with CsA for 30 and 180 days. Using a clinically relevant experimental rodent model (strain combination Wistar Furth [RT1u] into Lewis [RT1l]), heterotopic heart transplantation was performed, creating disparate cardiac allografts. The transplant study population was divided into three groups: controls and those receiving CsA immunosuppression therapy to maintain graft survival for 30-day and 180-day periods. Comparisons were made of intrarenal expression of TGF-beta, collagen, fibronectin, metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of MMP-2, using reverse transcriptase-polymerase chain reaction. Intrarenal expression of TGF-beta protein was also compared using immunochemical staining technique, and circulating levels of TGF-beta protein were quantified by ELISA. Intrarenal expression of TGF-beta, collagen, fibronectin, MMP-2, MMP-9, and tissue inhibitor of MMP-2 was significantly increased in rats treated with CsA for 180 days compared with untreated rats and those treated for 30 days. Circulating levels and intrarenal expression of TGF-beta were also significantly increased in rats treated for 180 days. Posttransplantation nephrotoxicity in cardiac transplant recipients treated with CsA for a long term is related to increased expression of TGF-beta and other fibrogenic genes. Therapies designed to inhibit expression of TGF-beta could ameliorate CsA-associated nephrotoxicity in cardiac transplant recipients.

  3. Cytokine-Enhanced Vaccine and Interferon-β plus Suicide Gene Therapy as Surgery Adjuvant Treatments for Spontaneous Canine Melanoma.

    Science.gov (United States)

    Finocchiaro, Liliana M E; Fondello, Chiara; Gil-Cardeza, María L; Rossi, Úrsula A; Villaverde, Marcela S; Riveros, María D; Glikin, Gerardo C

    2015-06-01

    We present here a nonviral immunogene therapy trial for canine malignant melanoma, an aggressive disease displaying significant clinical and histopathological overlapping with human melanoma. As a surgery adjuvant approach, it comprised the co-injection of lipoplexes bearing herpes simplex virus thymidine kinase and canine interferon-β genes at the time of surgery, combined with the periodic administration of a subcutaneous genetic vaccine composed of tumor extracts and lipoplexes carrying the genes of human interleukin-2 and human granulocyte-macrophage colony-stimulating factor. Following complete surgery (CS), the combined treatment (CT) significantly raised the portion of local disease-free canine patients from 11% to 83% and distant metastases-free (M0) from 44% to 89%, as compared with surgery-only-treated controls (ST). Even after partial surgery (PS), CT better controlled the systemic disease (M0: 82%) than ST (M0: 48%). Moreover, compared with ST, CT caused a significant 7-fold (CS) and 4-fold (PS) rise of overall survival, and >17-fold (CS) and >13-fold (PS) rise of metastasis-free survival. The dramatic increase of PS metastasis-free survival (>1321 days) and CS recurrence- and metastasis-free survival (both >2251 days) demonstrated that CT was shifting a rapidly lethal disease into a chronic one. In conclusion, this surgery adjuvant CT was able of significantly delaying or preventing postsurgical recurrence and distant metastasis, increasing disease-free and overall survival, and maintaining the quality of life. The high number of canine patients involved in CT (301) and the extensive follow-up (>6 years) with minimal or absent toxicity warrant the long-term safety and efficacy of this treatment. This successful clinical outcome justifies attempting a similar scheme for human melanoma.

  4. Rice Bran Protein Hydrolysates Improve Insulin Resistance and Decrease Pro-inflammatory Cytokine Gene Expression in Rats Fed a High Carbohydrate-High Fat Diet

    Directory of Open Access Journals (Sweden)

    Kampeebhorn Boonloh

    2015-08-01

    Full Text Available A high carbohydrate-high fat (HCHF diet causes insulin resistance (IR and metabolic syndrome (MS. Rice bran has been demonstrated to have anti-dyslipidemic and anti-atherogenic properties in an obese mouse model. In the present study, we investigated the beneficial effects of rice bran protein hydrolysates (RBP in HCHF-induced MS rats. After 12 weeks on this diet, the HCHF-fed group was divided into four subgroups, which were orally administered RBP 100 or 500 mg/kg, pioglitazone 10 mg/kg, or tap water for a further 6 weeks. Compared with normal diet control group, the MS rats had elevated levels of blood glucose, lipid, insulin, and HOMA-IR. Treatment with RBP significantly alleviated all those changes and restored insulin sensitivity. Additionally, RBP treatment increased adiponectin and suppressed leptin levels. Expression of Ppar-γ mRNA in adipose tissues was significantly increased whereas expression of lipogenic genes Srebf1 and Fasn was significantly decreased. Levels of mRNA of proinflammatory cytokines, Il-6, Tnf-α, Nos-2 and Mcp-1 were significantly decreased. In conclusion, the present findings support the consumption of RBP as a functional food to improve insulin resistance and to prevent the development of metabolic syndrome.

  5. Rice Bran Protein Hydrolysates Improve Insulin Resistance and Decrease Pro-inflammatory Cytokine Gene Expression in Rats Fed a High Carbohydrate-High Fat Diet.

    Science.gov (United States)

    Boonloh, Kampeebhorn; Kukongviriyapan, Veerapol; Kongyingyoes, Bunkerd; Kukongviriyapan, Upa; Thawornchinsombut, Supawan; Pannangpetch, Patchareewan

    2015-08-03

    A high carbohydrate-high fat (HCHF) diet causes insulin resistance (IR) and metabolic syndrome (MS). Rice bran has been demonstrated to have anti-dyslipidemic and anti-atherogenic properties in an obese mouse model. In the present study, we investigated the beneficial effects of rice bran protein hydrolysates (RBP) in HCHF-induced MS rats. After 12 weeks on this diet, the HCHF-fed group was divided into four subgroups, which were orally administered RBP 100 or 500 mg/kg, pioglitazone 10 mg/kg, or tap water for a further 6 weeks. Compared with normal diet control group, the MS rats had elevated levels of blood glucose, lipid, insulin, and HOMA-IR. Treatment with RBP significantly alleviated all those changes and restored insulin sensitivity. Additionally, RBP treatment increased adiponectin and suppressed leptin levels. Expression of Ppar-γ mRNA in adipose tissues was significantly increased whereas expression of lipogenic genes Srebf1 and Fasn was significantly decreased. Levels of mRNA of proinflammatory cytokines, Il-6, Tnf-α, Nos-2 and Mcp-1 were significantly decreased. In conclusion, the present findings support the consumption of RBP as a functional food to improve insulin resistance and to prevent the development of metabolic syndrome.

  6. Agaricus bisporus powder improved cutaneous mucosal and serum immune parameters and up-regulated intestinal cytokines gene expression in common carp (Cyprinus carpio) fingerlings.

    Science.gov (United States)

    Khodadadian Zou, Hassan; Hoseinifar, Seyed Hossein; Kolangi Miandare, Hamed; Hajimoradloo, Abdolmajid

    2016-11-01

    The aim of the present study was to investigate immunomodulatory effects of Agaricus bisporus, white bottom mushroom powder (WBMP) on common carp (Cyprinus carpio) fingerlings. Carps were fed on different levels of WBMP (0, 0.5, 1 and 2%) for 8 weeks and at the end of feeding trial, skin mucus immune parameters (total Ig, lysozyme and protease activity), cytokines gene expression (TNF-alpha, IL1b, IL8) in intestine as well as serum non-specific immune parameters (total Ig, lysozyme and ACH50) were measured. The results showed significant dose dependent increase of skin mucus immune parameters in carps fed WBMP (P  0.05). In case of serum non-specific immune parameters, except lysozyme activity, other parameters (Ig total and ACH50) were significantly affected by dietary inclusion of WBMP (P  0.05). Furthermore, feeding on WBMP supplemented diet significantly improved growth performance (P < 0.05). These results indicated that WBMP can be considered as a promising immunostimulants in early stage of common carp culture. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Infection of Atlantic salmon with Moritella viscosus compared to a mechanical tissue injury model in rainbow trout show similar expression patterns of cytokine genes and may be related to triggering of the same signaling pathways

    DEFF Research Database (Denmark)

    to real-time RT-PCR for measuring the expression of the genes IL-1β, IL-8, IL-10 and Collagen-1α. Overall, the results showed that all genes in both studies were locally induced by the infection or the injury and the expression patterns between the two models were very similar, although the kinetics were...... different. For both the experiments the expression of pro-inflammatory cytokines peaked first followed by an increase in the amount of IL-10 and Collagen-1α mRNA. Thus it is suggested that stimulation by pathogen associated molecular patterns (PAMPs) trigger the same genes and pathways as damage associated...

  8. Effects of feed contaminant deoxynivalenol on plasma cytokines and mRNA expression of immune genes in the intestine of broiler chickens.

    Directory of Open Access Journals (Sweden)

    Khaled Ghareeb

    Full Text Available An experiment was conducted to investigate the individual and combined effects of dietary deoxynivalenol (DON and a microbial feed additive on plasma cytokine level and on the expression of immune relevant genes in jejunal tissues of broilers. A total of 40 broiler chicks were obtained from a commercial hatchery and divided randomly into four groups (10 birds per group. Birds were reared in battery cages from one day old for 5 weeks. The dietary groups were 1 control birds fed basal diet; 2 DON group fed basal diet contaminated with 10 mg DON/ kg feed; 3 DON + Mycofix group fed basal diet contaminated with 10 mg DON/ kg feed and supplemented with a commercial feed additive, Mycofix® Select (MS (2.5 kg/ton of feed; 4 Mycofix group fed basal diet supplemented with MS (2.5 kg/ton of feed. At 35 days, the plasma levels of tumor necrosis factor alpha (TNF-α and interleukin 8 (IL-8 were quantified by ELISA test kits. Furthermore, the mRNA expression of TNF-α, IL-8, IL-1β, interferon gamma (IFNγ, transforming growth factor beta receptor I (TGFBR1 and nuclear factor kappa-light-chain-enhancer of activated B cells 1 (NF-κβ1 in jejunum were quantified by qRT-PCR. The results showed that the plasma TNF-α decreased in response to DON, while in combination with MS, the effect of DON was reduced. DON down-regulated the relative gene expression of IL-1β, TGFBR1 and IFN-γ, and addition of MS to the DON contaminated diet compensates these effects on IL-1β, TGFBR1 but not for IFN-γ. Furthermore, supplementation of MS to either DON contaminated or control diet up-regulated the mRNA expression of NF-κβ1. In conclusion, DON has the potential to provoke and modulate immunological reactions of broilers and subsequently could increase their susceptibility to disease. The additive seemed to have almost as much of an effect as DON, albeit on different genes.

  9. Anti-inflammatory potential of Capparis spinosa L. in vivo in mice through inhibition of cell infiltration and cytokine gene expression.

    Science.gov (United States)

    El Azhary, Khadija; Tahiri Jouti, Nadia; El Khachibi, Meryam; Moutia, Mouna; Tabyaoui, Imane; El Hou, Abdelhalim; Achtak, Hafid; Nadifi, Sellama; Habti, Norddine; Badou, Abdallah

    2017-01-31

    Several chronic inflammatory diseases are characterized by inappropriate CD4+ T cell response. In the present study, we assessed the ability of Capparis spinosa L. (CS) preparation to orientate, in vivo, the immune response mediated by CD4+ T cells towards an anti-inflammatory response. The in vivo study was carried out by using the contact hypersensitivity (CHS) model in Swiss mice. Then we performed a histological analysis followed by molecular study by using real time RT-PCR. We also realized a phytochemical screening and a liquid-liquid separation of CS preparation. Our study allowed us to detect a significantly reduced edema in mice treated with CS preparations relative to control. CS effect was dose dependent, statistically similar to that observed with indomethacin, independent of the plant genotype and of the period of treatment. Furthermore, our histology studies revealed that CS induced a significant decrease in immune cell infiltration, in vasodilatation and in dermis thickness in the inflammatory site. Interestingly, we showed that CS operated by inhibiting cytokine gene expression including IFNγ, IL-17 and IL-4. Besides, phytochemical screening of CS extract showed the presence of several chemical families such as saponins, flavonoids and alkaloids. One (hexane fraction) out of the three distinct prepared fractions, exhibited an anti-inflammatory effect similar to that of the raw preparation, and would likely contain the bioactive(s) molecule(s). Altogether, our data indicate that CS regulates inflammation induced in vivo in mice and thus could be a source of anti-inflammatory molecules, which could be used in some T lymphocyte-dependent inflammatory diseases.

  10. Cytokines as cellular communicators

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    R. Debets

    1996-01-01

    Full Text Available Cytokines and their receptors are involved in the pathophysiology of many diseases. Here we present a detailed review on cytokines, receptors and signalling routes, and show that one important lesson from cytokine biology is the complex and diverse regulation of cytokine activity. The activity of cytokines is controlled at the level of transcription, translation, storage, processing, posttranslational modification, trapping, binding by soluble proteins, and receptor number and/or function. Translation of this diverse regulation in strategies aimed at the control of cytokine activity will result in the development of more specific and selective drugs to treat diseases.

  11. Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients: Increased Genetic Load of Islet-Expressed and Cytokine-Regulated Candidate Genes Predicts Poorer Glycemic Control

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    Caroline A. Brorsson

    2016-01-01

    Full Text Available Genome-wide association studies (GWAS have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β-cell function in type 1 diabetes (T1D. As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease progression. Two-thirds of 46 GWAS candidate genes examined were expressed in human islets, and 11 of these significantly changed expression levels following exposure to proinflammatory cytokines (IL-1β + IFNγ + TNFα for 48 h. Using the GWAS single nucleotide polymorphisms (SNPs from each locus, we constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO analyses revealed that several of the 11 candidate genes have overlapping biological functions and interact in a common network. Our results may help predict disease progression in newly diagnosed children with T1D which can be exploited for optimizing treatment.

  12. Cytokines in Drosophila immunity.

    Science.gov (United States)

    Vanha-Aho, Leena-Maija; Valanne, Susanna; Rämet, Mika

    2016-02-01

    Cytokines are a large and diverse group of small proteins that can affect many biological processes, but most commonly cytokines are known as mediators of the immune response. In the event of an infection, cytokines are produced in response to an immune stimulus, and they function as key regulators of the immune response. Cytokines come in many shapes and sizes, and although they vary greatly in structure, their functions have been well conserved in evolution. The immune signaling pathways that respond to cytokines are remarkably conserved from fly to man. Therefore, Drosophila melanogaster, provides an excellent platform for studying the biology and function of cytokines. In this review, we will describe the cytokines and cytokine-like molecules found in the fly and discuss their roles in host immunity. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  13. Role of cytokine gene (interferon-γ, transforming growth factor-β1, tumor necrosis factor-α, interleukin-6, and interleukin-10 polymorphisms in the risk of oral precancerous lesions in Taiwanese

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    Han-Jen Hsu

    2014-11-01

    Full Text Available Oral squamous cell carcinoma can be preceded by some benign oral lesions with malignant potential, including leukoplakia, erythroplakia, oral lichen planus, and oral submucous fibrosis. There are different degrees of inflammatory cells infiltration in histopathology. Inflammatory cytokines may play a pathogenic role in the development of oral precancerous lesions (OPCLs. Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. We hypothesized that the risk of OPCLs might be associated with cytokine gene polymorphisms of interferon (IFN-γ, transforming growth factor (TGF-β1, tumor necrosis factor (TNF-α, interleukin (IL-6, and IL-10. In the present study, 42 OPCL patients and 128 controls were analyzed for eight polymorphisms in five different cytokine genes [IFN-γ (+874 T/A, TGF-β1 (codons 10 T/C and 25 G/C, TNF-α (−308 G/A, IL-6 (−174 G/C, and IL-10 (−1082 A/G, –819 T/C, and −592 A/C]. Cytokine genotyping was determined by the polymerase chain reaction sequence-specific primer technique using commercial primers. Allele and genotype data were analyzed for significance of differences between cases and controls using the Chi-square (χ2 test. Two-sided p < 0.05 were considered to be statistically significant. A series of multivariate logistic regression models, adjusted for age, sex, betel quid chewing, alcohol consumption, and smoking, was constructed in order to access the contribution of homozygous or heterozygous variant genotypes of polymorphisms. The TNF-α (−308 polymorphism was significantly associated with OPCLs. There were significant differences in the distribution of AA, GA, and GG genotypes between OPCL patients and controls (p = 0.0004. Patients with the AA or GA genotype had a 3.63-fold increased risk of OPCLs. The TGF-β1 (codon 10 and 25 polymorphism was also significantly associated with OPCLs (p < 0.001. The IL-6 polymorphism was significantly associated with OPCLs

  14. Characterization of human mucin gene MUC4 promoter: importance of growth factors and proinflammatory cytokines for its regulation in pancreatic cancer cells.

    Science.gov (United States)

    Perrais, M; Pigny, P; Ducourouble, M P; Petitprez, D; Porchet, N; Aubert, J P; Van Seuningen, I

    2001-08-17

    The human mucin gene MUC4 encodes a large transmembrane mucin that is thought to play important roles in tumor cell biology and that is overexpressed in human pancreatic carcinomas. In this report, we describe the structure and functional activity of the 5'-flanking region, including 1.0 kilobase of the promoter. The long 5'-untranslated region (2.7 kilobases) is characterized by a high content of GC in its 3'-end. The first TATA box was located at -2672/-2668. Multiple transcription start sites and a high density of putative binding sites for Sp1 (GC and CACCC boxes), AP-1/-2/-4, cAMP-responsive element-binding protein, GATA, GR, and STAT transcription factors were found within the 5'-flanking region. Transcriptional activity of the promoter was assessed using pGL3-luciferase deletion mutants in two MUC4-expressing (CAPAN-1 and CAPAN-2) and one nonexpressing (PANC-1) pancreatic cancer cell line. Two highly active fragments (-219/-1 and -2781/-2572) that drive MUC4 transcription in CAPAN-1 and CAPAN-2 cells were identified. Gel retardation assays indicated that Sp1 and Sp3 bind to cognate cis-elements found in the 5'-flanking region and that Sp1 transactivates, whereas Sp3 inhibits the GC-rich region (-464/-1) in CAPAN-2 cells. Activation of protein kinase C with phorbol ester and treatment of cells with epidermal growth factor and transforming growth factor-alpha resulted in up-regulation of the promoter. Tumor necrosis factor-alpha and interferon (IFN)-gamma inflammatory cytokines had no or mild effect on MUC4 transcriptional activity when used alone. However, a very strong synergistic effect (10-12-fold activation) between IFN-gamma and tumor necrosis factor-alpha or IFN-gamma and transforming growth factor-alpha was obtained in CAPAN-2 cells. Altogether these results demonstrate that the 5'-flanking region of MUC4 contains epithelial cell-specific, positive, and negative regulatory cis-elements, that Sp1/Sp3 are important regulators of MUC4 basal expression

  15. Quantitative analysis of interferon alpha receptor subunit 1 and suppressor of cytokine signaling 1 gene transcription in blood cells of patients with chronic hepatitis C.

    Science.gov (United States)

    Sedeño-Monge, Virginia; Santos-López, Gerardo; Rocha-Gracia, Rosa C; Meléndez-Mena, Daniel; Ramírez-Mata, Alberto; Vallejo-Ruiz, Verónica; Reyes-Leyva, Julio

    2010-09-18

    Interferon (IFN)-α receptor 1 (ifnar1) and suppressor of cytokine signaling 1 (socs1) transcription levels were quantified in peripheral blood mononuclear cells (PBMC) of 59 patients infected with hepatitis C virus (HCV) and 17 non-infected individuals. Samples were obtained from patients infected with HCV that were either untreated or treated with IFN-α2 plus ribavirin for 1 year and divided into responders and non-responders based on viral load reduction 6 months after treatment. Ifnar1 and socs1 transcription was quantified by real-time RT-PCR, and the fold difference (2(⁻ΔΔCT)) with respect to hprt housekeeping gene was calculated. Ifnar1 transcription increased significantly in HCV-infected patients either untreated (3.26 ± 0.31), responders (3.1 ± 0.23) and non-responders (2.18 ± 0.23) with respect to non-infected individuals (1 ± 0.34; P = 0.005). Ifnar1 transcription increased significantly (P = 0.003) in patients infected with HCV genotypes 1a (4.74 ± 0.25) and 1b (2.81 ± 0.25) but not in 1a1b (1.58 ± 0.21). No association was found of Ifnar1 transcription with disease progress, initial viral load or other clinical factors. With respect to socs1 transcription, values were similar for non-infected individuals (1 ± 0.28) and untreated patients (0.99 ± 0.41) but increased in responders (2.81 ± 0.17) and non-responder patients (1.67 ± 0.41). Difference between responder and non-responder patients was not statistically significant. Socs1 transcription increased in patients infected with HCV genotypes 1a and 1b (2.87 ± 0.45 and 2.22 ± 0.17, respectively) but not in 1a1b (1.28 ± 0.40). Socs1 transcript was absent in three patients infected with HCV genotype 1b. A weak correlation between ifnar1 and socs1 transcription was found, when Spearman's correlation coefficient was calculated. Our results suggest that HCV infection may up-regulate ifnar1 transcription. HCV genotypes differ in their capacity to affect ifnar1 and socs1 transcription, as

  16. Quantitative analysis of interferon alpha receptor subunit 1 and suppressor of cytokine signaling 1 gene transcription in blood cells of patients with chronic hepatitis C

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    Sedeño-Monge Virginia

    2010-09-01

    Full Text Available Abstract Background Interferon (IFN-α receptor 1 (ifnar1 and suppressor of cytokine signaling 1 (socs1 transcription levels were quantified in peripheral blood mononuclear cells (PBMC of 59 patients infected with hepatitis C virus (HCV and 17 non-infected individuals. Samples were obtained from patients infected with HCV that were either untreated or treated with IFN-α2 plus ribavirin for 1 year and divided into responders and non-responders based on viral load reduction 6 months after treatment. Ifnar1 and socs1 transcription was quantified by real-time RT-PCR, and the fold difference (2-ΔΔCT with respect to hprt housekeeping gene was calculated. Results Ifnar1 transcription increased significantly in HCV-infected patients either untreated (3.26 ± 0.31, responders (3.1 ± 0.23 and non-responders (2.18 ± 0.23 with respect to non-infected individuals (1 ± 0.34; P = 0.005. Ifnar1 transcription increased significantly (P = 0.003 in patients infected with HCV genotypes 1a (4.74 ± 0.25 and 1b (2.81 ± 0.25 but not in 1a1b (1.58 ± 0.21. No association was found of Ifnar1 transcription with disease progress, initial viral load or other clinical factors. With respect to socs1 transcription, values were similar for non-infected individuals (1 ± 0.28 and untreated patients (0.99 ± 0.41 but increased in responders (2.81 ± 0.17 and non-responder patients (1.67 ± 0.41. Difference between responder and non-responder patients was not statistically significant. Socs1 transcription increased in patients infected with HCV genotypes 1a and 1b (2.87 ± 0.45 and 2.22 ± 0.17, respectively but not in 1a1b (1.28 ± 0.40. Socs1 transcript was absent in three patients infected with HCV genotype 1b. A weak correlation between ifnar1 and socs1 transcription was found, when Spearman's correlation coefficient was calculated. Conclusion Our results suggest that HCV infection may up-regulate ifnar1 transcription. HCV genotypes differ in their capacity to affect

  17. Cytokines in sleep regulation.

    Science.gov (United States)

    Krueger, J M; Takahashi, S; Kapás, L; Bredow, S; Roky, R; Fang, J; Floyd, R; Renegar, K B; Guha-Thakurta, N; Novitsky, S

    1995-01-01

    The central thesis of this essay is that the cytokine network in brain is a key element in the humoral regulation of sleep responses to infection and in the physiological regulation of sleep. We hypothesize that many cytokines, their cellular receptors, soluble receptors, and endogenous antagonists are involved in physiological sleep regulation. The expressions of some cytokines are greatly amplified by microbial challenge. This excess cytokine production during infection induces sleep responses. The excessive sleep and wakefulness that occur at different times during the course of the infectious process results from dynamic changes in various cytokines that occur during the host's response to infectious challenge. Removal of any one somnogenic cytokine inhibits normal sleep, alters the cytokine network by changing the cytokine mix, but does not completely disrupt sleep due to the redundant nature of the cytokine network. The cytokine network operates in a paracrine/autocrine fashion and is responsive to neuronal use. Finally, cytokines elicit their somnogenic actions via endocrine and neurotransmitter systems as well as having direct effects neurons and glia. Evidence in support of these postulates is reviewed in this essay.

  18. Cytokine regulation of pro- and anti-apoptotic genes in rat hepatocytes: NF-kappaB-regulated inhibitor of apoptosis protein 2 (cIAP2) prevents apoptosis

    NARCIS (Netherlands)

    Schoemaker, Marieke H.; Ros, Jenny E.; Homan, Manon; Trautwein, Christian; Liston, Peter; Poelstra, Klaas; van Goor, Harry; Jansen, Peter L. M.; Moshage, Han

    2002-01-01

    BACKGROUND/AIMS: In acute liver failure, hepatocytes are exposed to various cytokines that activate both cell survival and apoptotic pathways. NF-kappaB is a central transcription factor in these responses. Recent studies indicate that blocking NF-kappaB causes apoptosis, indicating the existence of

  19. IL-2–Controlled Expression of Multiple T Cell Trafficking Genes and Th2 Cytokines in the Regulatory T Cell-Deficient Scurfy Mice: Implication to Multiorgan Inflammation and Control of Skin and Lung Inflammation

    Science.gov (United States)

    Sharma, Rahul; Sharma, Poonam R.; Kim, Youngchul; Leitinger, Norbert; Lee, Jae K.; Fu, Shu Man; Ju, Shyr-Te

    2011-01-01

    Scurfy (Sf) mice bear a mutation in the Foxp3 transcription factor, lack regulatory T cells (Treg), develop multiorgan inflammation, and die prematurely. The major target organs affected are skin, lungs, and liver. Sf mice lacking the Il2 gene (Sf.Il2−/−), despite being devoid of Treg, did not develop skin and lung inflammation, but the inflammation in liver, pancreas, submandibular gland, and colon remained. Genome-wide microarray analysis revealed hundreds of genes that were differentially regulated among Sf, Sf.Il2−/−, and B6 CD4+ T cells, but the most significant changes were those encoding receptors for trafficking/chemotaxis/retention and cytokines. Our study suggests that IL-2 controls the skin and lung inflammation in Sf mice in an apparent “organ-specific” manner through two novel mechanisms: by regulating the expression of genes encoding a variety of receptors for T cell trafficking/chemotaxis/retention and by regulating Th2 cell expansion and cytokine production. Thus, IL-2 is potentially a master regulator for multiorgan inflammation and an underlying etiological factor for various diseases associated with skin and lung inflammation. PMID:21169543

  20. Compartmentalized Cytokine Responses in Hidradenitis Suppurativa.

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    Theodora Kanni

    Full Text Available Favorable treatment outcomes with TNF blockade led us to explore cytokine responses in hidradenitis suppurativa (HS.Blood monocytes of 120 patients and 24 healthy volunteers were subtyped by flow cytometry. Isolated blood mononuclear cells (PBMCs were stimulated for cytokine production; this was repeated in 13 severe patients during treatment with etanercept. Cytokines in pus were measured.CD14brightCD16dim inflammatory monocytes and patrolling monocytes were increased in Hurley III patients. Cytokine production by stimulated PBMCs was low compared to controls but the cytokine gene copies did not differ, indicating post-translational inhibition. The low production of IL-17 was restored, when cells were incubated with adalimumab. In pus, high concentrations of pro-inflammatory cytokines were detected. Based on the patterns, six different cytokine profiles were discerned, which are potentially relevant for the choice of treatment. Clinical improvement with etanercept was predicted by increased production of IL-1β and IL-17 by PBMCs at week 8.Findings indicate compartmentalized cytokine expression in HS; high in pus but suppressed in PBMCs. This is modulated through blockade of TNF.

  1. Effect of re-expansion after short-period lung collapse on pulmonary capillary permeability and pro-inflammatory cytokine gene expression in isolated rabbit lungs.

    Science.gov (United States)

    Funakoshi, T; Ishibe, Y; Okazaki, N; Miura, K; Liu, R; Nagai, S; Minami, Y

    2004-04-01

    Re-expansion pulmonary oedema is a rare complication caused by rapid re-expansion of a chronically collapsed lung. Several cases of pulmonary oedema associated with one-lung ventilation (OLV) have been reported recently. Elevated levels of pro-inflammatory cytokines in pulmonary oedema fluid are suggested to play important roles in its development. Activation of cytokines after re-expansion of collapsed lung during OLV has not been thoroughly investigated. Here we investigated the effects of re-expansion of the collapsed lung on pulmonary oedema formation and pro-inflammatory cytokine expression. Lungs isolated from female white Japanese rabbits were perfused and divided into a basal (BAS) group (n=7, baseline measurement alone), a control (CONT) group (n=9, ventilated without lung collapse for 120 min) and an atelectasis (ATEL) group (n=9, lung collapsed for 55 min followed by re-expansion and ventilation for 65 min). Pulmonary vascular resistance (PVR) and the coefficient of filtration (Kfc) were measured at baseline and 60 and 120 min. At the end of perfusion, bronchoalveolar lavage fluid/plasma protein ratio (B/P), wet/dry lung weight ratio (W/D) and mRNA expressions of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and myeloperoxidase (MPO) were determined. TNF-alpha and IL-1beta mRNA were significantly up-regulated in lungs of the ATEL group compared with BAS and CONT, though no significant differences were noted in PVR, Kfc, B/P and W/D within and between groups. MPO increased at 120 min in CONT and ATEL groups. Pro-inflammatory cytokines were up-regulated upon re-expansion and ventilation after short-period lung collapse, though no changes were noted in pulmonary capillary permeability.

  2. The role of ionizing radiation dose and polymorphism of genes encoding for cytokines in the treatment of bone disease caused by multiple myeloma

    OpenAIRE

    Rudžianskienė, Milda

    2016-01-01

    Osseous tissue damage is one of the signs of multiple myeloma (MM). Long-lasting or sudden bone pain is the first sign of MM for 70% of patients and the patients receive radiation at least once in their MM treatment history. But which radiotherapy regimen is recommended is unclear. Cytokines emitted in the bone destructions sites sensitive peripheral pain receptors, then emission of P substance and irritant amino acids increases in neuron presynapses, what determines an increased pain sensati...

  3. Cytokines and intestinal inflammation.

    Science.gov (United States)

    Bamias, Giorgos; Cominelli, Fabio

    2016-11-01

    Cytokines of the intestinal microenvironment largely dictate immunological responses after mucosal insults and the dominance of homeostatic or proinflammatory pathways. This review presents important recent studies on the role of specific cytokines in the pathogenesis of intestinal inflammation. The particular mucosal effects of cytokines depend on their inherent properties but also the cellular origin, type of stimulatory antigens, intermolecular interactions, and the particular immunological milieu. Novel cytokines of the interleukin-1 (IL-1) family, including IL-33 and IL-36, have dominant roles in mucosal immunity, whereas more established ones such as IL-18 are constantly enriched with unique properties. Th17 cells are important mucosal constituents, although their profound plasticity, makes the specific set of cytokines they secrete more important than their mere numbers. Finally, various cytokines, such as tumor necrosis factor-α, IL-6, tumor necrosis factor-like cytokine 1A, and death receptor, 3 demonstrate dichotomous roles with mucosa-protective function in acute injury but proinflammatory effects during chronic inflammation. The role of cytokines in mucosal health and disease is increasingly revealed. Such information not only will advance our understanding of the pathogenesis of gut inflammation, but also set the background for development of reliable diagnostic and prognostic biomarkers and cytokine-specific therapies.

  4. Effect of pregnancy on anti-HEV antibody titres, plasma cytokines and the corresponding gene expression levels in the PBMCs of patients presenting with self-recovering clinical and subclinical hepatitis E.

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    Ashwini Y Ramdasi

    Full Text Available High mortality in pregnant women (PR is a characteristic of hepatitis E in developing countries. To understand the pathogenesis of HEV infection in self-limiting disease during pregnancy, we compared clinical (PR-patients and subclinical-HEV-infections in pregnant women in the first (SC-PR-1 and later (2nd and 3rd, SC-PR-2+3 trimesters with the respective healthy controls and acute non-PR patients. The SC-PR-2+3 exhibited lower ALT, bilirubin levels, anti-HEV-IgM/IgG titres than the acute-PR/non-PR-patients (p<0.05-0.0001. IFNγ/IL4ratios indicated Th2/Th1 bias in non-PR and PR-patients respectively. Raised levels of 10/20 plasma cytokines in the non-PR-patients reflect predominant inflammatory response, unaltered- IFNγ/reduced-IFNα responses and a robust chemokine secretion. On contrary, the acute-PR-patients exhibited drastic reduction in majority of the cytokines relative to in the non-PR-patients. Importantly, diminished or unaltered response was noted in the acute-PR-group when compared to the corresponding controls. The only exception was sIL2RA, increasing in both patient categories. Of the 14 genes evaluated, the expression of IFNγ/IL10/IL1A/IL7/CCL2/CCL3/CXCL8/CXCL10 was higher in the non-PR patients. Of these, the expression of IFNγ/IL10/IL1A/CCL2/CCL3/CXCL8 and, additionally, IL2/IL6/TNF genes was higher in the clinical-PRs. Almost identical pattern was noted in the control-PR-2+3 category indicating no influence of HEV infection. Comparison of patient-categories identified significant elevation of IFNγ(P<0.001, CCL2(p<0.01, CXCL8(P<0.05, IL1B(p<0.05 and IL10(P<0.0001 and decrease in CXCL10(<0.05 in the PR-patients. The results suggest antibody-dependent disease severity and impaired immune response in the PR patients. Higher expression of cytokine-genes in the PBMCs did not correlate with the plasma-cytokine levels in the PR-patients.

  5. Identification of a gene for an ancient cytokine, interleukin 15-like, in mammals; interleukins 2 and 15 co-evolved with this third family member, all sharing binding motifs for IL-15Rα.

    Science.gov (United States)

    Dijkstra, Johannes M; Takizawa, Fumio; Fischer, Uwe; Friedrich, Maik; Soto-Lampe, Veronica; Lefèvre, Christophe; Lenk, Matthias; Karger, Axel; Matsui, Taei; Hashimoto, Keiichiro

    2014-02-01

    Interleukins 2 and 15 (IL-2 and IL-15) are highly differentiated but related cytokines with overlapping, yet also distinct functions, and established benefits for medical drug use. The present study identified a gene for an ancient third IL-2/15 family member in reptiles and mammals, interleukin 15-like (IL-15L), which hitherto was only reported in fish. IL-15L genes with intact open reading frames (ORFs) and evidence of transcription, and a recent past of purifying selection, were found for cattle, horse, sheep, pig and rabbit. In human and mouse the IL-15L ORF is incapacitated. Although deduced IL-15L proteins share only ~21 % overall amino acid identity with IL-15, they share many of the IL-15 residues important for binding to receptor chain IL-15Rα, and recombinant bovine IL-15L was shown to interact with IL-15Rα indeed. Comparison of sequence motifs indicates that capacity for binding IL-15Rα is an ancestral characteristic of the IL-2/15/15L family, in accordance with a recent study which showed that in fish both IL-2 and IL-15 can bind IL-15Rα. Evidence reveals that the species lineage leading to mammals started out with three similar cytokines IL-2, IL-15 and IL-15L, and that later in evolution (1) IL-2 and IL-2Rα receptor chain acquired a new and specific binding mode and (2) IL-15L was lost in several but not all groups of mammals. The present study forms an important step forward in understanding this potent family of cytokines, and may help to improve future strategies for their application in veterinarian and human medicine.

  6. Myocardial Gene Expression of T-bet, GATA-3, Ror-γt, FoxP3, and Hallmark Cytokines in Chronic Chagas Disease Cardiomyopathy: An Essentially Unopposed TH1-Type Response

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    Luciana Gabriel Nogueira

    2014-01-01

    Full Text Available Background. Chronic Chagas disease cardiomyopathy (CCC, a late consequence of Trypanosoma cruzi infection, is an inflammatory cardiomyopathy with prognosis worse than those of noninflammatory etiology (NIC. Although the T cell-rich myocarditis is known to play a pathogenetic role, the relative contribution of each of the functional T cell subsets has never been thoroughly investigated. We therefore assessed gene expression of cytokines and transcription factors involved in differentiation and effector function of each functional T cell subset (TH1/TH2/TH17/Treg in CCC, NIC, and heart donor myocardial samples. Methods and Results. Quantitative PCR showed markedly upregulated expression of IFN-γ and transcription factor T-bet, and minor increases of GATA-3; FoxP3 and CTLA-4; IL-17 and IL-18 in CCC as compared with NIC samples. Conversely, cytokines expressed by TH2 cells (IL-4, IL-5, and IL-13 or associated with Treg (TGF-β and IL-10 were not upregulated in CCC myocardium. Expression of TH1-related genes such as T-bet, IFN-γ, and IL-18 correlated with ventricular dilation, FoxP3, and CTLA-4. Conclusions. Results are consistent with a strong local TH1-mediated response in most samples, possibly associated with pathological myocardial remodeling, and a proportionally smaller FoxP3+CTLA4+ Treg cell population, which is unable to completely curb IFN-γ production in CCC myocardium, therefore fueling inflammation.

  7. Cytokines and intraocular inflammation

    NARCIS (Netherlands)

    Hoekzema, R.; Murray, P. I.; Kijlstra, A.

    1990-01-01

    Although new endogenous mediators of inflammatory and immune responses are reported almost on a monthly basis, the cytokines IL-1, TNF, and IL-6 have emerged as the primary regulators of local inflammation in man. In this paper, uveitogenic and other properties of these particular cytokines are

  8. Cytokines in bipolar disorder

    DEFF Research Database (Denmark)

    Munkholm, Klaus; Vinberg, Maj; Vedel Kessing, Lars

    2012-01-01

    BACKGROUND: Current research and hypothesis regarding the pathophysiology of bipolar disorder suggests the involvement of immune system dysfunction that is possibly related to disease activity. Our objective was to systematically review evidence of cytokine alterations in bipolar disorder according...... to affective state. METHODS: We conducted a systemtic review of studies measuring endogenous cytokine concentrations in patients with bipolar disorder and a meta-analysis, reporting results according to the PRISMA statement. RESULTS: Thirteen studies were included, comprising 556 bipolar disorder patients...... and 767 healthy controls, evaluating 15 different cytokines-, cytokine receptors- or cytokine antagonists. The levels of tumor necrosis factor-α (TNF-α), the soluble tumor necrosis factor receptor type 1 (sTNF-R1) and the soluble inlerleukin-2 receptor (sIL-2R) were elevated in manic patients compared...

  9. Cytokines and major depression.

    Science.gov (United States)

    Schiepers, Olga J G; Wichers, Marieke C; Maes, Michael

    2005-02-01

    In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The 'cytokine hypothesis of depression' implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces 'sickness behaviour', which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of

  10. Cytokines in Radiobiological Responses: A Review

    Science.gov (United States)

    Schaue, Dörthe; Kachikwu, Evelyn L.; McBride, William H.

    2013-01-01

    Cytokines function in many roles that are highly relevant to radiation research. This review focuses on how cytokines are structurally organized, how they are induced by radiation, and how they orchestrate mesenchymal, epithelial and immune cell interactions in irradiated tissues. Pro-inflammatory cytokines are the major components of immediate early gene programs and as such can be rapidly activated after tissue irradiation. They converge with the effects of ionizing radiation in that both generate free radicals including reactive oxygen and nitrogen species (ROS/RNS). “Self” molecules secreted or released from cells after irradiation feed the same paradigm by signaling for ROS and cytokine production. As a result, multilayered feedback control circuits can be generated that perpetuate the radiation tissue damage response. The pro-inflammatory phase persists until such times as perceived challenges to host integrity are eliminated. Antioxidant, anti-inflammatory cytokines then act to restore homeostasis. The balance between pro-inflammatory and anti-inflammatory forces may shift to and fro for a long time after radiation exposure, creating waves as the host tries to deal with persisting pathogenesis. Individual cytokines function within socially interconnected groups to direct these integrated cellular responses. They hunt in packs and form complex cytokine networks that are nested within each other so as to form mutually reinforcing or antagonistic forces. This yin-yang balance appears to have redox as a fulcrum. Because of their social organization, cytokines appear to have a considerable degree of redundancy and it follows that an elevated level of a specific cytokine in a disease situation or after irradiation does not necessarily implicate it causally in pathogenesis. In spite of this, “driver” cytokines are emerging in pathogenic situations that can clearly be targeted for therapeutic benefit, including in radiation settings. Cytokines can greatly

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Identification and expression analysis of two fish-specific IL-6 cytokine family members, the ciliary neurotrophic factor (CNTF)-like and M17 genes, in rainbow trout Oncorhynchus mykiss.

    Science.gov (United States)

    Wang, Tiehui; Secombes, Christopher J

    2009-07-01

    The mammalian interleukin (IL)-6 family of cytokines consist of eight class-I helical cytokines and are major players in hematopoiesis, as well as in neuroendocrine and immune systems, and have pro- and anti-inflammatory properties. We have identified a novel fish CNTF-like molecule, for the first time, as well as the trout M17 gene. The trout CNTF-like gene encodes a putative 191 amino acid peptide without a signal peptide, and shares high amino acid sequence identities (39-99%) within the fish CNTF-like molecules that we have identified, but only limited identities (21-24%) to higher vertebrate CNTF molecules among the IL-6 family members. The fish CNTF-like gene has two phase 0 introns in the coding region whilst the mammalian CNTF gene has only one phase 0 intron. The trout M17 encodes a peptide of 227 amino acid residues which has a predicted signal peptide of 35 aa and shares the highest identities (38-95%) to other fish M17 molecules, but limited homology to other IL-6 family members. Both of the fish CNTF-like and M17 proteins have four predicted helices and their tertiary structure could be stabilised by multiple conserved disulphide bonds. Phylogenetic analysis suggests that the fish CNTF-like and M17 genes may have arisen from ancestral genes that have given rise to mammalian LIF/OSM, and CNTF/CLC/CT-1/CT-2 of the IL-6 family. The trout CNTF-like gene is highly expressed in brain and muscle, whilst the M17 is highly expressed in immune tissues, including gills, spleen and head kidney. Furthermore, immune stimulation of a macrophage cell line and bacterial infection in vivo up-regulated M17 expression but had little effect on CNTF-like expression. These results suggest a major role of the CNTF-like molecule in fish nervous and muscular systems and of M17 in the immune system.

  13. Comparison of gene expression of Toll-like receptors and cytokines between Piau and Commercial line (Landrace×Large White crossbred) pigs vaccinated against Pasteurella multocida type D.

    Science.gov (United States)

    Sousa, Katiene Régia Silva; Ribeiro, André Mauric Frossard; Dantas, Waleska de Melo Ferreira; Oliveira, Leandro Licursi de; Gasparino, Eliane; Guimarães, Simone Eliza Facioni

    2017-10-01

    We aimed to compare Toll-like receptors (TLR) and cytokines expression in local Piau breed and a Commercial line (Landrace×Large White crossbred) pigs in response to vaccination against Pasteurella multocida type D. Seronegative gilts for Pasteurella multocida type D and Mycoplasma hyopneumoniae were used, from which peripheral blood mononuclear cells (PBMC) were collected in four time points (T0, T1, T2 and T3; before and after each vaccination dose). For bronchoalveolar lavage fluid cells (BALF), we set groups of vaccinated and unvaccinated animals for both genetic groups. Gene expression was evaluated on PBMC and BALF. In PBMC, when we analyzed time points within breeds, significant differences in expression for TLRs and cytokines, except TGFβ, were observed for Commercial animals. For the Piau pigs, only TGFβ showed differential expression. Comparing the expression among genetic groups, the Commercial pigs showed higher expression for TLRs after first vaccination dose, while for IL2, IL6, IL12 and IL13, higher expression was also observed in T3 and IL8 and IL10, in T1 and T3. Still comparing the breeds, the crossbred animals showed higher expression for TNFα in T1 and T2, while for TGFβ only in T2. For gene expression in BALF, vaccinated Commercial pigs showed higher expression of TLR6, TLR10, IL6, IL8, IL10, TNFα and TGFβ genes than vaccinated Piau pigs. The Commercial line pigs showed higher sensitivity to vaccination, while in local Piau breed lower responsiveness, which may partly explain genetic variability in immune response and will let us better understand the tolerance/susceptibility for pasteurellosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. The effect of dimethyl fumarate on gene expression and the level of cytokines related to different T helper cell subsets in peripheral blood mononuclear cells of patients with psoriasis.

    Science.gov (United States)

    Tahvili, Sahar; Zandieh, Basira; Amirghofran, Zahra

    2015-07-01

    Fumaric acid esters such as dimethyl fumarate (DMF) have proven to be effective in the treatment of psoriasis. In view of the role of Th17 in the pathogenesis of psoriasis, the present study was conducted to investigate the effects of DMF on Th1, Th2, and Th17 responses in patients. Peripheral blood mononuclear cells (PBMCs) were isolated from psoriasis patients and healthy individuals and were cultured in the presence or absence of phytohemagglutinin and DMF. The cell supernatants were removed to measure cytokine secretion, and the lymphocytes were used for real-time polymerase chain reaction to establish gene expression. An increase in gene expression of interferon-γ (IFN-γ), as a marker for Th1 activity, and interleukin-17 (IL-17), granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-22 representing the Th17 subset in the PBMCs of patients in comparison with those of control subjects was observed. Culture of PBMCs from psoriasis patients and controls in the presence of DMF decreased IFN-γ and increased IL-4 gene expression in both groups. Treatment with DMF could significantly decrease IL-17, GM-CSF, and IL-22 mRNA levels in the PBMCs of patients. Decreased release of IFN-γ and GM-CSF cytokine secretion after DMF treatment was also observed in PBMC cultures of patients and controls. These data show the effectiveness of DMF in modulating Th17 cells in addition to Th1/Th2 cells and reflect one of the underlying mechanisms of action of DMF in psoriasis. These findings may also support the possible benefits of using fumarate in the treatment of other autoimmune diseases in the pathogeneses of which Th1 and Th17 cells play major roles. © 2015 The International Society of Dermatology.

  15. Cytokines and Liver Diseases

    Directory of Open Access Journals (Sweden)

    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.

  16. New insight to IL-23/IL-17 axis in Iranian infected adult patients with gastritis: effects of genes polymorphisms on expression of cytokines.

    Science.gov (United States)

    Shirzad, H; Bagheri, N; Azadegan-Dehkordi, F; Zamanzad, B; Izadpanah, E; Abdi, M; Ramazani, G; Sanei, M H; Ayoubian, H; Ahmadi, A; Jamalzehi, S; Aslani, P; Zandi, F

    2015-06-01

    Chronic inflammation is the hallmark of the pathogenesis of H. pylori-induced gastric cancer. IL-17A and IL-17F are inflammatory cytokines expressed by a novel subset of CD4+Th cells and play critical function in inflammation. We evaluated the relationship between IL-17A G197A, IL-17F A7488G and IL23R+2199 A/C polymorphisms with IL-6, IL-17, IL-21, IL-23 and TGF-β1 mRNAs expression in regard to H. pylori infection with chronic gastritis. Total RNA and genomic DNA were extracted from gastric biopsies of 58 H. pylori-infected patient with gastritis. Afterward, mucosal IL-6, IL-17, IL-21, IL-23 and TGF-β1 mRNAs expression and polymorphisms in IL-17A G197A, IL-17F A7488G and IL-23R +2199A/Cin gastric biopsies were determined by real-time PCR and PCR-RFLP. Our results show that IL-17A G197A, IL-17F A7488G andIL23R +2199A/C polymorphisms have no effect on mucosal expression of IL-6, IL-17, IL-21 and TGF-β1 mRNAs expression in H. pylori-infected patients with chronic gastritis. These results suggest that IL-17A G197A, IL-17F A7488G and IL23R +2199A/C polymorphisms no alter mucosal cytokine pattern in Iranian patients with H. pylori-associated gastritis diseases. © Acta Gastro-Enterologica Belgica.

  17. Proinflammatory Cytokines in the Prefrontal Cortex of Teenage Suicide Victims

    OpenAIRE

    Pandey, Ghanshyam N.; Rizavi, Hooriyah S.; Ren, Xinguo; Fareed, Jawed; Hoppensteadt, Debra A.; Roberts, Rosalinda C.; Conley, Robert R.; Dwivedi, Yogesh

    2011-01-01

    Teenage suicide is a major public health concern, but its neurobiology is not well understood. Proinflammatory cytokines play an important role in stress and in the pathophysiology of depression—two major risk factors for suicide. Cytokines are increased in the serum of patients with depression and suicidal behavior; however, it is not clear if similar abnormality in cytokines occurs in brains of suicide victims. We therefore measured the gene and protein expression levels of proinflammatory ...

  18. Censored correlated cytokine concentrations

    DEFF Research Database (Denmark)

    Andersen, Andreas; Benn, Christine Stabell; Jørgensen, Mathias J

    2013-01-01

    Interest in cytokines as markers for the function of the immune system is increasing. Methods quantifying cytokine concentrations are often subject to detection limits, which lead to non-detectable observations and censored distributions. When distributions are skewed, geometric mean ratios (GMRs......) can be used to describe the relative concentration between two cytokines, and the GMR ratio (GMRR) can be used to compare two groups. The problem is how to estimate GMRRs from censored distributions.We evaluated methods, including simple deletion and substitution, in simulated and real data. One...... method applies Tobit directly to the censored difference between the two cytokine log-concentrations (Diff). However, censoring is correlated to the outcome and is therefore not independent. The correlation increases as the correlation between the two log-concentrations decreases. We propose a Tobit...

  19. Inflammatory Cytokines in Depression: Neurobiological Mechanisms and Therapeutic Implications

    Science.gov (United States)

    Felger, Jennifer C.; Lotrich, Francis E.

    2013-01-01

    Mounting evidence indicates that inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals. Cytokines are important for development and normal brain function, and have the ability to influence neurocircuitry and neurotransmitter systems to produce behavioral alterations. Acutely, inflammatory cytokine administration or activation of the innate immune system produces adaptive behavioral responses that promote conservation of energy to combat infection or recovery from injury. However, chronic exposure to elevated inflammatory cytokines and persistent alterations in neurotransmitter systems can lead to neuropsychiatric disorders and depression. Mechanisms of cytokine behavioral effects involve activation of inflammatory signaling pathways in the brain that results in changes in monoamine, glutamate, and neuropeptide systems, and decreases in growth factors, e.g. brain derived neurotrophic factor. Furthermore, inflammatory cytokines may serve as mediators of both environmental (e.g. childhood trauma, obesity, stress, and poor sleep) and genetic (functional gene polymorphisms) factors that contribute to depression’s development. This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression. Additionally, potential therapeutic strategies that target inflammatory cytokine signaling or the consequences of cytokines on neurotransmitter systems in the brain to prevent or reverse cytokine effects on behavior are discussed. PMID:23644052

  20. Amniotic fluid inflammatory cytokines

    DEFF Research Database (Denmark)

    Abdallah, Morsi; Larsen, Nanna; Grove, Jakob

    2013-01-01

    The aim of the study was to analyze cytokine profiles in amniotic fluid (AF) samples of children developing autism spectrum disorders (ASD) and controls, adjusting for maternal autoimmune disorders and maternal infections during pregnancy.......The aim of the study was to analyze cytokine profiles in amniotic fluid (AF) samples of children developing autism spectrum disorders (ASD) and controls, adjusting for maternal autoimmune disorders and maternal infections during pregnancy....

  1. Cytokine responses in primary chicken embryo intestinal cells infected with Campylobacter jejuni strains of human and chicken origin and the expression of bacterial virulence-associated genes

    DEFF Research Database (Denmark)

    Li, Yiping; Ingmer, Hanne; Madsen, Mogens

    2008-01-01

    -free media from another co-cultivation experiment also increased the expression of the virulence-associated genes in the C. jejuni chicken isolate, indicating that the expression of bacterial genes is regulated by component(s) secreted upon co-cultivation of bacteria and CEICs. Conclusion We show that under...... in vitro culture condition C. jejuni strains of both human and chicken origins can invade avian host cells with a pro-inflammatory response and that the virulence-associated genes of C. jejuni may play a role in this process....

  2. dlk1/FA1 regulates the function of human bone marrow mesenchymal stem cells by modulating gene expression of pro-inflammatory cytokines and immune response-related factors

    DEFF Research Database (Denmark)

    Abdallah, Basem M.; Boissy, Patrice; Tan, Qihua

    2007-01-01

    HG-U133A microarrays. In response to Dlk1 expression, 128 genes were significantly up-regulated (with >2-fold; p immune response-related factors, including pro-inflammatory cytokines, in addition to factors involved in the complement system......, apoptosis, and cell adhesion. Also, addition of purified FA1 to hMSC up-regulated the same factors in a dose-dependent manner. As biological consequences of up-regulating these immune response-related factors, we showed that the inhibitory effects of dlk1 on osteoblast and adipocyte differentiation of h......dlk1/FA1 (delta-like 1/fetal antigen-1) is a member of the epidermal growth factor-like homeotic protein family whose expression is known to modulate the differentiation signals of mesenchymal and hematopoietic stem cells in bone marrow. We have demonstrated previously that Dlk1 can maintain...

  3. [Cytokine storm in avian influenza].

    Science.gov (United States)

    Us, Dürdal

    2008-04-01

    genes (NS1, PB2, HA and NA) are responsible for the cytokine storm, by increasing the viral replication rate, expending the tissue tropism, facilitating the systemic invasion and emerging of resistance against the host antiviral response. It has been shown that Glu92 and Ala149 mutations, and carboxyl-terminal ESEV/EPEV motif of NS1 protein have been implicated as determinants of virulence for A/H5N1 strains. In addition, Lys627 mutation in PB2 protein, polybasic aminoacid mutations in the cleavage region of hemagglutinin (HA) polyprotein, and glycosylation and sialylation mutations in HA and neuraminidase (NA) proteins were found to enhance the immune-mediated patology of highly virulent A/H5N1 strains. In this review article, the immunopathogenesis of influenza infection and the mechanisms of cytokine storm caused by influenza A/H5N1 viruses have been discussed under the light of recent literature.

  4. IFN-gamma: Novel antiviral cytokines

    DEFF Research Database (Denmark)

    Ank, Nina; West, Hans; Paludan, Søren Riis

    2006-01-01

    and adaptive immune responses. Recently, a novel class of cytokines was discovered and named IFN-lambda (alternatively type III IFN or interleukin-28/29 [IL- 28/29]), based on IFN-like antiviral activity and induction of typical IFN-inducible genes. Here, we review the literature on IFN-lambda and discuss...

  5. Effect of immunization with polyvinylpyrrolidone on the counts of stromal precursor cells in bone marrow and spleen of CBA and CBA/N mice and cytokine gene expression in primary cultures of these cells.

    Science.gov (United States)

    Gorskaya, U F; Danilova, T A; Mezentzeva, M V; Shapoval, M M; Nesterenko, V G

    2012-05-01

    Injection of polyvinylpyrrolidone (synthetic type 2 T-independent antigen) stimulated the efficiency of clone-forming efficiency and the content of stromal precursor cells in CBA mice in the femoral bone marrow (almost 3-fold) and in the spleen (by 1.7 times) with the peak within 24 h and normalization by day 3 after immunization. The expression of IL-6, IL-8, and TNF-α genes in bone marrow and spleen cultures from immunized animals appeared on day 1 and disappeared on day 3. Hence, stimulation of stromal tissue in response to polyvinylpyrrolidone immunization was significantly less pronounced in comparison with immunization with S. typhimurium antigens. The counts of stromal precursor cells in these organs did not increase in CBA/N mice not responding to polyvinylpyrrolidone because they had no xid-mutation in Brutton's tyrosine kinase (Btk) gene, and the proinflammatory cytokine genes expression in primary cultures derived from these animals did not increase either. These data indicated that the degree of stromal tissue stimulation in immunized mice correlated with the immune response intensity. This indicated a close relationship between the stromal tissue and immune system. Stromal tissue seemed to be stimulated not only and not so much through the stromal cell Toll-like receptors, but mainly through interactions of immunocompetent and stromal cells, the former presumably playing the leading role in this process.

  6. Polymorphisms within the IL-1 gene cluster: effects on cytokine profiles in peripheral blood and whole blood cell cultures of patients with aggressive periodontitis, juvenile idiopathic arthritis, and rheumatoid arthritis

    DEFF Research Database (Denmark)

    Poulsen, Anne Havemose; Sørensen, Lars Korsbaek; Bendtzen, Klaus

    2007-01-01

    Genetic polymorphisms of cytokines have been associated with the susceptibility, severity, and clinical outcome of inflammatory diseases, such as periodontitis and chronic arthritis. An important question to address is how interleukin (IL)-1 polymorphisms affect the cytokine profiles of patients...

  7. Cytokines in lethal graft-versus-host disease

    NARCIS (Netherlands)

    Knulst, A.C.; Bril-Bazuin, C.; Tibbe, G.J.M.; Oudenaren, van A.; Savelkoul, H.F.J.; Benner, R.

    1992-01-01

    Graft-versus-host disease (GVHD) is caused by donor T lymphocytes that recognize foreign antigens on host tissues. This leads to T cell activation, which involves a cascade of events including the transcription of genes for cytokines and their receptors and the production of cytokines. One of the

  8. Cytotoxic effects and changes in cytokine gene expression induced by microcystin-containing extract in fish immune cells--an in vitro and in vivo study.

    Science.gov (United States)

    Rymuszka, Anna; Adaszek, Łukasz

    2013-06-01

    Blooms of cyanobacteria producing very toxic secondary metabolites (especially microcystins) are potent environmental stressors, hazardous not only to aquatic animals but also to public health. The purpose of this study was to investigate the effects of an extract containing microcystins on immune cells isolated from the common carp (Cyprinus carpio L.). In the present study it has been found that the extract induced apoptosis and inhibited in vitro lymphocyte proliferation. In addition, the results indicated the possible role of oxidative stress in this cytotoxicity and apoptosis. The in vivo investigations showed that the extract containing microcystins had greater suppressive effects on the essential functions of immune cells (intracellular reactive oxygen species production and lymphocyte proliferation) than the pure toxin alone. Moreover, immersion of fish in the toxic extract caused changes in the mRNA levels of various pro- and anti-inflammatory cytokines in carp leukocytes, while after exposure to the pure toxin, only IL1-β expression was markedly up-regulated. The observed modulatory effects on immune cells could have important implications for the health of planktivorous fish, which feed more frequently on toxic cyanobacteria. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Weissella paramesenteroides WpK4 reduces gene expression of intestinal cytokines, and hepatic and splenic injuries in a murine model of typhoid fever.

    Science.gov (United States)

    Alvim, L B; Sandes, S H C; Silva, B C; Steinberg, R S; Campos, M H A; Acurcio, L B; Arantes, R M E; Nicoli, J R; Neumann, E; Nunes, Á C

    2016-02-01

    Diarrhoea in piglets by Salmonella and other pathogens can be a serious health problem. Non-drug treatments such as probiotic microorganisms have various effects on the gastrointestinal microbiota dysbiosis and host immune system modulation. The aim of this study was to demonstrate the suitable use of Weissella paramesenteroides WpK4 strain isolated from healthy piglets as an alternative prophylactic or therapeutic treatment against Salmonella Typhimurium. Out of 37 lactic acid bacteria isolates, 24 strains belonging to the Weissella and Lactobacillus genera were analysed in vitro for desirable probiotic characteristics. The W. paramesenteroides WpK4 strain fulfilled all in vitro tests: resistance to acidic pH and bile salts, hydrophobic cell surface, antagonism against bacterial pathogens, H2O2 production and exopolysaccharide secretion, and non-transferable resistance to antibiotics. Mice fed with WpK4 showed no signs of bacterial translocation to the liver or spleen and decreased Salmonella translocation to these organs. Significantly, WpK4 intake attenuated the weight loss, fostered the preservation of intestinal architecture and integrity, and promoted survival in mice following infection with Salmonella Typhimurium. In addition, WpK4 modulated immune cellular response by inhibiting the production of pro-inflammatory cytokines and inducing anti-inflammatory mediators. These findings validate the probiotic properties of W. paramesenteroides WpK4 strain, and its eventual use in piglets.

  10. Gene Expression of Indoleamine 2,3 Dioxygenase 1, Insulin-Growth Factor 1 and Red/IK Cytokine in Alopecia Areata

    Directory of Open Access Journals (Sweden)

    Simona Corina ȘENILĂ

    2014-09-01

    Full Text Available Alopecia areata (AA is a chronic, T-cell mediated autoimmune disease directed against the hair follicle, which partially evolves due to a loss of the immune privilege of the anagen hair follicle. The immune privilege is maintained by several factors, including a downregulation of MHC class I and II, local immunosupressants and expression of Fas ligand. The purpose of the study was to evaluate several factors involved in the collapse and restoration of the immune privilege. We investigated IDO1, IGF1 and red/IK gene expression in lesional and perilesionalscalp biopsies from alopecia areata patients. Seven paired punch-biopsies were taken from the active edge of alopecic plaque and from the perilesional scalp. Expression of IDO1, IGF1 and red/IK genes was performed by qRT-PCR. In lesional tissue, IGF1, IDO1 and red/IK genes showed an increase in the mRNA levels as compared with the perilesional scalp. By comparing the pairs of data for the investigated genes, IDO1was statistically upregulated in the lesional area. No significant differences were observed between the gene expression in mild or severe AA, from the lesional or perilesional areas. IDO1 mRNA expression was higher in patients with a relapse duration of less than 6 months as compared to patients with a relapse duration of more than 6 months; levels of IGF1 and red/IK mRNA are increased in lesionals compared to perilesional scalp area.

  11. Gene Expression Meta-Analysis identifies Cytokine Pathways and 5q Aberrations involved in Metastasis of ERBB2 Amplified and Basal Breast Cancer

    DEFF Research Database (Denmark)

    Thomassen, Mads; Tan, Qihua; Burton, Mark

    2013-01-01

    the subgroups impact metastasis. Results: We have scrutinized publicly available gene expression datasets and identified molecular subtypes in 1,394 breast tumors with outcome data. By analysis of chromosomal regions and pathways using “Gene set enrichment analysis” followed by a meta-analysis, we identified......Background: Breast tumors have been described by molecular subtypes characterized by pervasively different gene expression profiles. The subtypes are associated with different clinical parameters and origin of precursor cells. However, the biological pathways and chromosomal aberrations that differ...... comprehensive mechanistic differences between the subgroups. Furthermore, the same approach was used to investigate mechanisms related to metastasis within the subgroups. A striking finding is that the molecular subtypes account for the majority of biological mechanisms associated with metastasis. However, some...

  12. Deferoxamine Suppresses Collagen Cleavage and Protease, Cytokine, and COL10A1 Expression and Upregulates AMPK and Krebs Cycle Genes in Human Osteoarthritic Cartilage.

    Science.gov (United States)

    Tchetina, Elena V; Markova, Galina A; Poole, A Robin; Zukor, David J; Antoniou, John; Makarov, Sergey A; Kuzin, Aleksandr N

    2016-01-01

    This study reports the effects of the iron chelator deferoxamine (DFO) on collagen cleavage, inflammation, and chondrocyte hypertrophy in relation to energy metabolism-related gene expression in osteoarthritic (OA) articular cartilage. Full-depth explants of human OA knee articular cartilage from arthroplasty were cultured with exogenous DFO (1-50 μM). Type II collagen cleavage and phospho-adenosine monophosphate-activated protein kinase (pAMPK) concentrations were measured using ELISAs. Gene expression studies employed real-time PCR and included AMPK analyses in PBMCs. In OA explants collagen cleavage was frequently downregulated by 10-50 μM DFO. PCR analysis of 7 OA patient cartilages revealed that 10 μM DFO suppressed expression of MMP-1, MMP-13, IL-1β, and TNFα and a marker of chondrocyte hypertrophy, COL10A1. No changes were observed in the expression of glycolysis-related genes. In contrast, expressions of genes associated with the mitochondrial Krebs cycle (TCA), AMPK, HIF1α, and COL2A1 were upregulated. AMPK gene expression was reduced in OA cartilage and increased in PBMCs from the same patients compared to healthy controls. Our studies demonstrate that DFO is capable of suppressing excessive collagenase-mediated type II collagen cleavage in OA cartilage and reversing phenotypic changes. The concomitant upregulation of proanabolic TCA-related gene expressions points to a potential for availability of energy generating substrates required for matrix repair by end-stage OA chondrocytes. This might normally be prevented by high whole-body energy requirements indicated by elevated AMPK expression in PBMCs of OA patients.

  13. Interactions between PPAR-α and inflammation-related cytokine genes on the development of Alzheimer’s disease, observed by the Epistasis Project

    Science.gov (United States)

    Heun, Reinhard; Kölsch, Heike; Ibrahim-Verbaas, Carla A; Combarros, Onofre; Aulchenko, Yurii S; Breteler, Monique; Schuur, Maaike; van Duijn, Cornelia M; Hammond, Naomi; Belbin, Olivia; Cortina-Borja, Mario; Wilcock, Gordon K; Brown, Kristelle; Barber, Rachel; Kehoe, Patrick G; Coto, Eliecer; Alvarez, Victoria; Lehmann, Michael G; Deloukas, Panos; Mateo, Ignacio; Morgan, Kevin; Warden, Donald R; Smith, A David; Lehmann, Donald J

    2012-01-01

    Objective Neuroinflammation contributes to the pathogenesis of sporadic Alzheimer’s disease (AD). Variations in genes relevant to inflammation may be candidate genes for AD risk. Whole-genome association studies have identified relevant new and known genes. Their combined effects do not explain 100% of the risk, genetic interactions may contribute. We investigated whether genes involved in inflammation, i.e. PPAR-α, interleukins (IL) IL- 1α, IL-1β, IL-6, and IL-10 may interact to increase AD risk. Methods The Epistasis Project identifies interactions that affect the risk of AD. Genotyping of single nucleotide polymorphisms (SNPs) in PPARA, IL1A, IL1B, IL6 and IL10 was performed. Possible associations were analyzed by fitting logistic regression models with AD as outcome, controlling for centre, age, sex and presence of apolipoprotein ε4 allele (APOEε4). Adjusted synergy factors were derived from interaction terms (pinteractions between different SNPs in PPARA and in interleukins IL1A, IL1B, IL10 that may affect AD risk. There were no significant interactions between PPARA and IL6. Conclusions In addition to an association of the PPARA L162V polymorphism with the AD risk, we observed four significant interactions between SNPs in PPARA and SNPs in IL1A, IL1B and IL10 affecting AD risk. We prove that gene-gene interactions explain part of the heritability of AD and are to be considered when assessing the genetic risk. Necessary replications will require between 1450 and 2950 of both cases and controls, depending on the prevalence of the SNP, to have 80% power to detect the observed synergy factors. PMID:22493750

  14. Interactions between PPAR-α and inflammation-related cytokine genes on the development of Alzheimer's disease, observed by the Epistasis Project.

    Science.gov (United States)

    Heun, Reinhard; Kölsch, Heike; Ibrahim-Verbaas, Carla A; Combarros, Onofre; Aulchenko, Yurii S; Breteler, Monique; Schuur, Maaike; van Duijn, Cornelia M; Hammond, Naomi; Belbin, Olivia; Cortina-Borja, Mario; Wilcock, Gordon K; Brown, Kristelle; Barber, Rachel; Kehoe, Patrick G; Coto, Eliecer; Alvarez, Victoria; Lehmann, Michael G; Deloukas, Panos; Mateo, Ignacio; Morgan, Kevin; Warden, Donald R; Smith, A David; Lehmann, Donald J

    2012-01-01

    Neuroinflammation contributes to the pathogenesis of sporadic Alzheimer's disease (AD). Variations in genes relevant to inflammation may be candidate genes for AD risk. Whole-genome association studies have identified relevant new and known genes. Their combined effects do not explain 100% of the risk, genetic interactions may contribute. We investigated whether genes involved in inflammation, i.e. PPAR-α, interleukins (IL) IL- 1α, IL-1β, IL-6, and IL-10 may interact to increase AD risk. The Epistasis Project identifies interactions that affect the risk of AD. Genotyping of single nucleotide polymorphisms (SNPs) in PPARA, IL1A, IL1B, IL6 and IL10 was performed. Possible associations were analyzed by fitting logistic regression models with AD as outcome, controlling for centre, age, sex and presence of apolipoprotein ε4 allele (APOEε4). Adjusted synergy factors were derived from interaction terms (pinteractions between different SNPs in PPARA and in interleukins IL1A, IL1B, IL10 that may affect AD risk. There were no significant interactions between PPARA and IL6. In addition to an association of the PPARA L162V polymorphism with the AD risk, we observed four significant interactions between SNPs in PPARA and SNPs in IL1A, IL1B and IL10 affecting AD risk. We prove that gene-gene interactions explain part of the heritability of AD and are to be considered when assessing the genetic risk. Necessary replications will require between 1450 and 2950 of both cases and controls, depending on the prevalence of the SNP, to have 80% power to detect the observed synergy factors.

  15. Deferoxamine Suppresses Collagen Cleavage and Protease, Cytokine, and COL10A1 Expression and Upregulates AMPK and Krebs Cycle Genes in Human Osteoarthritic Cartilage

    Directory of Open Access Journals (Sweden)

    Elena V. Tchetina

    2016-01-01

    Full Text Available This study reports the effects of the iron chelator deferoxamine (DFO on collagen cleavage, inflammation, and chondrocyte hypertrophy in relation to energy metabolism-related gene expression in osteoarthritic (OA articular cartilage. Full-depth explants of human OA knee articular cartilage from arthroplasty were cultured with exogenous DFO (1–50 μM. Type II collagen cleavage and phospho-adenosine monophosphate-activated protein kinase (pAMPK concentrations were measured using ELISAs. Gene expression studies employed real-time PCR and included AMPK analyses in PBMCs. In OA explants collagen cleavage was frequently downregulated by 10–50 μM DFO. PCR analysis of 7 OA patient cartilages revealed that 10 μM DFO suppressed expression of MMP-1, MMP-13, IL-1β, and TNFα and a marker of chondrocyte hypertrophy, COL10A1. No changes were observed in the expression of glycolysis-related genes. In contrast, expressions of genes associated with the mitochondrial Krebs cycle (TCA, AMPK, HIF1α, and COL2A1 were upregulated. AMPK gene expression was reduced in OA cartilage and increased in PBMCs from the same patients compared to healthy controls. Our studies demonstrate that DFO is capable of suppressing excessive collagenase-mediated type II collagen cleavage in OA cartilage and reversing phenotypic changes. The concomitant upregulation of proanabolic TCA-related gene expressions points to a potential for availability of energy generating substrates required for matrix repair by end-stage OA chondrocytes. This might normally be prevented by high whole-body energy requirements indicated by elevated AMPK expression in PBMCs of OA patients.

  16. Class I Cytokine Receptors

    DEFF Research Database (Denmark)

    Steinocher, Helena

    The members of the class I cytokine receptor family are involved in a wide range of cellular processes and of high pharmaceutical importance, however, even though the transmembrane receptors have been studied for decades, it has not been fully elucidated yet, how these receptors induce their intr......The members of the class I cytokine receptor family are involved in a wide range of cellular processes and of high pharmaceutical importance, however, even though the transmembrane receptors have been studied for decades, it has not been fully elucidated yet, how these receptors induce...... their intracellular response. The overall goal of this thesis was to improve the understanding of class I cytokine receptor activation and regulation at an atomic level. Two members of the class I cytokine receptor family, the human growth hormone receptor (hGHR), and the human erythropoietin receptor (hEPOR) have...... the traptamers on the hEPOR TMD dimeric complex in detergent micelles. To gain a better understanding of hGHR regulation a point mutation in the hGHR intracellular domain (ICD), which has recently been linked to lung cancer, was characterized. The mutation was found to decrease binding of suppressor of cytokine...

  17. Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST)

    NARCIS (Netherlands)

    Crusius, J. B. A.; Canzian, F.; Capella, G.; Pena, A. S.; Pera, G.; Sala, N.; Agudo, A.; Rico, F.; Del Giudice, G.; Palli, D.; Plebani, M.; Boeing, H.; Bueno-de-Mesquita, H. B.; Carneiro, F.; Pala, V.; Save, V. E.; Vineis, P.; Tumino, R.; Panico, S.; Berglund, G.; Manjer, J.; Stenling, R.; Hallmans, G.; Martinez, C.; Dorronsoro, M.; Barricarte, A.; Navarro, C.; Quiros, J. R.; Allen, N.; Key, T. J.; Binghan, S.; Caldas, C.; Linseisen, J.; Kaaks, R.; Overvad, K.; Tjonneland, A.; Buechner, F. C.; Peeters, P. H. M.; Numans, M. E.; Clavel-Chapelon, F.; Trichopoulou, A.; Lund, E.; Jenab, M.; Rinaldi, S.; Ferrari, P.; Riboli, E.; Gonzalez, C. A.

    2008-01-01

    Background: The relative contribution to gastric cancer (GC) risk of variants in genes that determine the inflammatory response remains mostly unknown and results from genotyping studies are inconsistent. Patients and methods: A nested case-control study within the prospective European Prospective

  18. Determinism and randomness in the evolution of introns and sine inserts in mouse and human mitochondrial solute carrier and cytokine receptor genes.

    Science.gov (United States)

    Cianciulli, Antonia; Calvello, Rosa; Panaro, Maria A

    2015-04-01

    In the homologous genes studied, the exons and introns alternated in the same order in mouse and human. We studied, in both species: corresponding short segments of introns, whole corresponding introns and complete homologous genes. We considered the total number of nucleotides and the number and orientation of the SINE inserts. Comparisons of mouse and human data series showed that at the level of individual relatively short segments of intronic sequences the stochastic variability prevails in the local structuring, but at higher levels of organization a deterministic component emerges, conserved in mouse and human during the divergent evolution, despite the ample re-editing of the intronic sequences and the fact that processes such as SINE spread had taken place in an independent way in the two species. Intron conservation is negatively correlated with the SINE occupancy, suggesting that virus inserts interfere with the conservation of the sequences inherited from the common ancestor. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Formulated Delivery of Enzyme/Prodrug and Cytokine Gene Therapy to Promote Immune Reduction of Treated and Remote Tumors in Mouse Models of Prostate Cancer

    Science.gov (United States)

    2007-01-01

    the sensitivity of the human colon cancer cells to 5-fluorouracil. Eur J Cancer 2000;36:2403-2410. Martiniello-Wilks R, Garcia- Aragon J, Daja M...43. 24. PUHLMANN M, GNANT M, BROWN CK, ALEXANDER HR, BARTLETT DL: Thymidine kinase-deleted vaccinia virus expressing purine nucleoside...Urol. (2000) 85(6):759-766. 84. MARTINIELLO-WILKS R, GARCIA- ARAGON J, DAJA MM et al.: In vivo gene therapy for prostate cancer: preclinical

  20. Targeted Disruption of Guanylyl Cyclase-A/Natriuretic Peptide Receptor-A Gene Provokes Renal Fibrosis and Remodeling in Null Mutant Mice: Role of Proinflammatory Cytokines

    OpenAIRE

    Das, Subhankar; Au, Edward; Krazit, Stephen T.; Pandey, Kailash N.

    2010-01-01

    Binding of atrial and brain natriuretic peptides to guanylyl cyclase-A/natriuretic peptide receptor-A produces second messenger cGMP, which plays an important role in maintaining renal and cardiovascular homeostasis. Mice carrying a targeted disruption of the Npr1 gene coding for guanylyl cyclase-A/natriuretic peptide receptor-A exhibit changes that are similar to those that occur in untreated human hypertension, including elevated blood pressure, cardiac hypertrophy, and congestive heart fai...

  1. Pegylated interferons Lambda-1a and alfa-2a display different gene induction and cytokine and chemokine release profiles in whole blood, human hepatocytes and peripheral blood mononuclear cells.

    Science.gov (United States)

    Freeman, J; Baglino, S; Friborg, J; Kraft, Z; Gray, T; Hill, M; McPhee, F; Hillson, J; Lopez-Talavera, J C; Wind-Rotolo, M

    2014-06-01

    Pegylated interferon-lambda-1a (Lambda), a type III interferon (IFN) in clinical development for the treatment of chronic HCV infection, has shown comparable efficacy and an improved safety profile to a regimen based on pegylated IFN alfa-2a (alfa). To establish a mechanistic context for this improved profile, we investigated the ex vivo effects of Lambda and alfa on cytokine and chemokine release, and on expression of IFN-stimulated genes (ISGs) in primary human hepatocytes and peripheral blood mononuclear cells (PBMCs) from healthy subjects. Our findings were further compared with changes observed in blood analysed from HCV-infected patients treated with Lambda or alfa in clinical studies. mRNA transcript and protein expression of the IFN-λ-limiting receptor subunit was lower compared with IFN-α receptor subunits in all cell types. Upon stimulation, alfa and Lambda induced ISG expression in hepatocytes and PBMCs, although in PBMCs Lambda-induced ISG expression was modest. Furthermore, alfa and Lambda induced release of cytokines and chemokines from hepatocytes and PBMCs, although differences in their kinetics of induction were observed. In HCV-infected patients, alfa treatment induced ISG expression in whole blood after single and repeat dosing. Lambda treatment induced modest ISG expression after single dosing and showed no induction after repeat dosing. Alfa and Lambda treatment increased IP-10, iTAC, IL-6, MCP-1 and MIP-1β levels in serum, with alfa inducing higher levels of all mediators compared with Lambda. Overall, ex vivo and in vivo induction profiles reported in this analysis strongly correlate with clinical observations of fewer related adverse events for Lambda vs those typically associated with alfa. © 2014 John Wiley & Sons Ltd.

  2. Hepatoprotective effect of Commiphora myrrha against d-GalN/LPS-induced hepatic injury in a rat model through attenuation of pro inflammatory cytokines and related genes.

    Science.gov (United States)

    Ahmad, Ajaz; Raish, Mohammad; Ganaie, Majid A; Ahmad, Syed Rizwan; Mohsin, Kazi; Al-Jenoobi, Fahad I; Al-Mohizea, Abdullah M; Alkharfy, Khalid M

    2015-01-01

    Commiphora myrrha (Burseraceae), a shrub resembling a small tree, has been used for several centuries for the treatment of various diseases. This study investigates the hepatoprotective activity of C. myrrha ethanol extract against d-galactosamine/lipopolysaccharide (d-GalN/LPS)-induced acute hepatic injury in an animal model. Rats were pretreated with ethanolic extract C. myrrha (250 and 500 mg/kg; p.o.) for 7 d prior to the induction of an acute phase response by d-GalN/LPS. Animals were sacrificed 24 h after d-GalN/LPS (800 mg/kg and 50 µg/kg i.p.) administration for the biochemical and histological analyses. The administration of d-GalN/LPS increased plasma aminotransferases (174.47 ± 4.5761 and 260.96 ± 1.9839 µkat/l) and total bilirubin levels (1.012 ± 0.0288 mg/dl), which were attenuated by C. myrrha treatment. Hepatic lipid peroxidation activity and nitric oxide content also increased, while the antioxidant activity measured by GSH (0.76 nmol/g protein), SOD (81.91 U/mg protein), and CAT (15.78 U/mg protein) was reduced. Commiphora myrrha provided significant restoration of GSH (0.815 nmol/gm protein), SOD (140.57 U/mg protein), and CAT (27.02 U/mg protein) levels. Furthermore, the acute phase response elicited by d-GalN/LPS administration enhanced mRNA expressions of TNF-α, IL-6, IL-10, iNOS-2, and HO-1, which were ameliorated by C. myrrha treatment. These findings indicate that C. myrrha considerably reduces the oxidative stress of d-GalN/LPS-induced hepatic injury via multiple pathways including adown regulation of inflammatory mediators and cytokines. Such a property might be sufficient to combat cellular damage caused by various conditions that resemble fulminant hepatitis and could be of a potential clinical application.

  3. MiR-122 directly inhibits human papillomavirus E6 gene and enhances interferon signaling through blocking suppressor of cytokine signaling 1 in SiHa cells.

    Directory of Open Access Journals (Sweden)

    Junming He

    Full Text Available Human Papillomavirus (HPV 16 infection is considered as one of the significant causes of human cervical cancer. The expression of the viral oncogenes like E6 and E7 play an important role in the development of the cancer. MiR-122 has been reported to exhibit a strong relationship with hepatitis viruses and take part in several tumor development, while the effects of miR-122 on HPV infection and the HPV viral oncogenes expression still remain unexplored. In this study, using RNAhybrid software, the potential binding sites between miR-122 and HPV16 E6 and E7 mRNAs were identified. Over and loss of miR-122 function showed that miR-122 could directly bind with HPV16 E6 mRNA and significantly inhibit its expression in SiHa cells, which was further confirmed by constructing the miR-122-E6-mu to eliminate the miR-122 binding effects with E6. The increase of the expression of type I interferon (IFN and its classical effective molecules and the phosphorylation of signal transducers and activators of transcription (STAT1 protein indicated that miR-122 might enhance type I interferon in cervical carcinoma cells, which explained the significant reduction of HPV16 E7 and E6*I mRNA expression. This might be due to the binding between miR-122 and suppressor of cytokine signaling 1 (SOCS1 mRNA, which is the suppressor of interferon signaling pathway. Moreover, it was identified that the miR-122 binding position was nt359-nt375 in SOCS1 mRNA. Taken together, this study indicated that HPV16 could be effectively inhibited by miR-122 through both direct binding with E6 mRNA and promoting SOCS1-dependent IFN signaling pathway. Thus, miR-122 may serve as a new therapeutic option for inhibiting HPV infection.

  4. Host gene expression profiling and in vivo cytokine studies to characterize the role of linezolid and vancomycin in methicillin-resistant Staphylococcus aureus (MRSA murine sepsis model.

    Directory of Open Access Journals (Sweden)

    Batu K Sharma-Kuinkel

    Full Text Available Linezolid (L, a potent antibiotic for Methicillin Resistant Staphylococcus aureus (MRSA, inhibits bacterial protein synthesis. By contrast, vancomycin (V is a cell wall active agent. Here, we used a murine sepsis model to test the hypothesis that L treatment is associated with differences in bacterial and host characteristics as compared to V. Mice were injected with S. aureus USA300, and then intravenously treated with 25 mg/kg of either L or V at 2 hours post infection (hpi. In vivo alpha-hemolysin production was reduced in both L and V-treated mice compared to untreated mice but the reduction did not reach the statistical significance [P = 0.12 for L; P = 0.70 for V. PVL was significantly reduced in L-treated mice compared to untreated mice (P = 0.02. However the reduction of in vivo PVL did not reach the statistical significance in V- treated mice compared to untreated mice (P = 0.27. Both antibiotics significantly reduced IL-1β production [P = 0.001 for L; P = 0.006 for V]. IL-6 was significantly reduced with L but not V antibiotic treatment [P<0.001 for L; P = 0.11 for V]. Neither treatment significantly reduced production of TNF-α. Whole-blood gene expression profiling showed no significant effect of L and V on uninfected mice. In S. aureus-infected mice, L altered the expression of a greater number of genes than V (95 vs. 42; P = 0.001. Pathway analysis for the differentially expressed genes identified toll-like receptor signaling pathway to be common to each S. aureus-infected comparison. Expression of immunomodulatory genes like Cxcl9, Cxcl10, Il1r2, Cd14 and Nfkbia was different among the treatment groups. Glycerolipid metabolism pathway was uniquely associated with L treatment in S. aureus infection. This study demonstrates that, as compared to V, treatment with L is associated with reduced levels of toxin production, differences in host inflammatory response, and distinct host gene expression

  5. 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...... to gene expressional changes, endoplasmic reticulum stress, and triggering of mitochondrial dysfunction. Preclinical studies have shown preventive effects of cytokine antagonism in animal models of diabetes, and clinical trials demonstrating proof of concept are emerging. The full clinical potential...

  6. Cytokines in human milk.

    Science.gov (United States)

    Garofalo, Roberto

    2010-02-01

    Epidemiologic studies conducted in the past 30 years to investigate the protective functions of human milk strongly support the notion that breastfeeding prevents infantile infections, particularly those affecting the gastrointestinal and respiratory tracts. However, more recent clinical and experimental observations also suggest that human milk not only provides passive protection, but also can directly modulate the immunological development of the recipient infant. The study of this remarkable defense system in human milk has been difficult because of its biochemical complexity, the small concentration of certain bioactive components, the compartmentalization of some of these agents, the dynamic quantitative and qualitative changes of milk during lactation, and the lack of specific reagents to quantify these agents. However, a host of bioactive substances, including hormones, growth factors, and immunological factors such as cytokines, have been identified in human milk. Cytokines are pluripotent polypeptides that act in autocrine/paracrine fashions by binding to specific cellular receptors. They operate in networks and orchestrate the development and functions of immune system. Several different cytokines and chemokines have been discovered in human milk in the past years, and the list is growing very rapidly. This article will review the current knowledge about the increasingly complex network of chemoattractants, activators, and anti-inflammatory cytokines present in human milk and their potential role in compensating for the developmental delay of the neonate immune system. Copyright 2010. Published by Mosby, Inc.

  7. Capparis Spinosa L. promotes anti-inflammatory response in vitro through the control of cytokine gene expression in human peripheral blood mononuclear cells.

    Science.gov (United States)

    Moutia, Mouna; El Azhary, Khadija; Elouaddari, Anass; Al Jahid, Abdellah; Jamal Eddine, Jamal; Seghrouchni, Fouad; Habti, Norddine; Badou, Abdallah

    2016-08-02

    Capparis Spinosa L. is an aromatic plant growing wild in dry regions around the Mediterranean basin. Capparis Spinosa was shown to possess several properties such as antioxidant, antifungal, and anti-hepatotoxic actions. In this work, we aimed to evaluate immunomodulatory properties of Capparis Spinosa leaf extracts in vitro on human peripheral blood mononuclear cells (PBMCs) from healthy individuals. Using MTT assay, we identified a range of Capparis Spinosa doses, which were not toxic. Unexpectedly, we found out that Capparis Spinosa aqueous fraction exhibited an increase in cell metabolic activity, even though similar doses did not affect cell proliferation as shown by CFSE. Interestingly, Capparis Spinosa aqueous fraction appeared to induce an overall anti-inflammatory response through significant inhibition of IL-17 and induction of IL-4 gene expression when PBMCs were treated with the non toxic doses of 100 and/or 500 μg/ml. Phytoscreening analysis of the used Capparis Spinosa preparations showed that these contain tannins; sterols, alkaloids; polyphenols and flavonoids. Surprisingly, quantification assays showed that our Capparis Spinosa preparation contains low amounts of polyphenols relative to Capparis Spinosa used in other studies. This Capparis Spinosa also appeared to act as a weaker scavenging free radical agent as evidenced by DPPH radical scavenging test. Finally, polyphenolic compounds including catechin, caffeic acid, syringic acid, rutin and ferulic acid were identified by HPLC, in the Capparis spinosa preparation. Altogether, these findings suggest that our Capparis Spinosa preparation contains interesting compounds, which could be used to suppress IL-17 and to enhance IL-4 gene expression in certain inflammatory situations. Other studies are underway in order to identify the compound(s) underlying this effect.

  8. Cytokines in human leptospirosis.

    Science.gov (United States)

    Papa, Anna; Kotrotsiou, Tzimoula

    2015-12-01

    Leptospirosis is a zoonotic disease with increased public health concern. Cytokines produced in response to the infection with pathogenic leptospires have been proposed to be involved in the pathogenesis of the disease. The aim of the study was to measure and evaluate the levels of 27 cytokines in patients with acute leptospirosis. The levels of 27 cytokines were measured from 42 acute leptospirosis cases; 47 samples were obtained from severe cases. Statistical analysis was performed using SPSS. IL-6, IL-8, GM-CSF, IP-10, MCP-1, and VEGF levels differed significantly between the severe cases and the control group, while GM-CSF levels differed significantly between the mild cases and the control group (pleptospirosis could be the basis for immunotherapeutic targets, especially for the severe cases in which antibiotic treatment is not enough. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Cytokine gene polymorphism (interleukin-1β +3954, Interleukin-6 [-597/-174] and tumor necrosis factor-α -308) in chronic periodontitis with and without type 2 diabetes mellitus.

    Science.gov (United States)

    Sharma, Nitin; Joseph, Rosamma; Arun, R; Chandni, R; Srinivas, K Lekshmy; Banerjee, Moinak

    2014-01-01

    Pro-inflammatory cytokine gene polymorphisms are potential candidates for susceptibility for both type 2 diabetes mellitus (DM) and chronic periodontitis (CHP). This study explored the association of interleukin-1 beta (IL-1 β) +3954, interleukin-6 (IL-6) -597/-174 and tumor necrosis factor-alpha (TNF-α) -308 single nucleotide polymorphisms in CHP with and without type 2 DM in Malayalam speaking subjects of Dravidian ethnicity. This case control study consisted of 51 chronic periodontitis with type 2 diabetes mellitus (CHPDM) and 51 CHP patients as cases and 51 healthy subjects as controls. Polymorphisms were identified by polymerase chain reaction amplification followed by restriction enzyme digestion and gel electrophoresis. IL-1 β (+3954) TT genotype and T allele were significantly associated with CHPDM group when compared with CHP (P = 0.001), whereas CC genotype and allele C was higher in CHP subjects (P = 0.001). For IL-6 (-597) frequency of genotype GA/AA (P = 0.04) and allele A (P = 0.01) was lower in CHPDM group, and for TNF-α -308 the frequency of genotype GA (P = 0.01) and allele A (P = 0.01) was higher in CHP subjects when compared with controls. In Malayalam speaking Dravidian population, IL-6 (-597) genotype GA/AA and allele A appears to be protective for CHP with type 2 DM. Allele C of IL-1 β +3954 and allele A of TNF-α -308 appears to be risk factors for CHP individuals.

  10. Associations of polymorphisms in the cytokine genes IL1β (rs16944), IL6 (rs1800795), IL12b (rs3212227) and growth factor VEGFA (rs2010963) with anthracosilicosis in coal miners in Russia and related genotoxic effects.

    Science.gov (United States)

    Volobaev, Valentin P; Larionov, Aleksey V; Kalyuzhnaya, Ekaterina E; Serdyukova, Ekaterina S; Yakovleva, Svetlana; Druzhinin, Vladimir G; Babich, Olga O; Hill, Elena G; Semenihin, Victor A; Panev, Nikolay I; Minina, Varvara I; Sivanesan, Saravana Devi; Naoghare, Pravin; da Silva, Juliana; Barcelos, Gustavo R M; Prosekov, Alexander Y

    2018-01-25

    Anthracosilicosis (AS), a prevalent form of pneumoconiosis among coal miners, results from the accumulation of carbon and silica in the lungs from inhaled coal dust. This study investigated genotoxic effects and certain cytokine genes polymorphic variants in Russian coal miners with АS. Peripheral leukocytes were sampled from 129 patients with AS confirmed by X-ray and tissue biopsy and from 164 asymptomatic coal miners. Four single-nucleotide polymorphisms were genotyped in the extracted DNA samples: IL1β T-511C (rs16944), IL6 C-174G (rs1800795), IL12b A1188C (rs3212227) and VEGFA C634G (rs2010963). Genotoxic effects were assessed by the analysis of chromosome aberrations in cultured peripheral lymphocytes. The mean frequency of chromatid-type aberrations and chromosome-type aberrations, namely, chromatid-type breaks and dicentric chromosomes, was found to be higher in AS patients [3.70 (95% confidence interval {CI}, 3.29-4.10) and 0.28 (95% CI, 0.17-0.38)] compared to the control group [2.41 (95% CI, 2.00-2.82) and 0.09 (95% CI, 0.03-0.15)], respectively. IL1β gene T/T genotype (rs16944) was associated with AS [17.83% in AS patients against 4.35% in healthy donors, odds ratio = 4.77 (1.88-12.15), P < 0.01]. A significant increase in the level of certain chromosome interchanges among AS donors is of interest because such effects are typical for radiation damage and caused by acute oxidative stress. IL1β T allele probably may be considered as an AS susceptibility factor among coal miners. © The Author(s) 2018. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Detection of autoantibodies to cytokines

    DEFF Research Database (Denmark)

    Bendtzen, K; Hansen, M B; Ross, C

    2000-01-01

    Autoantibodies to various cytokines have been reported in normal individuals and in patients with various infectious and immunoinflammatory disorders, and similar antibodies (Ab) may be induced in patients receiving human recombinant cytokines. The clinical relevance of these Ab is often difficult...... to evaluate. Not only are in vitro neutralizing cytokine Ab not necessarily neutralizing in vivo, but assays for binding and neutralizing Ab to cytokines are often difficult to interpret. For example, denaturation of immobilized cytokines in immunoblotting techniques and immunometric assays may leave Ab...

  12. Arcuate nucleus transcriptome profiling identifies ankyrin repeat and suppressor of cytokine signalling box-containing protein 4 as a gene regulated by fasting in central nervous system feeding circuits.

    Science.gov (United States)

    Li, J-Y; Kuick, R; Thompson, R C; Misek, D E; Lai, Y-M; Liu, Y-Q; Chai, B-X; Hanash, S M; Gantz, I

    2005-06-01

    The arcuate nucleus of the hypothalamus is a primary site for sensing blood borne nutrients and hormonal messengers that reflect caloric status. To identify novel energy homeostatic genes, we examined RNA extracts from the microdissected arcuate nucleus of fed and 48-h fasted rats using oligonucleotide microarrays. The relative abundance of 118 mRNA transcripts was increased and 203 mRNA transcripts was decreased during fasting. One of the down-regulated mRNAs was ankyrin-repeat and suppressor of cytokine signalling box-containing protein 4 (Asb-4). The predicted structure of Asb-4 protein suggested that it might encode an intracellular regulatory protein, and therefore its mRNA expression was investigated further. Reverse transcription quantitative polymerase chain reaction was used to validate down-regulation of Asb-4 mRNA in the arcuate nucleus of the fasted Sprague-Dawley rat (relative expression of Asb-4 mRNA: fed = 4.66 +/- 0.26; fasted = 3.96 +/- 0.23; n = 4, P regulation was also demonstrated in the obese fa/fa Zucker rat, another model of energy disequilibrium (relative expression of Asb-4 mRNA: lean Zucker = 3.91 +/- 0.32; fa/fa = 2.93 +/- 0.26; n = 5, P energy homeostasis, including the arcuate nucleus, paraventricular nucleus, dorsomedial nucleus, lateral hypothalamus and posterodorsal medial amygdaloid area. Double in situ hybridisation revealed that Asb-4 mRNA colocalises with key energy homeostatic neurones. In the fed state, Asb-4 mRNA is expressed by 95.6% of pro-opiomelanocortin (POMC) neurones and 46.4% of neuropeptide Y (NPY) neurones. By contrast, in the fasted state, the percentage of POMC neurones expressing Asb-4 mRNA drops to 73.2% (P NPY neurones in the fasted state is modestly increased to 52.7% (P energy homeostasis.

  13. Inflammatory cytokine-associated depression

    OpenAIRE

    Lotrich, Francis E

    2014-01-01

    Inflammatory cytokines can sometimes trigger depression in humans, are often associated with depression, and can elicit some behaviors in animals that are homologous to major depression. Moreover, these cytokines can affect monoaminergic and glutamatergic systems, supporting an overlapping pathoetiology with major depression. This suggests that there could be a specific major depression subtype, inflammatory cytokine-associated depression (ICAD), which may require different therapeutic approa...

  14. Cytokine gene expression of peripheral blood lymphocytes ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-03-20

    PCR. The result showed that lymphocytes ... 996 Afr. J. Biotechnol. Table 1. Sequence of TLR primers used in semi-quantitative RT-PCR. ... hatchery of Poultry Institute, Chinese Academy of Agricultural. Science, Yangzhou and ...

  15. Cytokines and sudden infant death.

    Science.gov (United States)

    Vennemann, Mechtild M T; Loddenkötter, Brigitte; Fracasso, Tony; Mitchell, Edwin A; Debertin, Annette S; Larsch, Klaus P; Sperhake, Jan P; Brinkmann, Bernd; Sauerland, Cristina; Lindemann, Monika; Bajanowski, Thomas

    2012-03-01

    It has been hypothesised that inflammatory reactions could play an important role in the pathway(s) leading to sudden and unexpected death in infancy. On a molecular level, these reactions are regulated by various cytokines. To characterise the role of IL-1ß, IL-6 and TNFα more precisely, the concentrations of these cytokines were determined quantitatively using specific ELISA techniques in serum and cerebrospinal fluid (CSF) in 119 cases of sudden infant death. The infants were grouped into four categories (SIDS, SIDS with infection, natural death due to infection and unnatural death). A good correlation was found between CSF and serum for IL-6 (Spearman correlation coefficients (SCC), 0.73) and also for TNFα (SCC, 0.57), although the CSF concentrations were lower than that from the serum. There were no significant differences between the categories of death for any of the serum or CSF cytokines. Compared with normal values, increased serum concentrations of IL-1ß, IL-6 and TNFα were found in 70%, 69% and 38% of the cases respectively, indicating possible agonal or post-mortem changes of cytokine concentrations. In three cases very high cytokine concentrations were found (mainly for IL-6). This may have contributed to the mechanism of death (cytokine storm) in two of the cases. In a small group of patients, very high cytokine concentrations are a possible explanation for the cause of death ("cytokine storm").

  16. Detection of autoantibodies to cytokines

    DEFF Research Database (Denmark)

    Bendtzen, K; Hansen, M B; Ross, C

    2000-01-01

    Autoantibodies to various cytokines have been reported in normal individuals and in patients with various infectious and immunoinflammatory disorders, and similar antibodies (Ab) may be induced in patients receiving human recombinant cytokines. The clinical relevance of these Ab is often difficul...

  17. Serum Cytokine Profile in a Patient Diagnosed with Dysferlinopathy

    Directory of Open Access Journals (Sweden)

    Svetlana F. Khaiboullina

    2017-01-01

    Full Text Available Limb-girdle muscular dystrophy type 2 (LGMD2B is a mild form of dysferlinopathy, characterized by limb weakness and wasting. It is an autosomal recessive disease, with currently 140 mutations in the LGMD2B gene identified. Lack of functional dysferlin inhibits muscle fiber regeneration in voluntary muscles, the main pathological finding in LGMD2B patients. However, the immune system has been suggested to contribute to muscle cell death and tissue regeneration. Serum levels of 27 cytokines were evaluated in a dysferlinopathy patient. Levels of 8 cytokines differed in patient serum compared to controls. Five cytokines (IL-10, IL-17, CCL2, CXCL10, and G-CSF were higher while 3 were lower in the patient than in controls (IL-2, IL-8, and CCL11. Together, these data on serum cytokine profile of this dysferlinopathy patient suggest immune response activation, which could explain leukocyte infiltration in the muscle tissue.

  18. Interplay of cytokines in preterm birth

    Directory of Open Access Journals (Sweden)

    Monika Pandey

    2017-01-01

    Full Text Available Preterm infants (i.e., born before <37 wk of gestation are at increased risk of morbidity and mortality and long-term disabilities. Global prevalence of preterm birth (PTB varies from 5 to 18 per cent. There are multiple aetiological causes and factors associated with PTB. Intrapartum infections are conventionally associated with PTB. However, maternal genotype modulates response to these infections. This review highlights the association of cytokine gene polymorphisms and their levels with PTB. Varying PTB rates across the different ethnic groups may be as a result of genetically mediated varying cytokines response to infections. Studies on genetic variations in tumour necrosis factor-alpha, interleukin-1 alpha (IL-1α, IL-1β, IL-6, IL-10 and toll-like receptor-4 genes and their association with PTB, have been reviewed. No single polymorphism of the studied genes was found to be associated with PTB. However, increased maternal levels of IL-1β and IL-6 and low levels of IL-10 have been found to be associated with PTB.

  19. Cytokine regulation of pro- and anti-apoptotic genes in rat hepatocytes : NF-kappa B-regulated inhibitor of apoptosis protein 2 (cIAP2) prevents apoptosis

    NARCIS (Netherlands)

    Schoemaker, MH; Kootstra-Ros, Jenny; Homan, M; Trautwein, C; Liston, P; Poelstra, K; van Goor, H; Jansen, PLM; Moshage, H

    Background/Aims: In acute liver failure, hepatocytes are exposed to various cytokines that activate both cell survival and apoptotic pathways. NF-kappaB is a central transcription factor in these responses. Recent studies indicate that blocking NF-kappaB causes apoptosis, indicating the existence of

  20. Study of stem cell homing & self-renewal marker gene profile of ex vivo expanded human CD34+ cells manipulated with a mixture of cytokines & stromal cell-derived factor 1

    Directory of Open Access Journals (Sweden)

    Jyoti Kode

    2017-01-01

    Interpretation & conclusions: Cocktail of cytokines and SDF1 showed good potential to successfully expand HSPC which exhibited enhanced ability to generate multilineage cells in short-term and long-term repopulation assay. This cocktail-mediated stem cell expansion has potential to obviate the need for longer and large volume apheresis procedure making it convenient for donors.

  1. Inflammatory cytokine-associated depression.

    Science.gov (United States)

    Lotrich, Francis E

    2015-08-18

    Inflammatory cytokines can sometimes trigger depression in humans, are often associated with depression, and can elicit some behaviors in animals that are homologous to major depression. Moreover, these cytokines can affect monoaminergic and glutamatergic systems, supporting an overlapping pathoetiology with major depression. This suggests that there could be a specific major depression subtype, inflammatory cytokine-associated depression (ICAD), which may require different therapeutic approaches. However, most people do not develop depression, even when exposed to sustained elevations in inflammatory cytokines. Thus several vulnerabilities and sources of resilience to inflammation-associated depression have been identified. These range from genetic differences in neurotrophic and serotonergic systems to sleep quality and omega-3 fatty acid levels. Replicating these sources of resilience as treatments could be one approach for preventing "ICAD". This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Leucocytes, cytokines and satellite cells

    DEFF Research Database (Denmark)

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

    2012-01-01

    and inflammation in otherwise healthy human skeletal muscles. We approach this concept by comparing changes in muscle function (i.e., the force-generating capacity) with the degree of leucocyte accumulation in muscle following exercise. In the second section, we explore the cytokine response to 'muscle......-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...

  3. Plasma cytokines in acute stroke

    DEFF Research Database (Denmark)

    Christensen, Hanne Krarup; Boysen, Gudrun; Christensen, Erik

    2011-01-01

    GOALS: The aim of this study was to test the relations between plasma cytokines and the clinical characteristics, course, and risk factors in acute stroke. PATIENTS AND METHODS: The analysis was based on 179 patients with acute stroke included within 24 hours of stroke onset. On inclusion and 3...... measured by enzyme-linked immunoassay (ELISA). FINDINGS: The levels of most cytokines were significantly different in acute stroke from the levels 3 months later; but only IL-10 was positively associated with stroke severity. C-reactive protein and white blood cell count were positively associated...... with the cytokine response. CONCLUSIONS: We found a substantial overall cytokine reaction that reflected the stroke incident. However, these results do not, at present, suggest a potential for clinical use, as they do not seem to add to the information obtained from the clinical workup of the individual patient....

  4. Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis.

    Science.gov (United States)

    Mateen, Somaiya; Zafar, Atif; Moin, Shagufta; Khan, Abdul Qayyum; Zubair, Swaleha

    2016-04-01

    Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown etiology. It is characterized by the presence of rheumatoid factor and anti-citrullinated peptide antibodies. Initial phase of RA involves the activation of both T and B cells. Cytokines have a crucial role in the pathophysiology of RA as pro-inflammatory cytokines such as TNFα, IL-1, IL-17 stimulates inflammation and degradation of bone and cartilage. There occurs an imbalance between the pro- and anti-inflammatory cytokine activities which leads to multisystem immune complications. There occurs a decline in the number of Treg cells which may also play an important role in pathophysiology of the disease. In RA patients, serum or plasma level of cytokines may indicate the severity of disease. Cytokine gene polymorphism could be used as markers of susceptibility and severity of RA. Anti-cytokine agents seem to emerge as potent drug molecules to treat RA. Many clinical trials are ongoing and several positive results have been obtained. There is a need to develop potential anti-cytokine agents that target numerous pathways involved in the pathogenesis of RA. This review article describes the effector functions of pro- and anti-inflammatory cytokines and the role of cytokine gene polymorphism in the pathogenesis of RA. Anti-cytokine agents that are currently available and those that are still in clinical trials have also been summarized. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Cytokines in recurrent pregnancy loss.

    Science.gov (United States)

    Daher, Silvia; de Arruda Geraldes Denardi, Kátia; Blotta, Maria Heloísa Souza Lima; Mamoni, Ronei Luciano; Reck, Ana Paula Monteiro; Camano, Luiz; Mattar, Rosiane

    2004-06-01

    Cytokines seem to play a critical role in the pathogenesis of unexplained recurrent pregnancy loss (RPL). Th1 cytokines have been shown to exert deleterious effects on pregnancy, inhibiting foetal growth and development. On the other hand, Th2 cytokines have been associated with successful pregnancy. The purpose of this study was to evaluate cytokine production in women with RPL. The studied group comprised 29 women with RPL, with at least three consecutive spontaneous abortions. The control group included 27 women with a history of successful pregnancies and no miscarriage. We determined IL-6 and TNF-alpha production in peripheral blood cultured with LPS, as well as IFN-gamma and TGF-beta induced by PHA stimulation. Cytokines were measured by enzyme-linked immunoabsorbant assay (ELISA) using commercial kits (RD, Amersham-Pharmacia). Mann-Whitney test was applied to compare differences between groups. The level of significance was defined at P < 0.05. We observed significantly higher levels of IFN-gamma (355.8 pg/ml versus 98.0 pg/ml; P = 0.01) and a trend toward increased TNF-alpha production (2410.2 pg/ml versus1980.2 pg/ml; P = 0.07) in RPL women as compared to controls. In relation to IL-6 and TGF-beta, no significant difference was detected between RPL and control groups. In agreement with experimental observations, our data support the hypothesis of Th1 cytokine involvement in the pathogenesis of RPL.

  6. Th2 cytokines inhibit lymphangiogenesis.

    Directory of Open Access Journals (Sweden)

    Ira L Savetsky

    Full Text Available Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2 cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4 and interleukin-13 (IL-13 have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis.

  7. Inflammatory cytokines protect retinal pigment epithelial cells from oxidative stress-induced death

    DEFF Research Database (Denmark)

    Juel, Helene B; Faber, Carsten; Svendsen, Signe Goul

    2013-01-01

    -cultured with activated T cells, or treated with cytokines showed increased expression of anti-oxidative genes, with upregulation of superoxide dismutase 2 protein following PCM treatment. CONCLUSION: Oxidative stress-induced cell death was reduced by concomitant inflammatory stress. This is likely due to the cytokine...

  8. [Profile of RNA cytokines in blood plasma under conditions of normal physiological state of human body].

    Science.gov (United States)

    Turchaninova, M A; Rebrikov, D V

    2009-01-01

    The level of representation of extracellular RNA 14 cytokines in blood plasma in a group of apparently healthy subjects was analyzed. The level of representation of the transcripts of these cytokines in extracellular medium is characterized by specific profile different from the profile of expression of the genes in blood cells.

  9. CYTOKINES GENETIC POLYMORPHISM: THE PAST AND THE FUTURE

    Directory of Open Access Journals (Sweden)

    L. V. Puzyryova

    2016-01-01

    Full Text Available The molecular genetics opens the new horizons in modern medicine, especially now when many diseases are given huge value in a type of their prevalence among various groups of population. Extremely high interleukin genes polymorphism degrees are studied well especially genetic polymorphism of tumor necrosis factor. Patients with HIV infection in the territory of Russia cause now the highest degree of mortality that is the most actual and socially significant problem of healthcare. This problems studying attracts many researchers. Works in respect of genetic immunity to a virus and influence of cytokines production on the disease forecast are especially interesting. One of the HIV replication influencing factors are cytokines, some of which, including the tumor necrosis factor and interleukin-6 can promote replication of HIV, raising an expression of virus regulatory genes. During disease progress in parallel of anti-inflammatory cytokines level increase (causing in this case rather ineffective antibodies level increase there is an T-helpers suppression stimulating a strong cellular component. Cytokine network functioning during HIV infection depends on many reasons which the individual variation in cytokine production caused by a number of genetic features, as well as an existence of opportunistic infection. Cytokines polymorphism determination in HIV infected patients is necessary in clinical practice for disease progression forecast to adverse fast transition to AIDS that it is important to consider in a choice of tactics of the supporting therapy of HIV-positive patients. Considering insufficient efficiency of modern methods of treatment, restoration and modulation of cytokines balance will increase anti-virus activity of immune system, influencing the factors blocking replication of a HIV.

  10. Altered cytokine profiles in patients with Chuvash polycythemia.

    Science.gov (United States)

    Niu, Xiaomei; Miasnikova, Galina Y; Sergueeva, Adelina I; Polyakova, Lydia A; Okhotin, Daniel J; Tuktanov, Nikolai V; Nouraie, Mehdi; Ammosova, Tatiana; Nekhai, Sergei; Gordeuk, Victor R

    2009-02-01

    Chuvash polycythemia results from a homozygous 598C>T mutation in exon 3 of the von Hippel-Lindau (VHL) gene. This disrupts the normoxia pathway for degrading hypoxia inducible factor (HIF)-1alpha and HIF-2alpha causing altered expression of HIF-1 and HIF-2 inducible genes. As hypoxia induces expression of pro-inflammatory cytokines, we hypothesized that there might be an elevation of Th1 cytokines in the setting of Chuvash polycythemia. We analyzed plasma concentrations of Th1 (interleukins-2 and 12, interferon-gamma, granulocyte-monocyte colony-stimulating factor, tumor necrosis factor-alpha) and Th2 cytokines (interleukins-4, 5, 10, and 13) using the Bio-Plex multiplex suspension array system in 34 VHL598C>T homozygotes and 32 VHL wild-type participants from Chuvashia. Concentrations of all the Th1 and Th2 cytokines measured were elevated in the VHL598C>T homozygotes compared with the control wild-type participants, but the ratios of Th1 to Th2 cytokines did not differ by genotype. In parallel, peripheral blood concentrations of CD4 positive T-helper cells and CD4/CD8 ratio were lower in the VHL598C>T homozygotes. In conclusion, the up-regulated hypoxic response in Chuvash polycythemia is associated with increased plasma products of both the Th1 and Th2 pathways, but the balance between the two pathways seems to be preserved.

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

    Directory of Open Access Journals (Sweden)

    Sung S Choi

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

  12. Cytokines in Sjogren's syndrome: potential therapeutic targets

    NARCIS (Netherlands)

    Roescher, N.; Tak, P.P.; Illei, G.G.

    2010-01-01

    The dysregulated cytokine network in Sjogren's Syndrome (SS) is reflected by local and systemic overexpression of pro-inflammatory cytokines and absent or low levels of anti-inflammatory cytokines. To date, the use of cytokine based therapies in SS has been disappointing. Oral administration of low

  13. Expression of inflammatory cytokine and inducible nitric oxide synthase genes in the small intestine and mesenteric lymph node tissues of pauci- and multibacillary sheep naturally infected with Mycobacterium avium ssp. paratuberculosis

    Directory of Open Access Journals (Sweden)

    Ganesh G Sonawane

    2016-01-01

    Conclusion: The present study indicated that IFN-γ and iNOS were found to play important role in the induction of Th1 type immune response in PB sheep. MB sheep had significant reduction in expression of IFN-γ and iNOS and elevation of IL-10 and TGF-β, which was typical of Th2 cytokine pattern. Elevated expression of IL-10 and TGF-β in PB cases possibly suggests the role of T-regulatory cells and may follow an independent mechanism not typical of Th1 pattern. In view of significantly reduced expression in both forms of the disease, IL-1α may not be an important cytokine in ovine paratuberculosis.

  14. Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines.

    Directory of Open Access Journals (Sweden)

    Ayako Uto-Konomi

    Full Text Available Homeostatic regulation of epidermal keratinocytes is controlled by the local cytokine milieu. However, a role for suppressor of cytokine signaling (SOCS, a negative feedback regulator of cytokine networks, in skin homeostasis remains unclear. Keratinocyte specific deletion of Socs3 (Socs3 cKO caused severe skin inflammation with hyper-production of IgE, epidermal hyperplasia, and S100A8/9 expression, although Socs1 deletion caused no inflammation. The inflamed skin showed constitutive STAT3 activation and up-regulation of IL-6 and IL-20 receptor (IL-20R related cytokines, IL-19, IL-20 and IL-24. Disease development was rescued by deletion of the Il6 gene, but not by the deletion of Il23, Il4r, or Rag1 genes. The expression of IL-6 in Socs3 cKO keratinocytes increased expression of IL-20R-related cytokines that further facilitated STAT3 hyperactivation, epidermal hyperplasia and neutrophilia. These results demonstrate that skin homeostasis is strictly regulated by the IL-6-STAT3-SOCS3 axis. Moreover, the SOCS3-mediated negative feedback loop in keratinocytes has a critical mechanistic role in the prevention of skin inflammation caused by hyperactivation of STAT3.

  15. The role of cytokine deficiencies and cytokine autoantibodies in clinical dermatology

    DEFF Research Database (Denmark)

    Liszewski, Walter; Gniadecki, Robert

    2016-01-01

    Cytokines are small, secreted proteins that are essential for promoting and maintaining a normal immune response. Upregulation of cytokines frequently occurs in autoimmune and inflammatory diseases. Conversely, several immunodeficiency, autoimmune and autoinflammatory disorders are known to occur...... due to a downregulation or absence of cytokines. Here, we review the diagnosis and clinical management of cytokine deficiency syndromes in dermatology. We will review the biology of cytokines, and the current approved indications for recombinant cytokines and anticytokine antibodies. We will also...... review the role of cytokine deficiencies and cytokine autoantibodies in immunodeficiency syndromes, as well as in autoimmune disorders. Finally, we will examine autoinflammatory disorders due to cytokine deficiencies....

  16. Malaria: toxins, cytokines and disease

    DEFF Research Database (Denmark)

    Jakobsen, P H; Bate, C A; Taverne, J

    1995-01-01

    In this review the old concept of severe malaria as a toxic disease is re-examined in the light of recent discoveries in the field of cytokines. Animal studies suggest that the induction of TNF by parasite-derived molecules may be partly responsible for cerebral malaria and anemia, while hypoglyc......In this review the old concept of severe malaria as a toxic disease is re-examined in the light of recent discoveries in the field of cytokines. Animal studies suggest that the induction of TNF by parasite-derived molecules may be partly responsible for cerebral malaria and anemia, while...

  17. Cytokine crowdsourcing: multicellular production of TH17-associated cytokines.

    Science.gov (United States)

    Busman-Sahay, Kathleen O; Walrath, Travis; Huber, Samuel; O'Connor, William

    2015-03-01

    In the 2 decades since its discovery, IL-17A has become appreciated for mounting robust, protective responses against bacterial and fungal pathogens. When improperly regulated, however, IL-17A can play a profoundly pathogenic role in perpetuating inflammation and has been linked to a wide variety of debilitating diseases. IL-17A is often present in a composite milieu that includes cytokines produced by TH17 cells (i.e., IL-17F, IL-21, IL-22, and IL-26) or associated with other T cell lineages (e.g., IFN-γ). These combinatorial effects add mechanistic complexity and more importantly, contribute differentially to disease outcome. Whereas TH17 cells are among the best-understood cell types that secrete IL-17A, they are frequently neither the earliest nor dominant producers. Indeed, non-TH17 cell sources of IL-17A can dramatically alter the course and severity of inflammatory episodes. The dissection of the temporal regulation of TH17-associated cytokines and the resulting net signaling outcomes will be critical toward understanding the increasingly intricate role of IL-17A and TH17-associated cytokines in disease, informing our therapeutic decisions. Herein, we discuss important non-TH17 cell sources of IL-17A and other TH17-associated cytokines relevant to inflammatory events in mucosal tissues. © Society for Leukocyte Biology.

  18. Influence of host genetic variation on rubella-specific T cell cytokine responses following rubella vaccination

    OpenAIRE

    Ovsyannikova, Inna G.; Ryan, Jenna E.; Robert A Vierkant; O’Byrne, Megan M.; Pankratz, V. Shane; Jacobson, Robert M.; Poland, Gregory A.

    2009-01-01

    The variability of immune response modulated by immune response gene polymorphisms is a significant factor in the protective effect of vaccines. We studied the association between cellular (cytokine) immunity and HLA genes among 738 schoolchildren (396 males and 342 females) between the ages of 11 and 19 years, who received two doses of rubella vaccine (Merck). Cytokine secretion levels in response to rubella virus stimulation were determined in PBMC cultures by ELISA. Cell supernatants were ...

  19. The Sequestosome 1/p62 Attenuates Cytokine Gene Expression in Activated Macrophages by Inhibiting IFN Regulatory Factor 8 and TNF Receptor-Associated Factor 6/NF-κB Activity1

    Science.gov (United States)

    Kim, Ji Young; Ozato, Keiko

    2014-01-01

    Sequestosome 1/p62 (p62) is a scaffold/adaptor protein with multiple functions implicated for neuronal and bone diseases. It carries a ubiquitin binding domain through which it mediates proteasome-dependent proteolysis. In addition, p62 is reported to regulate NF-κB activity in some cells. To date, however, the role of p62 in innate immunity has not been fully elucidated. In this study, we report that IFN-γ plus TLR signaling stimulates late expression of p62 in murine macrophages. Overexpression of p62 inhibited expression of multiple cytokines, IL-12p40, TNF-α, IL-1β, IL-6, and IFN-β, whereas p62 underexpression by small hairpin RNA markedly elevated their expression, indicating that p62 is a broad negative regulator of cytokine expression in stimulated macrophages. We show that p62 interacts with IFN regulatory factor 8 and Ro52, the transcription factor and ubiquitin E3 ligase that are important for IL-12p40 expression. This interaction, detectable at a late stage in stimulated macrophages, led to increased polyubiquitination and destabilization of IFN regulatory factor 8. We also show that upon macrophage stimulation, p62 binds to TNFR-associated factor 6, another E3 ligase important for NF-κB activation, but later this interaction was replaced by the recruitment of the deubiquitinating enzyme, cylindromatosis, an inhibitor of NF-κB activity. Recruitment of cylindromatosis coincided with reduced TNFR-associated factor 6 autoubiquitination and lower NF-κB activation. Our results indicate that p62 orchestrates orderly regulation of ubiquitin modification processes in macrophages to ensure attenuation of cytokine transcription postactivation. Together, p62 may provide a mechanism by which to control excessive inflammatory responses after macrophage activation. PMID:19201866

  20. Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims.

    Science.gov (United States)

    Pandey, Ghanshyam N; Rizavi, Hooriyah S; Ren, Xinguo; Fareed, Jawed; Hoppensteadt, Debra A; Roberts, Rosalinda C; Conley, Robert R; Dwivedi, Yogesh

    2012-01-01

    Teenage suicide is a major public health concern, but its neurobiology is not well understood. Proinflammatory cytokines play an important role in stress and in the pathophysiology of depression-two major risk factors for suicide. Cytokines are increased in the serum of patients with depression and suicidal behavior; however, it is not clear if similar abnormality in cytokines occurs in brains of suicide victims. We therefore measured the gene and protein expression levels of proinflammatory cytokines interleukin (IL)-1β, IL-6, and tissue necrosis factor (TNF)-α in the prefrontal cortex (PFC) of 24 teenage suicide victims and 24 matched normal control subjects. Our results show that the mRNA and protein expression levels of IL-1β, IL-6, and TNF-α were significantly increased in Brodmann area 10 (BA-10) of suicide victims compared with normal control subjects. These results suggest an important role for IL-1β, IL-6, and TNF-α in the pathophysiology of suicidal behavior and that proinflammatory cytokines may be an appropriate target for developing therapeutic agents. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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.

  2. FLT3 ligand preserves the uncommitted CD34+CD38- progenitor cells during cytokine prestimulation for retroviral transduction

    DEFF Research Database (Denmark)

    Nielsen, S D; Husemoen, L L; Sørensen, T U

    2000-01-01

    in a higher percentage of cells than the EGFP gene, but there seemed to be a positive correlation between expression of the two genes. The effect of cytokine prestimulation was therefore monitored using EGFP as marker for transduction. When SCF was compared to SCF in combination with more potent cytokines......Before stem cell gene therapy can be considered for clinical applications, problems regarding cytokine prestimulation remain to be solved. In this study, a retroviral vector carrying the genes for the enhanced version of green fluorescent protein (EGFP) and neomycin resistance (neo(r)) was used...... for transduction of CD34+ cells. The effect of cytokine prestimulation on transduction efficiency and the population of uncommitted CD34+CD38- cells was determined. CD34+ cells harvested from umbilical cord blood were kept in suspension cultures and stimulated with combinations of the cytokines stem cell factor...

  3. Cytokines and mood in healthy young adults

    NARCIS (Netherlands)

    Jansen, J.; Fernstrand, A.M.; Van De Loo, A.J.A.E.; Garssen, J.; Verster, J.C.

    2015-01-01

    Purpose: A link between chronic inflammation and neuropsychiatric disorders has been demonstrated previously. For example, pro- and anti-inflammatory cytokines have shown to impact neurocircuits relevant to mood regulation. Elevated levels of inflammatory cytokines have been associated with the

  4. Effects of as-cast and wrought Cobalt-Chrome-Molybdenum and Titanium-Aluminium-Vanadium alloys on cytokine gene expression and protein secretion in J774A.1 macrophages

    DEFF Research Database (Denmark)

    Jakobsen, Stig Storgaard; Larsen, Agnete; Stoltenberg, Meredin

    2007-01-01

    to the metal implant and wear-products. The aim of the present study was to compare surfaces of as-cast and wrought Cobalt-Chrome-Molybdenum (CoCrMo) alloys and Titanium-Aluminium-Vanadium (TiAlV) alloy when incubated with mouse macrophage J774A.1 cell cultures. Changes in pro- and anti-inflammatory cytokines...... transcription, the chemokine MCP-1 secretion, and M-CSF secretion by 77%, 36%, and 62%, respectively. Furthermore, we found that reducing surface roughness did not affect this reduction. The results suggest that as-cast CoCrMo alloy is more inert than wrought CoCrMo and wrought TiAlV alloys and could prove...

  5. Gene

    Data.gov (United States)

    U.S. Department of Health & Human Services — Gene integrates information from a wide range of species. A record may include nomenclature, Reference Sequences (RefSeqs), maps, pathways, variations, phenotypes,...

  6. Avian cytokines in health and disease

    Directory of Open Access Journals (Sweden)

    Wigley P

    2003-01-01

    Full Text Available Cytokines are proteins secreted by cells that play an important role in the activation and regulation of other cells and tissues during inflammation and immune responses. Although well described in several mammalian species, the role of cytokines and other related proteins is poorly understood in avian species. Recent advances in avian genetics and immunology have begun to allow the exploration of cytokines in health and disease. Cytokines may be classified in a number of ways, but may be conveniently arranged into four broad groups on the basis of their function. Proinflammatory cytokines such as interleukin-6 and interleukin-1beta play a role in mediating inflammation during disease or injury. Th1 cytokines, including interleukin-12 and interferon-gamma, are involved in the induction of cell-mediated immunity, whereas Th2 cytokines such as interleukin-4 are involved in the induction of humoral immunity. The final group Th3 or Tr cytokines play a role in regulation of immunity. The role of various cytokines in infectious and non-infectious diseases of chickens and turkeys is now being investigated. Although there are only a few reliable ELISAs or bioassays developed for avian cytokines, the use of molecular techniques, and in particular quantitative RT-PCR (Taqman has allowed investigation of cytokine responses in a number of diseases including salmonellosis, coccidiosis and autoimmune thyroiditis. In addition the use of recombinant cytokines as therapeutic agents or as vaccine adjuvants is now being explored.

  7. Cytokine Signature in Infective Endocarditis

    Science.gov (United States)

    Araújo, Izabella Rodrigues; Ferrari, Teresa Cristina Abreu; Teixeira-Carvalho, Andréa; Campi-Azevedo, Ana Carolina; Rodrigues, Luan Vieira; Guimarães Júnior, Milton Henriques; Barros, Thais Lins Souza; Gelape, Cláudio Léo; Sousa, Giovane Rodrigo; Nunes, Maria Carmo Pereira

    2015-01-01

    Infective endocarditis (IE) is a severe disease with high mortality rate. Cytokines participate in its pathogenesis and may contribute to early diagnosis improving the outcome. This study aimed to evaluate the cytokine profile in IE. Serum concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor (TNF)-α were measured by cytometric bead array (CBA) at diagnosis in 81 IE patients, and compared with 34 healthy subjects and 30 patients with non-IE infections, matched to the IE patients by age and gender. Mean age of the IE patients was 47±17 years (range, 15–80 years), and 40 (50%) were male. The IE patients had significantly higher serum concentrations of IL-1β, IL-6, IL-8, IL-10 and TNF-α as compared to the healthy individuals. The median levels of IL-1β, TNF-α and IL-12 were higher in the IE than in the non-IE infections group. TNF-α and IL-12 levels were higher in staphylococcal IE than in the non-staphylococcal IE subgroup. There was a higher proportion of both low IL-10 producers and high producers of IL-1β, TNF-α and IL-12 in the staphylococcal IE than in the non-staphylococcal IE subgroup. This study reinforces a relationship between the expression of proinflammatory cytokines, especially IL-1β, IL-12 and TNF-α, and the pathogenesis of IE. A lower production of IL-10 and impairment in cytokine network may reflect the severity of IE and may be useful for risk stratification. PMID:26225421

  8. Regulation of Gastric Carcinogenesis by Inflammatory CytokinesSummary

    Directory of Open Access Journals (Sweden)

    Kevin A. Bockerstett

    2017-07-01

    Full Text Available Chronic inflammation caused by infection with Helicobacter pylori and autoimmune gastritis increases an individual’s risk of developing gastric cancer. More than 90% of gastric cancers are adenocarcinomas, which originate from epithelial cells in the chronically inflamed gastric mucosa. However, only a small subset of chronic gastritis patients develops gastric cancer, implying a role for genetic and environmental factors in cancer development. A number of DNA polymorphisms that increase gastric cancer risk have mapped to genes encoding cytokines. Many different cytokines secreted by immune cells and epithelial cells during chronic gastritis have been identified, but a better understanding of how cytokines regulate the severity of gastritis, epithelial cell changes, and neoplastic transformation is needed. This review summarizes studies in both human and mouse models, describing a number of different findings that implicate various cytokines in regulating the development of gastric cancer. Keywords: Gastric Cancer, Inflammation, Cytokines

  9. Leptin–cytokine crosstalk in breast cancer

    Science.gov (United States)

    Newman, Gale; Gonzalez-Perez, Ruben Rene

    2013-01-01

    Despite accumulating evidence suggesting a positive correlation between leptin levels, obesity, post-menopause and breast cancer incidence, our current knowledge on the mechanisms involved in these relationships is still incomplete. Since the cloning of leptin in 1994 and its receptor (OB-R) 1 year later by Friedman’s laboratory (Zhang et al., 1994) and Tartaglia et al. (Tartaglia et al., 1995), respectively, more than 22,000 papers related to leptin functions in several biological systems have been published (Pubmed, 2012). The ob gene product, leptin, is an important circulating signal for the regulation of body weight. Additionally, leptin plays critical roles in the regulation of glucose homeostasis, reproduction, growth and the immune response. Supporting evidence for leptin roles in cancer has been shown in more than 1000 published papers, with almost 300 papers related to breast cancer (Pubmed, 2012). Specific leptin-induced signaling pathways are involved in the increased levels of inflammatory, mitogenic and pro-angiogenic factors in breast cancer. In obesity, a mild inflammatory condition, deregulated secretion of proinflammatory cytokines and adipokines such as IL-1, IL-6, TNF-α and leptin from adipose tissue, inflammatory and cancer cells could contribute to the onset and progression of cancer. We used an in silico software program, Pathway Studio 9, and found 4587 references citing these various interactions. Functional crosstalk between leptin, IL-1 and Notch signaling (NILCO) found in breast cancer cells could represent the integration of developmental, proinflammatory and pro-angiogenic signals critical for leptin-induced breast cancer cell proliferation/migration, tumor angiogenesis and breast cancer stem cells (BCSCs). Remarkably, the inhibition of leptin signaling via leptin peptide receptor antagonists (LPrAs) significantly reduced the establishment and growth of syngeneic, xenograft and carcinogen-induced breast cancer and, simultaneously

  10. Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-κB in 4-nitroquinoline 1-oxide-induced murine oral cancer model

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yu-Ching [Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan (China); Department of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan (China); Ho, Heng-Chien; Lee, Miau-Rong [Department of Biochemistry, China Medical University, Taichung 404, Taiwan (China); Lai, Kuang-Chi [Department of Surgery, China Medical University Beigang Hospital, Yunlin 651, Taiwan (China); School of Medicine, China Medical University, Taichung 404, Taiwan (China); Yeh, Chung-Min; Lin, Yueh-Min [Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan (China); Ho, Tin-Yun [School of Chinese Medicine, China Medical University, Taichung 404, Taiwan (China); Hsiang, Chien-Yun, E-mail: cyhsiang@mail.cmu.edu.tw [Department of Microbiology, China Medical University, Taichung 404, Taiwan (China); Chung, Jing-Gung, E-mail: jgchung@mail.cmu.edu.tw [Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan (China); Department of Biotechnology, Asia University, Taichung 413, Taiwan (China)

    2012-07-15

    The purpose of this study was to identify the genes induced early in murine oral carcinogenesis. Murine tongue tumors induced by the carcinogen, 4-nitroquinoline 1-oxide (4-NQO), and paired non-tumor tissues were subjected to microarray analysis. Hierarchical clustering of upregulated genes in the tumor tissues revealed an association of induced genes with inflammation. Cytokines/cytokine receptors induced early were subsequently identified, clearly indicating their involvement in oral carcinogenesis. Hierarchical clustering also showed that cytokine-mediated inflammation was possibly linked with Mapk6. Cox2 exhibited the greatest extent (9–18 fold) of induction in the microarray data, and its early induction was observed in a 2 h painting experiment by RT-PCR. MetaCore analysis showed that overexpressed Cox2 may interact with p53 and transcriptionally inhibit expression of several downstream genes. A painting experiment in transgenic mice also demonstrated that NF-κB activates early independently of Cox2 induction. MetaCore analysis revealed the most striking metabolic alterations in tumor tissues, especially in lipid metabolism resulting from the reduction of Pparα and Rxrg. Reduced expression of Mapk12 was noted, and MetaCore analysis established its relationship with decreased efficiency of Pparα phosphorylation. In conclusion, in addition to cytokines/cytokine receptors, the early induction of Cox2 and NF-κB activation is involved in murine oral carcinogenesis.

  11. Cytokine Network Involvement in Subjects Exposed to Benzene

    Science.gov (United States)

    Gangemi, Sebastiano

    2014-01-01

    Benzene represents an ubiquitous pollutant both in the workplace and in the general environment. Health risk and stress posed by benzene have long been a concern because of the carcinogenic effects of the compound which was classified as a Group 1 carcinogen to humans and animals. There is a close correlation between leukemia, especially acute myeloid leukemia, and benzene exposure. In addition, exposure to benzene can cause harmful effects on immunological, neurological, and reproductive systems. Benzene can directly damage hematopoietic progenitor cells, which in turn could lead to apoptosis or may decrease responsiveness to cytokines and cellular adhesion molecules. Alternatively, benzene toxicity to stromal cells or mature blood cells could disrupt the regulation of hematopoiesis, including hematopoietic commitment, maturation, or mobilization, through the network of cytokines, chemokines, and adhesion molecules. Today there is mounting evidence that benzene may alter the gene expression, production, or processing of several cytokines in vitro and in vivo. The purpose of this review was to systematically analyze the published cases of cytokine effects on human benzene exposure, particularly hematotoxicity, and atopy, and on lungs. PMID:25202711

  12. Cytokine Profiling in Patients with VCP‐Associated Disease

    Science.gov (United States)

    Dec, Eric; Rana, Prachi; Katheria, Veeral; Dec, Rachel; Khare, Manaswitha; Nalbandian, Angèle; Leu, Szu‐Yun; Radom‐Aizik, Shlomit; Llewellyn, Katrina; BenMohamed, Lbachir; Zaldivar, Frank

    2013-01-01

    Abstract Valosin containing protein (VCP) disease (also known as Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia [IBMPFD] syndrome) is caused by mutations in the gene encoding VCP classically affecting the muscle, bone and brain. Although the genetic cause has been identified, details regarding the pathogenesis of IBMPFD have not been fully determined. Muscle wasting observed in VCP disease is suggestive of cytokine imbalance. We hypothesized that dysfunctional protein homeostasis caused by VCP mutations leads to cytokine imbalances thereby contributing to the muscle wasting phenotype. Circulating levels of interleukin‐4 (IL‐4), interleukin‐6 (IL‐6), tumor necrosis factor alpha (TNF a) and epidermal growth factor (EGF) were measured in plasma of patients with VCP disease or controls. TNF a and EGF were significantly altered in VCP disease as compared to control. TNF a was up‐regulated, consistent with a cachexia phenotype and EGF levels were increased. No significant differences were observed in IL‐4 and IL‐6. Cytokine imbalances may be associated with VCP disease and may play a contributory role in VCP myopathy. Further understanding of how VCP dysfunction leads to aberrant protein homeostasis and subsequent cytokine imbalances may also aid in the understanding of other proteinopathies and in the development of novel treatments. PMID:24119107

  13. PCTAIRE1-knockdown sensitizes cancer cells to TNF family cytokines.

    Directory of Open Access Journals (Sweden)

    Teruki Yanagi

    Full Text Available While PCTAIRE1/PCTK1/Cdk16 is overexpressed in malignant cells and is crucial in tumorigenesis, its function in apoptosis remains unclear. Here we investigated the role of PCTAIRE1 in apoptosis, especially in the extrinsic cell death pathway. Gene-knockdown of PCTAIRE1 sensitized prostate cancer PPC1 and Du145 cells, and breast cancer MDA-MB-468 cells to TNF-family cytokines, including TNF-related apoptosis-inducing ligand (TRAIL. Meanwhile, PCTAIRE1-knockdown did not sensitize non-malignant cells, including diploid fibroblasts IMR-90 and the immortalized prostate epithelial cell line 267B1. PCTAIRE1-knockdown did not up-regulate death receptor expression on the cell surface or affect caspase-8, FADD and FLIP expression levels. PCTAIRE1-knockdown did promote caspase-8 cleavage and RIPK1 degradation, while RIPK1 mRNA knockdown sensitized PPC1 cells to TNF-family cytokines. Furthermore, the kinase inhibitor SNS-032, which inhibits PCTAIRE1 kinase activity, sensitized PPC1 cells to TRAIL-induced apoptosis. Together these results suggest that PCTAIRE1 contributes to the resistance of cancer cell lines to apoptosis induced by TNF-family cytokines, which implies that PCTAIRE1 inhibitors could have synergistic effects with TNF-family cytokines for cytodestruction of cancer cells.

  14. Soluble cytokine receptors in biological therapy.

    Science.gov (United States)

    Fernandez-Botran, Rafael; Crespo, Fabian A; Sun, Xichun

    2002-08-01

    Due to their fundamental involvement in the pathogenesis of many diseases, cytokines constitute key targets for biotherapeutic approaches. The discovery that soluble forms of cytokine receptors are involved in the endogenous regulation of cytokine activity has prompted substantial interest in their potential application as immunotherapeutic agents. As such, soluble cytokine receptors have many advantages, including specificity, low immunogenicity and high affinity. Potential disadvantages, such as low avidity and short in vivo half-lifes, have been addressed by the use of genetically-designed receptors, hybrid proteins or chemical modifications. The ability of many soluble cytokine receptors to inhibit the binding and biological activity of their ligands makes them very specific cytokine antagonists. Several pharmaceutical companies have generated a number of therapeutic agents based on soluble cytokine receptors and many of them are undergoing clinical trials. The most advanced in terms of clinical development is etanercept (Enbrel, Immunex), a fusion protein between soluble TNF receptor Type II and the Fc region of human IgG1. This TNF-alpha; antagonist was the first soluble cytokine receptor to receive approval for use in humans. In general, most agents based on soluble cytokine receptors have been safe, well-tolerated and have shown only minor side effects in the majority of patients. Soluble cytokine receptors constitute a new generation of therapeutic agents with tremendous potential for applications in a wide variety of human diseases. Two current areas of research are the identification of their most promising applications and characterisation of their long-term effects.

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

    Science.gov (United States)

    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.

  16. Involvement of the ubiquitin-proteasome system in the expression of extracellular matrix genes in retinal pigment epithelial cells

    Directory of Open Access Journals (Sweden)

    J. Emanuel Ramos de Carvalho

    2018-03-01

    Full Text Available Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system is involved in the pathogenesis of numerous senile degenerative diseases including retinal disorders. The aim of this study was to assess whether there is a link between proteasome regulation and retinal pigment epithelium (RPE-mediated expression of extracellular matrix genes. For this purpose, human retinal pigment epithelial cells (ARPE-19 were treated with different concentrations of transforming growth factor-β (TGFβ, connective tissue growth factor (CTGF, interferon-γ (IFNγ and the irreversible proteasome inhibitor epoxomicin. First, cytotoxicity and proliferation assays were carried out. The expression of proteasome-related genes and proteins was assessed and proteasome activity was determined. Then, expression of fibrosis-associated factors fibronectin (FN, fibronectin EDA domain (FN EDA, metalloproteinase-2 (MMP-2, tissue inhibitor of metalloproteinases-1 (TIMP-1 and peroxisome proliferator-associated receptor-γ (PPARγ was assessed. The proteasome inhibitor epoxomicin strongly arrested cell cycle progression and down-regulated TGFβ gene expression, which in turn was shown to induce expression of pro-fibrogenic genes in ARPE-19 cells. Furthermore, epoxomicin induced a directional shift in the balance between MMP-2 and TIMP-1 and was associated with down-regulation of transcription of extracellular matrix genes FN and FN-EDA and up-regulation of the anti-fibrogenic factor PPARγ. In addition, both CTGF and TGFβ were shown to affect expression of proteasome-associated mRNA and protein levels. Our results suggest a link between proteasome activity and pro-fibrogenic mechanisms in the RPE, which could imply a role for proteasome-modulating agents in the treatment of retinal disorders characterized by RPE-mediated fibrogenic responses.

  17. Anti-Inflammatory Cytokines: Important Immunoregulatory Factors Contributing to Chemotherapy-Induced Gastrointestinal Mucositis

    Directory of Open Access Journals (Sweden)

    Masooma Sultani

    2012-01-01

    Full Text Available “Mucositis” is the clinical term used to describe ulceration and damage of the mucous membranes of the entire gastrointestinal tract (GIT following cytotoxic cancer chemotherapy and radiation therapy common symptoms include abdominal pain, bloating, diarrhoea, vomiting, and constipation resulting in both a significant clinical and financial burden. Chemotherapeutic drugs cause upregulation of stress response genes including NFκB, that in turn upregulate the production of proinflammatory cytokines such as interleukin-1β (IL-1β, Interleukin-6 (IL-6, and tumour necrosis factor-α (TNF-α. These proinflammatory cytokines are responsible for initiating inflammation in response to tissue injury. Anti-inflammatory cytokines and specific cytokine inhibitors are also released to limit the sustained or excessive inflammatory reactions. In the past decade, intensive research has determined the role of proinflammatory cytokines in development of mucositis. However, a large gap remains in the knowledge of the role of anti-inflammatory cytokines in the setting of chemotherapy-induced mucositis. This critical paper will highlight current literature available relating to what is known regarding the development of mucositis, including the molecular mechanisms involved in inducing inflammation particularly with respect to the role of proinflammatory cytokines, as well as provide a detailed discussion of why it is essential to consider extensive research in the role of anti-inflammatory cytokines in chemotherapy-induced mucositis so that effective targeted treatment strategies can be developed.

  18. Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines

    DEFF Research Database (Denmark)

    Lundh, M; Christensen, D P; Rasmussen, D N

    2010-01-01

    Cytokine-induced beta cell toxicity is abrogated by non-selective inhibitors of lysine deacetylases (KDACs). The KDAC family consists of 11 members, namely histone deacetylases HDAC1 to HDAC11, but it is not known which KDAC members play a role in cytokine-mediated beta cell death. The aim...... of the present study was to examine the KDAC gene expression profile of the beta cell and to investigate whether KDAC expression is regulated by cytokines. In addition, the protective effect of the non-selective KDAC inhibitor ITF2357 and interdependent regulation of four selected KDACs were investigated....

  19. The cre-inducer doxycycline lowers cytokine and chemokine transcript levels in the gut of mice

    DEFF Research Database (Denmark)

    Hansen, Axel Kornerup; Malm, Sara Astrup; Metzdorff, Stine B.

    2017-01-01

    a strong impact on the immune system. Here we show that in C57BL/6 mice, the most commonly applied strain for genetic modification, doxycycline treatment lowered transcription of the genes Il1b, Il10, Il18, Tnf, Cxcl1, and Cxcl2 in the ileum, and of the gene Il18 in colon. Cytokines and chemokines encoded...

  20. High Incidence of ACE/PAI-1 in Association to a Spectrum of Other Polymorphic Cardiovascular Genes Involving PBMCs Proinflammatory Cytokines in Hypertensive Hypercholesterolemic Patients: Reversibility with a Combination of ACE Inhibitor and Statin

    Science.gov (United States)

    Mouawad, Charbel; Haddad, Katia; Hamoui, Samar; Azar, Albert; Fajloun, Ziad; Makdissy, Nehman

    2015-01-01

    Cardiovascular diseases (CVDs) are significantly high in the Lebanese population with the two most predominant forms being atherosclerosis and venous thrombosis. The purpose of our study was to assess the association of a spectrum of CVD related genes and combined state of hypertension hypercholesterolemia (HH) in unrelated Lebanese. Twelve polymorphisms were studied by multiplex PCR and reverse hybridization of DNA from 171 healthy individuals and 144 HH subjects. Two genes were significantly associated with HH: ACE (OR: 9.20, PACE activity and PAI-I increased significantly with Del/Del and 4G/5G genotypes. The co-expression of Del/4G(+/+) was detected in 113 out of 171 (66.0%) controls and 125 out of 144 (86.8%) HH subjects. Del/4G(-/-) was detected in only 6 (3.5%) controls and undetected in the HH group. Three venous thrombosis related genes [FV(Leiden), MTHFR(A1298C) and FXIII(V34L)] were significantly related to the prominence of the co-expression of Del/4G(+/+). A range of 2 to 8 combined polymorphisms co-expressed per subject where 5 mutations were the most detected. In Del/4G(+/+) subjects, peripheral blood mononuclear cells (PBMCs) produced significant elevated levels of IFN-γ and TNF-α contrary to IL-10, and no variations occurred for IL-4. ACE inhibitor (ramipril) in combination with statin (atorvastatin) and not alone reversed significantly the situation. This first report from Lebanon sheds light on an additional genetic predisposition of a complex spectrum of genes involved in CVD and suggests that the most requested gene FVL by physicians may not be sufficient to diagnose eventual future problems that can occur in the cardiovascular system. Subjects expressing the double mutations (Del/4G) are at high risk for the onset of CVDs. PMID:25973747

  1. Bioanalytical Chemistry of Cytokines-A Review

    Science.gov (United States)

    Stenken, Julie A.; Poschenrieder, Andreas J.

    2014-01-01

    Cytokines are bioactive proteins produced by many different cells of the immune system. Due to their role in different inflammatory disease states and maintaining homeostasis, there is enormous clinical interest in the quantitation of cytokines. The typical standard methods for quantitation of cytokines are immunoassay-based techniques including enzyme-linked immusorbent assays (ELISA) and bead-based immunoassays read by either standard or modified flow cytometers. A review of recent developments in analytical methods for measurements of cytokine proteins is provided. This review briefly covers cytokine biology and the analysis challenges associated with measurement of these biomarker proteins for understanding both health and disease. New techniques applied to immunoassay-based assays are presented along with the uses of aptamers, electrochemistry, mass spectrometry, optical resonator-based methods. Methods used for elucidating the release of cytokines from single cells as well as in vivo collection methods are described. PMID:25467452

  2. Cytokine Response to Exercise and Its Modulation

    Directory of Open Access Journals (Sweden)

    Katsuhiko Suzuki

    2018-01-01

    Full Text Available Strenuous exercise induces such inflammatory responses as leukocytosis (neutrophilia and symptoms as delayed-onset muscle soreness and swelling. However, the association between inflammatory mediator cytokines and oxidative stress is not fully delineated. Herein, in addition to basic background information on cytokines, research findings on exertional effects on cytokine release and the underlying mechanisms and triggers are introduced. Then, the associations among cytokine responses, oxidative stress, and tissue damage are described not only in overloaded skeletal muscle, but also in other internal organs. Furthermore, we introduce preventive countermeasures against the exhaustive exercise-induced pathogenesis together with the possibility of antioxidant interventions.

  3. Cancer Cytokines and the Relevance of 3D Cultures for Studying Those Implicated in Human Cancers.

    Science.gov (United States)

    Maddaly, Ravi; Subramaniyan, Aishwarya; Balasubramanian, Harini

    2017-09-01

    Cancers are complex conditions and involve several factors for oncogenesis and progression. Of the various factors influencing the physiology of cancers, cytokines are known to play significant roles as mediators of functions. Intricate cytokine networks have been identified in cancers and interest in cytokines associated with cancers has been gaining ground. Of late, some of these cytokines are even identified as potential targets for cancer therapy apart from a few others such as IL-6 being identified as markers for disease prognosis. Of the major contributors to cancer research, cancer cell lines occupy the top slot as the most widely used material in vitro. In vitro cell cultures have seen significant evolution by the introduction of 3-dimensional (3D) culture systems. 3D cell cultures are now widely accepted as excellent material for cancer research which surpass the traditional monolayer cultures. Cancer research has benefited from 3D cell cultures for understanding the various hallmarks of cancers. However, the potential of these culture systems are still unexploited for cancer cytokine research compared to the other aspects of cancers such as gene expression changes, drug-induced toxicity, morphology, angiogenesis, and invasion. Considering the importance of cancer cytokines, 3D cell cultures can be better utilized in understanding their roles and functions. Some of the possibilities where 3D cell cultures can contribute to cancer cytokine research arise from the distinct morphology of the tumor spheroids, the extracellular matrix (ECM), and the spontaneous occurrence of nutrient and oxygen gradients. Also, the 3D culture models enable one to co-culture different types of cells as a simulation of in vivo conditions, enhancing their utility to study cancer cytokines. We review here the cancer associated cytokines and the contributions of 3D cancer cell cultures for studying cancer cytokines. J. Cell. Biochem. 118: 2544-2558, 2017. © 2017 Wiley Periodicals

  4. RNA-seq reveals activation of both common and cytokine-specific pathways following neutrophil priming.

    Directory of Open Access Journals (Sweden)

    Helen L Wright

    Full Text Available Neutrophils are central to the pathology of inflammatory diseases, where they can damage host tissue through release of reactive oxygen metabolites and proteases, and drive inflammation via secretion of cytokines and chemokines. Many cytokines, such as those generated during inflammation, can induce a similar "primed" phenotype in neutrophils, but it is unknown if different cytokines utilise common or cytokine-specific pathways to induce these functional changes. Here, we describe the transcriptomic changes induced in control human neutrophils during priming in vitro with pro-inflammatory cytokines (TNF-α and GM-CSF using RNA-seq. Priming led to the rapid expression of a common set of transcripts for cytokines, chemokines and cell surface receptors (CXCL1, CXCL2, IL1A, IL1B, IL1RA, ICAM1. However, 580 genes were differentially regulated by TNF-α and GM-CSF treatment, and of these 58 were directly implicated in the control of apoptosis. While these two cytokines both delayed apoptosis, they induced changes in expression of different pro- and anti-apoptotic genes. Bioinformatics analysis predicted that these genes were regulated via differential activation of transcription factors by TNF-α and GM-CSF and these predictions were confirmed using functional assays: inhibition of NF-κB signalling abrogated the protective effect of TNF-α (but not that of GM-CSF on neutrophil apoptosis, whereas inhibition of JAK/STAT signalling abrogated the anti-apoptotic effect of GM-CSF, but not that of TNF-α (p<0.05. These data provide the first characterisation of the human neutrophil transcriptome following GM-CSF and TNF-α priming, and demonstrate the utility of this approach to define functional changes in neutrophils following cytokine exposure. This may provide an important, new approach to define the molecular properties of neutrophils after in vivo activation during inflammation.

  5. Cytokine response to vitamin E supplementation is dependent on pre-supplementation cytokine levels

    Science.gov (United States)

    Belisle, Sarah E.; Leka, Lynette S.; Dallal, Gerard E.; Jacques, Paul F.; Delgado-Lista, Javier; Ordovas, Jose M.; Meydani, Simin Nikbin

    2009-01-01

    Vitamin E supplementation has been suggested to improve immune response in the aged in part by altering cytokine production. However, there is not a consensus regarding the effect of supplemental vitamin E on cytokine production in humans. There is evidence that baseline immune health can affect immune response to supplemental vitamin E in the elderly. Thus, the effect of vitamin E on cytokines may depend on their pre-supplementation cytokine response. Using data from a vitamin E intervention in elderly nursing home residents, we examined if the effect of vitamin E on ex vivo cytokine production of IL-1β, IL-6, TNF-α, and IFN-γ depended on baseline cytokine production. . We observed that the effect of vitamin E supplementation on cytokine production depended on pre-supplementation production of the respective cytokines. The interactions between vitamin E and baseline cytokine production were not explained covariates known to impact cytokine production. Our results offer evidence that baseline cytokine production should be considered in studies that examine the effect of supplemental vitamin E on immune and inflammatory responses. Our results could have implications in designing clinical trials to determine the impact of vitamin E on conditions in which cytokines are implicated such as infections and atherosclerotic disease. PMID:19478423

  6. Compartmentalized Cytokine Responses in Hidradenitis Suppurativa

    NARCIS (Netherlands)

    Kanni, T.; Tzanetakou, V.; Savva, A.; Kersten, B.; Pistiki, A.; Veerdonk, F.L. van de; Netea, M.G.; Meer, J.W.M. van der; Giamarellos-Bourboulis, E.J.

    2015-01-01

    BACKGROUND: Favorable treatment outcomes with TNF blockade led us to explore cytokine responses in hidradenitis suppurativa (HS). METHODS: Blood monocytes of 120 patients and 24 healthy volunteers were subtyped by flow cytometry. Isolated blood mononuclear cells (PBMCs) were stimulated for cytokine

  7. 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

  8. Study of cytokines microenvironment during autoimmune diseases ...

    African Journals Online (AJOL)

    The development of autoimmun diseases involves an intricate network of cytokines that recruit and activate TREGS/ TH17 cells. This study was aimed to compare PBMC levels of pro-inflammatory and anti-inflammatory cytokines in AID patients and non-AID controls from Bobo Dioulasso. We prospectively enrolled 17 ...

  9. Cytokines and organ failure in acute pancreatitis

    DEFF Research Database (Denmark)

    Malmstrøm, Marie Louise; Hansen, Mark Berner; Andersen, Anders Møller

    2012-01-01

    We aimed at synchronously examining the early time course of 4 proinflammatory cytokines as predictive factors for development of organ failure in patients with acute pancreatitis (AP).......We aimed at synchronously examining the early time course of 4 proinflammatory cytokines as predictive factors for development of organ failure in patients with acute pancreatitis (AP)....

  10. Cytokine signalling in embryonic stem cells

    DEFF Research Database (Denmark)

    Kristensen, David Møbjerg; Kalisz, Mark; Nielsen, Jens Høiriis

    2006-01-01

    Cytokines play a central role in maintaining self-renewal in mouse embryonic stem (ES) cells through a member of the interleukin-6 type cytokine family termed leukemia inhibitory factor (LIF). LIF activates the JAK-STAT3 pathway through the class I cytokine receptor gp130, which forms a trimeric...... pathways seem to converge on c-myc as a common target to promote self-renewal. Whereas LIF does not seem to stimulate self-renewal in human embryonic stem cells it cannot be excluded that other cytokines are involved. The pleiotropic actions of the increasing number of cytokines and receptors signalling...... via JAKs, STATs and SOCS exhibit considerable redundancy, compensation and plasticity in stem cells in accordance with the view that stem cells are governed by quantitative variations in strength and duration of signalling events known from other cell types rather than qualitatively different stem...

  11. Interactions between Autophagy and Inhibitory Cytokines.

    Science.gov (United States)

    Wu, Tian-Tian; Li, Wei-Min; Yao, Yong-Ming

    2016-01-01

    Autophagy is a degradative pathway that plays an essential role in maintaining cellular homeostasis. Most early studies of autophagy focused on its involvement in age-associated degeneration and nutrient deprivation. However, the immunological functions of autophagy have become more widely studied in recent years. Autophagy has been shown to be an intrinsic cellular defense mechanism in the innate and adaptive immune responses. Cytokines belong to a broad and loose category of proteins and are crucial for innate and adaptive immunity. Inhibitory cytokines have evolved to permit tolerance to self while also contributing to the eradication of invading pathogens. Interactions between inhibitory cytokines and autophagy have recently been reported, revealing a novel mechanism by which autophagy controls the immune response. In this review, we discuss interactions between autophagy and the regulatory cytokines IL-10, transforming growth factor-β, and IL-27. We also mention possible interactions between two newly discovered cytokines, IL-35 and IL-37, and autophagy.

  12. Dietary phenylalanine-improved intestinal barrier health in young grass carp (Ctenopharyngodon idella) is associated with increased immune status and regulated gene expression of cytokines, tight junction proteins, antioxidant enzymes and related signalling molecules.

    Science.gov (United States)

    Feng, Lin; Li, Wen; Liu, Yang; Jiang, Wei-Dan; Kuang, Sheng-Yao; Jiang, Jun; Tang, Ling; Wu, Pei; Tang, Wu-Neng; Zhang, Yong-An; Zhou, Xiao-Qiu

    2015-08-01

    The present work evaluated the effects of dietary phenylalanine (Phe) on the intestinal immune response, tight junction proteins transcript abundance, and the gene expression of immune- and antioxidant-related signalling molecules in the intestine. In addition, the dietary Phe (and Phe + Tyr) requirement of young grass carp (Ctenopharyngodon idella) was also estimated. Fish were fed fish meal-casein-gelatin based diets (302.3 g crude protein kg(-1)) containing 3.4 (basal diet), 6.1, 9.1, 11.5, 14.0 and 16.8 g Phe kg(-1) with a fixed amount of 10.7 g tyrosine kg(-1) for 8 weeks. The results showed that Phe deficiency or excess Phe reduced the lysozyme and acid phosphatase activities and complement C 3 content in the intestine (P dietary Phe (P > 0.05). Gene expression of interleukin-10 (IL-10), transforming growth factor-β1 (TGF-β1), target of rapamycin (TOR) and inhibitor of nuclear factor κBα (IκBα) in proximal intestine (PI), mid intestine (MI) and distal intestine (DI) increased as dietary Phe increased up to 6.1, 9.1, 11.5 and 14.0 g kg(-1), respectively (P dietary Phe increased up to 9.1 g kg(-1) (P proteins, antioxidant enzymes, NF-κB p65, IκBα, TOR, and Nrf2 in the fish intestine. Based on the quadratic regression analysis of lysozyme activity at a 95% maximum, the dietary Phe requirement of young grass carp (256-629 g) was estimated to be 8.31 g kg(-1), corresponding to 2.75 g 100 g(-1) protein. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Novel methods of cytokine detection: Real-time PCR, ELISPOT, and intracellular cytokine staining

    Directory of Open Access Journals (Sweden)

    Eliza Turlej

    2009-05-01

    Full Text Available Cytokines are small hormone-like proteins that play important roles in immune system control. Cytokines regulate the proliferation and differentiation of cells and hematopoiesis and act as mediators in the inflammatory reaction. Changes in cytokine levels are found in many diseases, such as sepsis, bowel inflammatory disease, autoimmune diseases, as well as graft-versus-host disease. Cytokines levels can be detected using in vivo, in vitro, and ex vivo techniques. The level of cytokine produced can be measured by immunoenzymatic test (ELISA in supernatant after cell culture with the addition of stimulant and in plasma by techniques that measure the level of cytokine secretion in cells (e.g. immunohistochemical staining, ELISPOT, and intracellular cytokine staining, and by molecular biological methods (RPA, real-time PCR, in situ hybridization, and Northern blot. Detection of cytokine mRNA in tissues is useful in the direct determination of heterogenic populations of cytokine-producing cells. Nowadays the most frequently used methods for measuring cytokine level are ELISPOT, intracellular cytokine staining with flow cytometry detection, and real-time PCR. These methods have an important clinical role in vaccine efficacy, in viral, bacterial, and verminous diagnostics, and in determining the efficacy of cancer treatment.

  14. Complement activation by cholesterol crystals triggers a subsequent cytokine response

    DEFF Research Database (Denmark)

    Niyonzima, Nathalie; Halvorsen, Bente; Sporsheim, Bjørnar

    2017-01-01

    may under certain circumstances drive processes leading to adverse inflammation. One example is cholesterol crystals (CC) that accumulate in the vessel wall during early phases of atherogenesis and represent an important endogenous danger signal promoting inflammation. CC is recognized by the lectin...... of inflammation processes before downstream release of cytokines including IL-1β. Another therapeutic candidate can be broad-acting 2-hydroxypropyl-β-cyclodextrin, a compound that targets several mechanisms such as cholesterol efflux, complement gene expression, and the NLRP3 pathway. In summary, emerging...

  15. Cytokine array after cyclosporine treatment in rats.

    Science.gov (United States)

    Jin, K B; Choi, H J; Kim, H T; Hwang, E A; Han, S Y; Park, S B; Kim, H C; Ha, E Y; Kim, Y H; Suh, S I; Mun, K C

    2008-10-01

    Long-term treatment with cyclosporine (CsA) results in chronic nephrotoxicity, which is known to be mediated by several cytokines including transforming growth factor-betal. Cytokines are known to play an important role in innate immunity, apoptosis, angiogenesis, cell growth, and differentiation. They are known to be involved in most disease processes, including cancer, cardiac disease, and nephrotoxicity. To evaluate changes of cytokines in a rat model of CsA-induced chronic nephrotoxicity, we performed a cytokine array. Experiments were performed on two groups of rats; normal control group and CsA-treated group. Cytokine array in rat serum was performed using Cytokine Antibody Array I kit from RayBiotech. Serum creatinine, urine creatinine, and creatinine clearance increased in the CsA-treated group. Among the several cytokines, the expressions of the lipopolysaccharide-induced CXC chemokine (LIX), monocyte chemoattractant protein 1 (MCP-1), nerve growth factor (beta-NGF), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the CsA-treated group were increased above that of cytokines in the control group. The density of the LIX in controls was 0.62, and in the CsA-treated group was 1.24. The density of the MCP-1 in controls was 0.68, and in CsA-treated, 1.43. The density of the beta-NGF in controls was 0.62, and that in CsA-treated, 1.24. The density of the TIMP-1 in controls 1.13, and in CsA-treated, 1.40. Our data suggested that among several cytokines elevated levels of the LIX, MCP-1, beta-NGF, and TIMP-1 are the contributing factors to CsA-induced nephropathy.

  16. How Do Cytokines Trigger Genomic Instability?

    Directory of Open Access Journals (Sweden)

    Ioannis L. Aivaliotis

    2012-01-01

    Full Text Available Inflammation is a double-edged sword presenting a dual effect on cancer development, from one hand promoting tumor initiation and progression and from the other hand protecting against cancer through immunosurveillance mechanisms. Cytokines are crucial components of inflammation, participating in the interaction between the cells of tumor microenvironment. A comprehensive study of the role of cytokines in the context of the inflammation-tumorigenesis interplay helps us to shed light in the pathogenesis of cancer. In this paper we focus on the role of cytokines in the development of genomic instability, an evolving hallmark of cancer.

  17. Mimitin - a novel cytokine-regulated mitochondrial protein.

    Science.gov (United States)

    Wegrzyn, Paulina; Yarwood, Stephen J; Fiegler, Nathalie; Bzowska, Monika; Koj, Aleksander; Mizgalska, Danuta; Malicki, Stanisław; Pajak, Magdalena; Kasza, Aneta; Kachamakova-Trojanowska, Neli; Bereta, Joanna; Jura, Jacek; Jura, Jolanta

    2009-03-31

    The product of a novel cytokine-responsive gene discovered by differential display analysis in our earlier studies on HepG2 cells was identified as mimitin - a small mitochondrial protein. Since proinflammatory cytokines are known to affect components of the respiratory chain in mitochondria, and mimitin was reported as a possible chaperone for assembly of mitochondrial complex I, we looked for the effects of modulation of mimitin expression and for mimitin-binding partners. By blocking mimitin expression in HepG2 cells by siRNA we found that mimitin has no direct influence on caspase 3/7 activities implicated in apoptosis. However, when apoptosis was induced by TNF and cycloheximide, and mimitin expression blocked, the activities of these caspases were significantly increased. This was accompanied by a slight decrease in proliferation of HepG2 cells. Our observations suggest that mimitin may be involved in the control of apoptosis indirectly, through another protein, or proteins. Using the yeast two-hybrid system and coimmunoprecipitation we found MAP1S among proteins interacting with mimitin. MAP1S is a recently identified member of the microtubule-associated protein family and has been shown to interact with NADH dehydrogenase I and cytochrome oxidase I. Moreover, it was implicated in the process of mitochondrial aggregation and nuclear genome destruction. The expression of mimitin is stimulated more than 1.6-fold by IL-1 and by IL-6, with the maximum level of mimitin observed after 18-24 h exposure to these cytokines. We also found that the cytokine-induced signal leading to stimulation of mimitin synthesis utilizes the MAP kinase pathway. Mimitin is a mitochondrial protein upregulated by proinflammatory cytokines at the transcriptional and protein levels, with MAP kinases involved in IL-1-dependent induction. Mimitin interacts with a microtubular protein (MAP1S), and some changes of mimitin gene expression modulate activity of apoptotic caspases 3

  18. Mimitin – a novel cytokine-regulated mitochondrial protein

    Directory of Open Access Journals (Sweden)

    Kachamakova-Trojanowska Neli

    2009-03-01

    Full Text Available Abstract Background The product of a novel cytokine-responsive gene discovered by differential display analysis in our earlier studies on HepG2 cells was identified as mimitin – a small mitochondrial protein. Since proinflammatory cytokines are known to affect components of the respiratory chain in mitochondria, and mimitin was reported as a possible chaperone for assembly of mitochondrial complex I, we looked for the effects of modulation of mimitin expression and for mimitin-binding partners. Results By blocking mimitin expression in HepG2 cells by siRNA we found that mimitin has no direct influence on caspase 3/7 activities implicated in apoptosis. However, when apoptosis was induced by TNF and cycloheximide, and mimitin expression blocked, the activities of these caspases were significantly increased. This was accompanied by a slight decrease in proliferation of HepG2 cells. Our observations suggest that mimitin may be involved in the control of apoptosis indirectly, through another protein, or proteins. Using the yeast two-hybrid system and coimmunoprecipitation we found MAP1S among proteins interacting with mimitin. MAP1S is a recently identified member of the microtubule-associated protein family and has been shown to interact with NADH dehydrogenase I and cytochrome oxidase I. Moreover, it was implicated in the process of mitochondrial aggregation and nuclear genome destruction. The expression of mimitin is stimulated more than 1.6-fold by IL-1 and by IL-6, with the maximum level of mimitin observed after 18–24 h exposure to these cytokines. We also found that the cytokine-induced signal leading to stimulation of mimitin synthesis utilizes the MAP kinase pathway. Conclusion Mimitin is a mitochondrial protein upregulated by proinflammatory cytokines at the transcriptional and protein levels, with MAP kinases involved in IL-1-dependent induction. Mimitin interacts with a microtubular protein (MAP1S, and some changes of mimitin gene

  19. Mimitin – a novel cytokine-regulated mitochondrial protein

    Science.gov (United States)

    Wegrzyn, Paulina; Yarwood, Stephen J; Fiegler, Nathalie; Bzowska, Monika; Koj, Aleksander; Mizgalska, Danuta; Malicki, Stanisław; Pajak, Magdalena; Kasza, Aneta; Kachamakova-Trojanowska, Neli; Bereta, Joanna; Jura, Jacek; Jura, Jolanta

    2009-01-01

    Background The product of a novel cytokine-responsive gene discovered by differential display analysis in our earlier studies on HepG2 cells was identified as mimitin – a small mitochondrial protein. Since proinflammatory cytokines are known to affect components of the respiratory chain in mitochondria, and mimitin was reported as a possible chaperone for assembly of mitochondrial complex I, we looked for the effects of modulation of mimitin expression and for mimitin-binding partners. Results By blocking mimitin expression in HepG2 cells by siRNA we found that mimitin has no direct influence on caspase 3/7 activities implicated in apoptosis. However, when apoptosis was induced by TNF and cycloheximide, and mimitin expression blocked, the activities of these caspases were significantly increased. This was accompanied by a slight decrease in proliferation of HepG2 cells. Our observations suggest that mimitin may be involved in the control of apoptosis indirectly, through another protein, or proteins. Using the yeast two-hybrid system and coimmunoprecipitation we found MAP1S among proteins interacting with mimitin. MAP1S is a recently identified member of the microtubule-associated protein family and has been shown to interact with NADH dehydrogenase I and cytochrome oxidase I. Moreover, it was implicated in the process of mitochondrial aggregation and nuclear genome destruction. The expression of mimitin is stimulated more than 1.6-fold by IL-1 and by IL-6, with the maximum level of mimitin observed after 18–24 h exposure to these cytokines. We also found that the cytokine-induced signal leading to stimulation of mimitin synthesis utilizes the MAP kinase pathway. Conclusion Mimitin is a mitochondrial protein upregulated by proinflammatory cytokines at the transcriptional and protein levels, with MAP kinases involved in IL-1-dependent induction. Mimitin interacts with a microtubular protein (MAP1S), and some changes of mimitin gene expression modulate activity of

  20. Interleukin-24 as a target cytokine of environmental aryl hydrocarbon receptor agonist exposure in the lung.

    Science.gov (United States)

    Luo, Yueh-Hsia; Kuo, Yu-Chun; Tsai, Ming-Hsien; Ho, Chia-Chi; Tsai, Hui-Ti; Hsu, Chin-Yu; Chen, Yu-Cheng; Lin, Pinpin

    2017-06-01

    Exposure to environmental aryl hydrocarbon receptor (AhR) agonists, such as halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs), has great impacts on the development of various lung diseases. As emerging molecular targets for AhR agonists, cytokines may contribute to the inflammatory or immunotoxic effects of environmental AhR agonists. However, general cytokine expression may not specifically indicate environmental AhR agonist exposure. By comparing cytokine and chemokine expression profiles in human lung adenocarcinoma cell line CL5 treated with AhR agonists and the non-AhR agonist polychlorinated biphenyl (PCB) 39, we identified a target cytokine of environmental AhR agonist exposure of in the lungs. Thirteen cytokine and chemokine genes were altered in the AhR agonists-treated cells, but none were altered in the PCB39-treated cells. Interleukin (IL)-24 was the most highly induced gene among AhR-modulated cytokines. Cotreatment with AhR antagonist completely prevented IL-24 induction by AhR agonists in the CL5 cells. Knockdown AhR expression with short-hairpin RNA (shRNA) significantly reduced benzo[a]pyrene (BaP)-induced IL-24 mRNA levels. We further confirmed that gene transcription, but not mRNA stability, was involved in IL-24 upregulation by BaP. Particulate matter (PM) in the ambient air contains some PAHs and is reported to activate AhR. Oropharyngeal aspiration of PM significantly increased IL-24 levels in lung epithelia and in bronchoalveolar lavage fluid of mice 4weeks after treatment. Thus, our data suggests that IL-24 is a pulmonary exposure target cytokine of environmental AhR agonists. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Th17 cytokines induce pro-fibrotic cytokines release from human eosinophils

    Science.gov (United States)

    2013-01-01

    Background Subepithelial fibrosis is one of the most critical structural changes affecting bronchial airway function during asthma. Eosinophils have been shown to contribute to the production of pro-fibrotic cytokines, TGF-β and IL-11, however, the mechanism regulating this process is not fully understood. Objective In this report, we investigated whether cytokines associated with inflammation during asthma may induce eosinophils to produce pro-fibrotic cytokines. Methods Eosinophils were isolated from peripheral blood of 10 asthmatics and 10 normal control subjects. Eosinophils were stimulated with Th1, Th2 and Th17 cytokines and the production of TGF-β and IL-11 was determined using real time PCR and ELISA assays. Results The basal expression levels of eosinophil derived TGF-β and IL-11 cytokines were comparable between asthmatic and healthy individuals. Stimulating eosinophils with Th1 and Th2 cytokines did not induce expression of pro-fibrotic cytokines. However, stimulating eosinophils with Th17 cytokines resulted in the enhancement of TGF-β and IL-11 expression in asthmatic but not healthy individuals. This effect of IL-17 on eosinophils was dependent on p38 MAPK activation as inhibiting the phosphorylation of p38 MAPK, but not other kinases, inhibited IL-17 induced pro-fibrotic cytokine release. Conclusions Th17 cytokines might contribute to airway fibrosis during asthma by enhancing production of eosinophil derived pro-fibrotic cytokines. Preventing the release of pro-fibrotic cytokines by blocking the effect of Th17 cytokines on eosinophils may prove to be beneficial in controlling fibrosis for disorders with IL-17 driven inflammation such as allergic and autoimmune diseases. PMID:23496774

  2. Cytokines and Organ Failure in Acute Pancreatitis

    DEFF Research Database (Denmark)

    Malmstrøm, Marie Louise; Hansen, Mark Berner; Andersen, Anders Møller

    2012-01-01

    Objectives: We aimed at synchronously examining the early time course of 4 proinflammatory cytokines as predictive factors for development of organ failure in patients with acute pancreatitis (AP). Methods: Interleukin (IL) 6, IL-8, IL-18, and tumor necrosis factor > were measured on admission...... and at days 1, 2, and 14 in 60 patients admitted with first attack of AP. The prediction of single-organ and multiorgan failure from the cytokine profiles was evaluated by receiver operating characteristic analyses. Results: Interleukin 6 and IL-8 levels were significantly higher in patients who developed....... Conclusions: Synchronous measurements of 4 cytokines demonstrated IL-6 and IL-8 to be predictive as early surrogate markers with regard to organ failures in AP. The fact that all of the cytokines were particularly elevated in patients with organ failures calls for evaluation of agents modifying the severe...

  3. Cytokines and inflammatory bowel disease: a review.

    Science.gov (United States)

    McClane, S J; Rombeau, J L

    1999-01-01

    The etiology and pathogenesis of inflammatory bowel disease (IBD) remains an area under intense investigation. Cytokine secretion, which is important in the regulation of normal gastrointestinal immune responses, appears to be dysregulated in IBD. In Crohn's disease, there appears to be an excessive T(H)1 T-cell response to an antigenic stimulus, leading to increased levels of proinflammatory cytokines, such as interferon-gamma (IFN-gamma), interleukin (IL)-12, IL-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha). In ulcerative colitis, a T(H)2 T-cell response appears to be the pathological process responsible for the inflammatory disease. New and innovative therapeutic strategies targeting cytokines, such as TNF-alpha, are producing some promising results in animal and human studies. As more is learned about the complex cytokine interactions in IBD, more effective treatments will undoubtedly ensue.

  4. Eosinophil cytokines: Emerging roles in immunity

    Directory of Open Access Journals (Sweden)

    Paige eLacy

    2014-11-01

    Full Text Available Eosinophils derive from the bone marrow and circulate at low levels in the blood in healthy individuals. These granulated cells preferentially leave the circulation and marginate to tissues, where they are implicated in the regulation of innate and adaptive immunity. In diseases such as allergic inflammation, eosinophil numbers escalate markedly in the blood and tissues where inflammatory foci are located. Eosinophils possess a range of immunomodulatory factors that are released upon cell activation, including over 35 cytokines, growth factors, and chemokines. Unlike T and B cells, eosinophils can rapidly release cytokines within minutes in response to stimulation. While some cytokines are stored as preformed mediators in crystalloid granules and secretory vesicles, eosinophils are also capable of undergoing de novo synthesis and secretion of these immunological factors. Some of the molecular mechanisms that coordinate the final steps of cytokine secretion are hypothesized to involve binding of membrane fusion complexes comprised of soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs. These intracellular receptors regulate the release of granules and vesicles containing a range of secreted proteins, among which are cytokines and chemokines. Emerging evidence from both human and animal model-based research has suggested an active participation of eosinophils in several physiological/pathological processes such as immunomodulation and tissue remodeling. The observed eosinophil effector functions in health and disease implicate eosinophil cytokine secretion as a fundamental immunoregulatory process. The focus of this review is to describe the cytokines, growth factors, and chemokines that are elaborated by eosinophils, and to illustrate some of the intracellular events leading to the release of eosinophil-derived cytokines.

  5. On the existence of cytokines in invertebrates.

    Science.gov (United States)

    Beschin, A; Bilej, M; Torreele, E; De Baetselier, P

    2001-05-01

    Based on the assumption that invertebrates, like vertebrates, possess factors regulating responses to infection or wounding, studies dealing with the evolution of immunity have focussed on the isolation and characterisation of putative cytokine-related molecules from invertebrates. Until recently, most of our knowledge of cytokine- and cytokine receptor-like molecules in invertebrates relies on functional assays and similarities at the physicochemical level. As such, a phylogenetic relationship between invertebrate cytokine-like molecules and vertebrate counterparts could not be convincingly demonstrated. Recent genomic sequence analyses of interleukin-1-receptor-related molecules, that is Toll-like receptors, and members of the transforming growth factor-beta superfamily suggest that the innate immune system of invertebrates and vertebrates evolved independently. In addition, data from protochordates and annelids suggest that invertebrate cytokine-like molecules and vertebrate factors do not have the same evolutionary origin. We propose instead that the convergence of function of invertebrate cytokine-like molecules and vertebrate counterparts involved in innate immune defences may be based on similar lectin-like activities.

  6. IL-17 family: cytokines, receptors and signaling

    Science.gov (United States)

    Gu, Chunfang; Wu, Ling; Li, Xiaoxia

    2013-01-01

    The interleukin 17 (IL-17) family, a subset of cytokines consisting of IL-17A-F, plays crucial roles in host defense against microbial organisms and in the development of inflammatory diseases. Although IL-17A is the signature cytokine produced by T helper 17 (Th17) cells, IL-17A and other IL-17 family cytokines have multiple sources ranging from immune cells to non-immune cells. The IL-17 family signals via their correspondent receptors and activates downstream pathways that include NFκB, MAPKs and C/EBPs to induce the expression of anti-microbial peptides, cytokines and chemokines. The proximal adaptor Act1 is a common mediator during the signaling of all IL-17 cytokines so far and is thus involved in IL-17 mediated host defense and IL-17-driven autoimmune conditions. This review will give an overview and recent updates on the IL-17family, the activation and regulation of IL-17 signaling as well as diseases associated with this cytokine family PMID:24011563

  7. Human_Leishmaniasis@cytokines.bahia.br

    Directory of Open Access Journals (Sweden)

    M. Barral-Netto

    1998-01-01

    Full Text Available The cell-mediated immune response is critical in the resistance to and recovery from leishmaniasis. Cytokines are central elements in mounting an immune response and have received a great deal of attention in both human and experimental leishmaniasis. IFN-g is responsible for macrophage activation leading to leishmanicidal mechanisms. Understanding the balance of cytokines that lead to enhanced production of or synergize with IFN-g, and those cytokines that counterbalance its effects is fundamental for developing rational immunotherapeutic or immunoprophylactic approaches to leishmaniasis. Here we focus on the cytokine balance in human leishmaniasis, particularly IL-10 as an IFN-g opposing cytokine, and IL-12 as an IFN-g inducer. The effects of these cytokines were evaluated in terms of several parameters of the human immune response. IL-10 reduced lymphocyte proliferation, IFN-g production and cytotoxic activity of responsive human peripheral blood mononuclear cells. Neutralization of IL-10 led to partial restoration of lymphoproliferation, IFN-g production and cytotoxic activity in unresponsive visceral leishmaniasis patients. IL-12 also restored the responses of peripheral blood mononuclear cells from visceral leishmaniasis patients. The responses obtained with IL-12 are higher than those obtained with anti-IL-10, even when anti-IL-10 is combined with anti-IL-4

  8. The association between inherited cytokine polymorphisms and cerebral palsy.

    Science.gov (United States)

    Gibson, Catherine S; MacLennan, Alastair H; Goldwater, Paul N; Haan, Eric A; Priest, Kevin; Dekker, Gustaaf A

    2006-03-01

    The purpose of this study was to investigate associations between inherited cytokine polymorphisms and cerebral palsy. This was a case-control study that used DNA from the newborn infant screening cards of 443 white infants with cerebral palsy and 883 white control infants to test for the following cytokine polymorphisms: tumor necrosis factor-alpha-308, mannose-binding lectin-221, and 3 polymorphisms in exon-1 of the mannose-binding lectin gene at codon-52, -54, and -57. At all gestational ages mannose-binding lectin codon-54 increased the risk of the development of diplegia (homozygous or heterozygous odds ratio, 1.55; 95% CI, 1.03-2.32). For babies who were born at term, the risk of the development of quadriplegia was associated with heterozygous tumor necrosis factor-alpha (odds ratio, 1.82; 95% CI, 1.04-3.15), and mannose-binding lectin codon-54 was associated with diplegia (homozygous or heterozygous odds ratio, 2.12; 95% CI, 1.10-4.05). The presence of any polymorphism in mannose-binding lectin exon-1 at term approximately doubled the risk of the development of diplegia (odds ratio, 1.94; 95% CI, 1.05-3.62). Homozygous or heterozygous tumor necrosis factor-alpha was associated with hemiplegia for babies who were born at <32 weeks of gestation (odds ratio, 2.38; 95% CI, 1.02-5.58). Overall, the presence of any cytokine polymorphism was associated with cerebral palsy (odds ratio, 1.37; 95% CI, 1.02-1.84). Carriage of polymorphisms in the tumor necrosis factor-alpha and mannose-binding lectin genes are associated with an increased risk of cerebral palsy.

  9. Biomarkers and genes predictive of disease predisposition and ...

    African Journals Online (AJOL)

    serological marker used, rheumatoid factor. Table 1. The 2010 ... of gene expression, cytokines, acute phase reactants, autoantibodies and ... Circulating cytokines. Cytokines are small protein or glycoprotein molecules which form an integral part of the immune system and have regulatory functions. They are secreted by, ...

  10. Cytokines and beta-cell biology: from concept to clinical translation

    DEFF Research Database (Denmark)

    Donath, M.Y.; Storling, J.; Berchtold, L.A.

    2007-01-01

    The tale of cytokines and the beta-cell is a long story, starting with in vitro discovery in 1984, evolving via descriptive and phenomenological studies to detailed mapping of the signalling pathways, gene- and protein expression patterns, molecular and biochemical effector mechanisms to in vivo...

  11. Generation and sustained expansion of mouse spleen invariant NKT cell lines with preserved cytokine releasing capacity.

    NARCIS (Netherlands)

    Molling, J.W.; Moreno, M.; Vliet, H.J. van der; Blomberg, B.M.E. von; Eertwegh, A.J. van den; Scheper, R.J.; Bontkes, H.J.

    2007-01-01

    Invariant Natural Killer T (iNKT) cells are CD1d restricted innate lymphoid cells with an invariant T cell receptor (TCR) alpha chain gene rearrangement (Valpha24-Jalpha18 in human and Valpha14-Jalpha18 in mouse). iNKT cells play a pivotal role in anti-tumor immune responses via cytokine mediated

  12. 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

  13. Implantable synthetic cytokine converter cells with AND-gate logic treat experimental psoriasis.

    Science.gov (United States)

    Schukur, Lina; Geering, Barbara; Charpin-El Hamri, Ghislaine; Fussenegger, Martin

    2015-12-16

    Psoriasis is a chronic inflammatory skin disease characterized by a relapsing-remitting disease course and correlated with increased expression of proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin 22 (IL22). Psoriasis is hard to treat because of the unpredictable and asymptomatic flare-up, which limits handling of skin lesions to symptomatic treatment. Synthetic biology-based gene circuits are uniquely suited for the treatment of diseases with complex dynamics, such as psoriasis, because they can autonomously couple the detection of disease biomarkers with the production of therapeutic proteins. We designed a mammalian cell synthetic cytokine converter that quantifies psoriasis-associated TNF and IL22 levels using serially linked receptor-based synthetic signaling cascades, processes the levels of these proinflammatory cytokines with AND-gate logic, and triggers the corresponding expression of therapeutic levels of the anti-inflammatory/psoriatic cytokines IL4 and IL10, which have been shown to be immunomodulatory in patients. Implants of microencapsulated cytokine converter transgenic designer cells were insensitive to simulated bacterial and viral infections as well as psoriatic-unrelated inflammation. The designer cells specifically prevented the onset of psoriatic flares, stopped acute psoriasis, improved psoriatic skin lesions and restored normal skin-tissue morphology in mice. The antipsoriatic designer cells were equally responsive to blood samples from psoriasis patients, suggesting that the synthetic cytokine converter captures the clinically relevant cytokine range. Implanted designer cells that dynamically interface with the patient's metabolism by detecting specific disease metabolites or biomarkers, processing their blood levels with synthetic circuits in real time, and coordinating immediate production and systemic delivery of protein therapeutics may advance personalized gene- and cell-based therapies. Copyright © 2015

  14. Cerebrospinal fluid and serum cytokine profiles in narcolepsy with cataplexy: a case-control study.

    Science.gov (United States)

    Dauvilliers, Yves; Jaussent, Isabelle; Lecendreux, Michel; Scholz, Sabine; Bayard, Sophie; Cristol, Jean Paul; Blain, Hubert; Dupuy, Anne-Marie

    2014-03-01

    Recent advances in the identification of susceptibility genes and environmental exposures provide strong support that narcolepsy-cataplexy is an immune-mediated disease. Only few serum cytokine studies with controversial results were performed in narcolepsy and none in the cerebrospinal fluid. We measured a panel of 12 cytokines by a proteomic approach in the serum of 35 patients with narcolepsy-cataplexy compared to 156 healthy controls, and in the cerebrospinal fluid of 34 patients with narcolepsy-cataplexy compared to 17 non-narcoleptic patients; and analyzed the effect of age, duration and severity of disease on the cytokine levels. After multiple adjustments we reported lower serum IL-2, IL-8, TNF-α, MCP-1 and EGF levels, and a tendency for higher IL-4 level in narcolepsy compared to controls. Significant differences were only found for IL-4 in cerebrospinal fluid, being higher in narcolepsy. Positive correlations were found in serum between IL-4, daytime sleepiness, and cataplexy frequency. The expression of some pro-inflammatory cytokines (MCP-1, VEGF, EGF, IL2, IL-1β, IFN-γ) in either serum or CSF was negatively correlated with disease severity and duration. No correlation was found for any specific cytokine in 18 of the patients with narcolepsy with peripheral and central samples collected the same day. Significant decreased pro/anti-inflammatory cytokine profiles were found at peripheral and central levels in narcolepsy, together with a T helper 2/Th1 serum cytokine secretion imbalance. To conclude, we showed some evidence for alterations in the cytokine profile in patients with narcolepsy-cataplexy compared to controls at peripheral and central levels, with the potential role of IL-4 and significant Th1/2 imbalance in the pathophysiology of narcolepsy. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Eosinophil secretion of granule-derived cytokines

    Directory of Open Access Journals (Sweden)

    Lisa A Spencer

    2014-10-01

    Full Text Available Eosinophils are tissue-dwelling leukocytes, present in the thymus, and gastrointestinal and genitourinary tracts of healthy individuals at baseline, and recruited, often in large numbers, to allergic inflammatory foci and sites of active tissue repair. The biological significance of eosinophils is vast and varied. In health, eosinophils support uterine and mammary gland development, and maintain bone marrow plasma cells and adipose tissue alternatively activated macrophages, while in response to tissue insult eosinophils function as inflammatory effector cells, and, in the wake of an inflammatory response, promote tissue regeneration and wound healing. One common mechanism driving many of the diverse eosinophil functions is the regulated and differential secretion of a vast array of eosinophil-derived cytokines. Eosinophils are distinguished from most other leukocytes in that many, if not all, of the over three dozen eosinophil-derived cytokines are pre-synthesized and stored within intracellular granules, poised for very rapid, stimulus-induced secretion. Eosinophils engaged in cytokine secretion in situ utilize distinct pathways of cytokine release that include: classical exocytosis, whereby granules themselves fuse with the plasma membrane and release their entire contents extracellularly; piecemeal degranulation, whereby granule-derived cytokines are selectively mobilized into vesicles that emerge from granules, traverse the cytoplasm and fuse with the plasma membrane to release discrete packets of cytokines; and eosinophil cytolysis, whereby intact granules are extruded from eosinophils, and deposited within tissues. In this latter scenario, extracellular granules can themselves function as stimulus-responsive secretory-competent organelles within the tissue. Here we review the distinctive processes of differential secretion of eosinophil granule-derived cytokines.

  16. RELATED CHANGES OF SERUM CYTOKINES AND MARKERS OF THE SECRETORY ACTIVITY OF THE GASTRIC MUCOSA AT ULCEROUS PROCESS

    Directory of Open Access Journals (Sweden)

    L. V. Matveeva

    2013-01-01

    Full Text Available Abstract. The aim of the study was to determine the concentrations of cytokines and pepsinogen in identifying the presence and strength of them relationship with acute gastric ulcer. ELISA method in the serum of the subjects were evaluated levels pro- and antiinflammatory cytokines and pepsinоgenes. Found a number of statistically significant, pathogenetic correla-tions that can be recommended for the combined determination of the immunodiagnostics and individual correction therapy.

  17. ANTIBODY-CYTOKINE FUSION PROTEINS FOR TREATMENT OF CANCER: ENGINEERING CYTOKINES FOR IMPROVED EFFICACY AND SAFETY

    Science.gov (United States)

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

    2014-01-01

    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 IL-2, IL-12, IL-21, TNFα, and interferons α, β and γ have been constructed and have shown anti-tumor activity in pre-clinical 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. PMID:25440607

  18. 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.

  19. Differential DNA methylation regions in cytokine and transcription factor genomic loci associate with childhood physical aggression.

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    Nadine Provençal

    Full Text Available Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1α, IL-4, IL-6, IL-8 and IL-10, later in early adulthood. This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects and a trajectory of physical aggression from childhood to adolescence.We compared the methylation profiles of the entire genomic loci encompassing the IL-1α, IL-6, IL-4, IL-10 and IL-8 and three of their regulatory transcription factors (TF NFkB1, NFAT5 and STAT6 genes in adult males on a chronic physical aggression trajectory (CPA and males with the same background who followed a normal physical aggression trajectory (control group from childhood to adolescence. We used the method of methylated DNA immunoprecipitation with comprehensive cytokine gene loci and TF loci microarray hybridization, statistical analysis and false discovery rate correction. We found differentially methylated regions to associate with CPA in both the cytokine loci as well as in their transcription factors loci analyzed. Some of these differentially methylated regions were located in known regulatory regions whereas others, to our knowledge, were previously unknown as regulatory areas. However, using the ENCODE database, we were able to identify key regulatory elements in many of these regions that indicate that they might be involved in the regulation of cytokine expression.We provide here the first evidence for an association between differential DNA methylation in cytokines and their regulators in T cells and monocytes and male physical aggression.

  20. Monitoring bottlenose dolphin leukocyte cytokine mRNA responsiveness by qPCR

    Science.gov (United States)

    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

  1. 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.

  2. Influence of proinflammatory cytokine gene polymorphism on childhood obesity

    OpenAIRE

    Popko K; Górska E; Pyrzak B; Telmaszczyk-Emmel A; Wisniewska A; Majcher A; Wasik M; Demkow U

    2009-01-01

    Abstract Background Obesity development is a complex process which can be influenced by genetic predisposition modified by environmental factors. Nowadays, the problem of overweight and obesity, including related complications, occurs in increasingly younger children. Thus, there is a need for new genetic markers of increased risk of excessive body mass. Objective The aim of the present study was to examine the relation between polymorphisms located in promoter regions of IL-1beta, IL-6, and ...

  3. HBV Core Protein Enhances Cytokine Production

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    Tatsuo Kanda

    2015-09-01

    Full Text Available Hepatitis B virus (HBV infection, a cause of hepatocellular carcinoma (HCC, remains a serious global health concern. HCC development and human hepatocarcinogenesis are associated with hepatic inflammation caused by host interferons and cytokines. This article focused on the association between the HBV core protein, which is one of the HBV-encoding proteins, and cytokine production. The HBV core protein induced the production of interferons and cytokines in human hepatoma cells and in a mouse model. These factors may be responsible for persistent HBV infection and hepatocarcinogenesis. Inhibitors of programmed death (PD-1 and HBV core and therapeutic vaccines including HBV core might be useful for the treatment of patients with chronic HBV infection. Inhibitors of HBV core, which is important for hepatic inflammation, could be helpful in preventing the progression of liver diseases in HBV-infected patients.

  4. Inflammatory cytokines and neurological and neurocognitive alterations in the course of schizophrenia

    Science.gov (United States)

    Fineberg, Anna M.; Ellman, Lauren M.

    2013-01-01

    A growing body of evidence suggests that immune alterations, especially those related to inflammation, are associated with increased risk of schizophrenia and schizophrenia-related brain alterations. Much of this work has focused on the prenatal period, since infections during pregnancy have been repeatedly (albeit inconsistently) linked to risk of schizophrenia. Given that most infections do not cross the placenta, cytokines associated with inflammation (proinflammatory cytokines) have been targeted as potential mediators of the damaging effects of infection on the fetal brain in prenatal studies. Moreover, additional evidence from both human and animal studies suggests links between increased levels of proinflammatory cytokines, immune-related genes, and schizophrenia, as well as brain alterations associated with the disorder. Additional support for the role of altered immune factors in the etiology of schizophrenia comes from neuroimaging studies, which have linked proinflammatory cytokine gene polymorphisms with some of the structural and functional abnormalities repeatedly found in schizophrenia. These findings are reviewed and discussed using a life course perspective, examining the contribution of inflammation from the fetal period to disorder presentation. Unexplored areas and future directions, such as the interplay between inflammation, genes, and individual-level environmental factors (e.g., stress, sleep, and nutrition), are also discussed. PMID:23414821

  5. Cytokines: muscle protein and amino acid metabolism

    DEFF Research Database (Denmark)

    van Hall, Gerrit

    2012-01-01

    raises TNF-α and IL-6 to moderate levels, has only identified IL-6 as a potent cytokine, decreasing systemic amino acid levels and muscle protein metabolism. The marked decrease in circulatory and muscle amino acid concentrations was observed with a concomitant reduction in both the rates of muscle...... of IL-6 on the regulation of muscle protein metabolism but indirectly via IL-6 reducing amino acid availability. SUMMARY: Recent studies suggest that the best described cytokines TNF-α and IL-6 are unlikely to be the major direct mediators of muscle protein loss in inflammatory diseases. However...

  6. Cytokine inhibition in the treatment of COPD

    Directory of Open Access Journals (Sweden)

    Caramori G

    2014-04-01

    Full Text Available Gaetano Caramori,1 Ian M Adcock,2,3 Antonino Di Stefano,4 Kian Fan Chung2,3 1Dipartimento di Scienze Mediche, Centro Interdipartimentale per lo Studio delle Malattie Infiammatorie delle Vie Aeree e Patologie Fumo-correlate (CEMICEF; formerly Centro di Ricerca su Asma e BPCO, Sezione di Medicina Interna e Cardiorespiratoria, Università di Ferrara, Ferrara, Italy; 2Airway Diseases Section, National Heart and Lung Institute, Imperial College London, UK; 3Biomedical Research Unit, Royal Brompton and Harefield NHS Trust, London, UK; 4Divisione di Pneumologia e Laboratorio di Citoimmunopatologia dell'Apparato Cardio-Respiratorio, Fondazione Salvatore Maugeri, IRCCS, Veruno, Italy Abstract: Cytokines play an important part in many pathobiological processes of chronic obstructive pulmonary disease (COPD, including the chronic inflammatory process, emphysema, and altered innate immune response. Proinflammatory cytokines of potential importance include tumor necrosis factor (TNF-α, interferon-γ, interleukin (IL-1β, IL-6, IL-17, IL-18, IL-32, and thymic stromal lymphopoietin (TSLP, and growth factors such as transforming growth factor-β. The current objectives of COPD treatment are to reduce symptoms, and to prevent and reduce the number of exacerbations. While current treatments achieve these goals to a certain extent, preventing the decline in lung function is not currently achievable. In addition, reversal of corticosteroid insensitivity and control of the fibrotic process while reducing the emphysematous process could also be controlled by specific cytokines. The abnormal pathobiological process of COPD may contribute to these fundamental characteristics of COPD, and therefore targeting cytokines involved may be a fruitful endeavor. Although there has been much work that has implicated various cytokines as potentially playing an important role in COPD, there have been very few studies that have examined the effect of specific cytokine blockade in

  7. Arsenic affects inflammatory cytokine expression in Gallus gallus brain tissues.

    Science.gov (United States)

    Sun, Xiao; He, Ying; Guo, Ying; Li, Siwen; Zhao, Hongjing; Wang, Yu; Zhang, Jingyu; Xing, Mingwei

    2017-06-05

    The heavy metal arsenic is widely distributed in nature and posses a serious threat to organism's health. However, little is known about the arsenic-induced inflammatory response in the brain tissues of birds and the relationship and mechanism of the inflammatory response. The purpose of this study was to explore the effects of dietary arsenic on the expression of inflammatory cytokines in the brains of Gallus gallus. Seventy-two 1-day-old male Hy-line chickens were divided into a control group, a low arsenic trioxide (As2O3)-treated (7.5 mg/kg) group, a middle As2O3-treated (15 mg/kg) group, and a high As2O3-treated (30 mg/kg) group. Arsenic exposure caused obvious ultrastructural changes. The mRNA levels of the transcription factor nuclear factor-κB (NF-κB) and of pro-inflammatory cytokines, including inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and prostaglandin E synthase (PTGEs), in chicken brain tissues (cerebrum, cerebellum, thalamus, brainstem and myelencephalon) on days 30, 60 and 90, respectively, were measured by real-time PCR. The protein expression of iNOS was detected by western blot. The results showed that after being treated with As2O3, the levels of inflammatory-related factor NF-κB and pro-inflammatory cytokines in chicken brain tissues increased (P Arsenic exposure in the chickens triggered host defence and induced an inflammatory response by regulating the expression of inflammatory-related genes in the cerebrum, cerebellum, thalamus, brainstem and myelencephalon. These data form a foundation for further research on arsenic-induced neurotoxicity in Gallus gallus.

  8. The role of cytokines in the initiation and progression of myelofibrosis

    DEFF Research Database (Denmark)

    Hasselbalch, Hans K

    2013-01-01

    Myelofibrosis (MF) is a life-threatening blood cancer characterized by progressive bone marrow fibrosis, splenomegaly, cytopenias, and debilitating constitutional symptoms. Abnormal expression and activity of a number of proinflammatory cytokines are associated with MF, in which immune dysregulat......Myelofibrosis (MF) is a life-threatening blood cancer characterized by progressive bone marrow fibrosis, splenomegaly, cytopenias, and debilitating constitutional symptoms. Abnormal expression and activity of a number of proinflammatory cytokines are associated with MF, in which immune...... dysregulation is pronounced as evidenced by dysregulation of several immune and inflammation genes. The discovery of the Janus kinase 2 (JAK2) V617F mutation has led to the development of a number of JAK1/2 inhibitors in the treatment of MF and similar neoplasms. Here, the role of cytokines in MF initiation...

  9. Cytokine and cytokine receptor single-nucleotide polymorphisms predict risk for non-small cell lung cancer among women.

    Science.gov (United States)

    Van Dyke, Alison L; Cote, Michele L; Wenzlaff, Angie S; Chen, Wei; Abrams, Judith; Land, Susan; Giroux, Craig N; Schwartz, Ann G

    2009-06-01

    Studies on the relationships between inflammatory pathway genes and lung cancer risk have not included African-Americans and have only included a handful of genes. In a population-based case-control study on 198 African-American and 744 Caucasian women, we examined the association between 70 cytokine and cytokine receptor single-nucleotide polymorphisms (SNPs) and risk of non-small cell lung cancer (NSCLC). Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals in a dominant model adjusting for major risk factors for lung cancer. Separate analyses were conducted by race and by smoking history and history of chronic obstructive pulmonary disease among Caucasians. Random forest analysis was conducted by race. On logistic regression analysis, IL6 (interleukin 6), IL7R, IL15, TNF (tumor necrosis factor), and IL10 SNP were associated with risk of non-small cell lung cancer among African-Americans; IL7R and IL10 SNPs were also associated with risk of lung cancer among Caucasians. Although random forest analysis showed IL7R and IL10 SNPs as being associated with risk for lung cancer among African-Americans, it also identified TNFRSF10A SNP as an important predictor. On random forest analysis, an IL1A SNP was identified as an important predictor of lung cancer among Caucasian women. Inflammatory SNPs differentially predicted risk for NSCLC according to race, as well as based on smoking history and history of chronic obstructive pulmonary disease among Caucasian women. Pathway analysis results are presented. Inflammatory pathway genotypes may serve to define a high risk group; further exploration of these genes in minority populations is warranted.

  10. Cytokine and Cytokine Receptor Single-Nucleotide Polymorphisms Predict Risk for Non–Small Cell Lung Cancer among Women

    Science.gov (United States)

    Van Dyke, Alison L.; Cote, Michele L.; Wenzlaff, Angie S.; Chen, Wei; Abrams, Judith; Land, Susan; Giroux, Craig N.; Schwartz, Ann G.

    2013-01-01

    Studies on the relationships between inflammatory pathway genes and lung cancer risk have not included African-Americans and have only included a handful of genes. In a population-based case-control study on 198 African-American and 744 Caucasian women, we examined the association between 70 cytokine and cytokine receptor single-nucleotide polymorphisms (SNPs) and risk of non–small cell lung cancer (NSCLC). Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals in a dominant model adjusting for major risk factors for lung cancer. Separate analyses were conducted by race and by smoking history and history of chronic obstructive pulmonary disease among Caucasians. Random forest analysis was conducted by race. On logistic regression analysis, IL6 (interleukin 6), IL7R, IL15, TNF (tumor necrosis factor), and IL10 SNP were associated with risk of non–small cell lung cancer among African-Americans; IL7R and IL10 SNPs were also associated with risk of lung cancer among Caucasians. Although random forest analysis showed IL7R and IL10 SNPs as being associated with risk for lung cancer among African-Americans, it also identified TNFRSF10A SNP as an important predictor. On random forest analysis, an IL1A SNP was identified as an important predictor of lung cancer among Caucasian women. Inflammatory SNPs differentially predicted risk for NSCLC according to race, as well as based on smoking history and history of chronic obstructive pulmonary disease among Caucasian women. Pathway analysis results are presented. Inflammatory pathway genotypes may serve to define a high risk group; further exploration of these genes in minority populations is warranted. PMID:19505916

  11. Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms

    Science.gov (United States)

    Hoermann, Gregor; Greiner, Georg; Valent, Peter

    2015-01-01

    The term myeloproliferative neoplasms (MPN) refers to a heterogeneous group of diseases including not only polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), but also chronic myeloid leukemia (CML), and systemic mastocytosis (SM). Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN. Second, alterations of the bone marrow microenvironment are found in all MPN types and have been implicated in the pathogenesis of the diseases. Finally, elevated levels of proinflammatory and microenvironment-regulating cytokines are commonly found in all MPN-variants. In this paper, we review the effects of MPN-related oncogenes on cytokine expression and release and describe common as well as distinct pathogenetic mechanisms underlying microenvironmental changes in various MPN. Furthermore, targeting of the microenvironment in MPN is discussed. Such novel therapies may enhance the efficacy and may overcome resistance to established tyrosine kinase inhibitor treatment in these patients. Nevertheless, additional basic studies on the complex interplay of neoplastic and stromal cells are required in order to optimize targeting strategies and to translate these concepts into clinical application. PMID:26543328

  12. Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Gregor Hoermann

    2015-01-01

    Full Text Available The term myeloproliferative neoplasms (MPN refers to a heterogeneous group of diseases including not only polycythemia vera (PV, essential thrombocythemia (ET, and primary myelofibrosis (PMF, but also chronic myeloid leukemia (CML, and systemic mastocytosis (SM. Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN. Second, alterations of the bone marrow microenvironment are found in all MPN types and have been implicated in the pathogenesis of the diseases. Finally, elevated levels of proinflammatory and microenvironment-regulating cytokines are commonly found in all MPN-variants. In this paper, we review the effects of MPN-related oncogenes on cytokine expression and release and describe common as well as distinct pathogenetic mechanisms underlying microenvironmental changes in various MPN. Furthermore, targeting of the microenvironment in MPN is discussed. Such novel therapies may enhance the efficacy and may overcome resistance to established tyrosine kinase inhibitor treatment in these patients. Nevertheless, additional basic studies on the complex interplay of neoplastic and stromal cells are required in order to optimize targeting strategies and to translate these concepts into clinical application.

  13. Cytokine production by lymphocytes in pregnancy.

    Science.gov (United States)

    Szereday, L; Varga, P; Szekeres-Bartho, J

    1997-12-01

    In the presence of progesterone lymphocytes of pregnant women release a 34-kDa protein named the progesterone-induced blocking factor (PIBF). PIBF mediates the immunomodulatory and anti-abortive effects of progesterone and its presence is related to the outcome of pregnancy. PIBF induces production of Th2 type cytokines by activated lymphocytes. The in vivo relationship between PIBF- and cytokine production of pregnancy lymphocytes and the outcome of pregnancy was investigated. Interleukin (IL)-12 and IL-10 production and PIBF expression in peripheral lymphocytes of 111 healthy pregnant women and 120 women at risk for premature pregnancy termination were detected by immunocytochemistry. We found increased IL-12 and low PIBF and IL-10 expression on lymphocytes of "risk" patients, and a high rate of IL-10 and PIBF positivity on lymphocytes from healthy pregnant women. The cytokine production pattern of the lymphocytes was related to the presence or absence of previous abortions as well as to the outcome of pregnancy. These data suggest the involvement of an altered cytokine production pattern in the immunologic effects of progesterone.

  14. Cytokines regulating hematopoietic stem cell function.

    Science.gov (United States)

    Zhang, Cheng C; Lodish, Harvey F

    2008-07-01

    Regulation of the multiple fates of hematopoietic stem cells - including quiescence, self-renewal, differentiation, apoptosis, and mobilization from the niche - requires the cooperative actions of several cytokines and other hormones that bind to receptors on these cells. In this review we discuss recent advances in the identification of novel hematopoietic stem cell supportive cytokines and the mechanisms by which they control hematopoietic stem cell fate decisions. Several extrinsic factors that stimulate ex-vivo expansion of hematopoietic stem cells were recently identified by a number of experimental approaches, including forward genetic screening and transcriptional profiling of supportive stromal cells. Recent experiments in which multiple cytokine signaling pathways are activated or suppressed in hematopoietic stem cells reveal the complexity of signal transduction and cell-fate choice in hematopoietic stem cells in vivo and in vitro. The study of genetically modified mice and improvements in the in-vitro hematopoietic stem cell culture system will be powerful tools to elucidate the functions of cytokines that regulate hematopoietic stem cell function. These will further reveal the complex nature of the mechanisms by which extrinsic factors regulate signal transduction and cell-fate decisions of hematopoietic stem cells.

  15. Salivary cytokine levels in early gingival inflammation

    DEFF Research Database (Denmark)

    Belstrøm, Daniel; Damgaard, Christian; Könönen, Eija

    2017-01-01

    Salivary protein levels have been studied in periodontitis. However, there is lack of information on salivary cytokine levels in early gingival inflammation. The aim of this study was to determine salivary levels of vascular endothelial growth factor (VEGF), interleukin (IL)-8, monocyte chemoattr......Salivary protein levels have been studied in periodontitis. However, there is lack of information on salivary cytokine levels in early gingival inflammation. The aim of this study was to determine salivary levels of vascular endothelial growth factor (VEGF), interleukin (IL)-8, monocyte...... chemoattractant protein (MCP)-1, IL-1β, and IL-1 receptor antagonist (IL-1Ra) in gingival inflammation. Twenty-eight systemically and orally healthy nonsmokers abstained from oral hygiene protocols for 10 days. After that, self-performed cleaning was resumed for 14 days. Plaque and gingival indexes were measured...... levels decreased and remained low during development and resolution of experimental gingivitis. Initial inflammation in gingival tissues is associated with a decrease in inflammatory cytokines in saliva. Further studies are needed to evaluate if inflammatory cytokines bind to their functional receptors...

  16. Cytokines and immune surveillance in humans

    Science.gov (United States)

    Sonnenfeld, Gerald

    1994-01-01

    Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. Among the parameters shown, by us and others, to be affected is the production of interferons. Interferons are a family of cytokines that are antiviral and play a major role in regulating immune responses that control resistance to infection. Alterations in interferon and other cytokine production and activity could result in changes in immunity and a possible compromise of host defenses against both opportunistic and external infections. The purpose of the present study is to explore further the effects of space flight on cyotokines and cytokine-directed immunological function. Among the tests carried out are interferon-alpha production, interferon-gamma production, interleukin-1 and -2 production, signal transduction in neutrophils, signal transduction in monocytes, and monocyte phagocytic activity. The experiments will be performed using peripheral blood obtained from human subjects. It is our intent to eventually carry out these experiments using astronauts as subjects to determine the effects of space flight on cytokine production and activity. However, these subjects are not currently available. Until they become available, we will carry out these experiments using subjects maintained in the bed-rest model for microgravity.

  17. Cytokines in Sjögren's syndrome

    NARCIS (Netherlands)

    Roescher, N.; Tak, P. P.; Illei, G. G.

    2009-01-01

    Cytokines play a central role in the regulation of immunity and are often found to be deregulated in autoimmune diseases. Sjögren's syndrome is a chronic autoimmune disease characterized by inflammation and loss of secretory function of the salivary and lachrymal glands. This review highlights the

  18. Cytokines as biomarkers of nanoparticle immunotoxicity

    Science.gov (United States)

    Elsabahy, Mahmoud; Wooley, Karen L.

    2013-01-01

    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. PMID:23549679

  19. Cytokines in atherosclerosis: an intricate balance

    NARCIS (Netherlands)

    Boshuizen, M.C.S.

    2016-01-01

    Atherosclerosis is the underlying pathology in the majority of clinical manifestations of cardiovascular diseases, which are nowadays the main global cause of mortality. Atherosclerosis is a lipid-driven chronic inflammatory disease of the arterial wall. This inflammatory response, with cytokines as

  20. Cytokines and Immune Responses in Murine Atherosclerosis

    NARCIS (Netherlands)

    Kusters, Pascal J. H.; Lutgens, Esther

    2015-01-01

    Atherosclerosis is an inflammatory disease of the vessel wall characterized by activation of the innate immune system, with macrophages as the main players, as well as the adaptive immune system, characterized by a Th1-dominant immune response. Cytokines play a major role in the initiation and

  1. 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.

  2. Distinct cytokines balance the development of regulatory T cells and interleukin-10-producing regulatory B cells

    Science.gov (United States)

    Holan, Vladimir; Zajicova, Alena; Javorkova, Eliska; Trosan, Peter; Chudickova, Milada; Pavlikova, Michaela; Krulova, Magdalena

    2014-01-01

    Regulatory T cells have been well described and the factors regulating their development and function have been identified. Recently, a growing body of evidence has documented the existence of interleukin-10 (IL-10)-producing B cells, which are called regulatory B10 cells. These cells attenuate autoimmune, inflammatory and transplantation reactions, and the main mechanism of their inhibitory action is the production of IL-10. We show that the production of IL-10 by lipopolysaccharide-stimulated B cells is significantly enhanced by IL-12 and interferon-γ and negatively regulated by IL-21 and transforming growth factor-β. In addition, exogenous IL-10 also inhibits B-cell proliferation and the expression of the IL-10 gene in lipopolysaccharide-stimulated B cells. The negative autoregulation of IL-10 production is supported by the observation that the inclusion of anti-IL-10 receptor monoclonal antibody enhances IL-10 production and the proliferation of activated B cells. The effects of cytokines on IL-10 production by B10 cells did not correlate with their effects on B-cell proliferation or on IL-10 production by T cells or macrophages. The cytokine-induced changes in IL-10 production occurred on the level of IL-10 gene expression, as confirmed by increased or decreased IL-10 mRNA expression in the presence of a particular cytokine. The regulatory cytokines modulate the number of IL-10-producing cells rather than augmenting or decreasing the secretion of IL-10 on a single-cell level. Altogether these data show that the production of IL-10 by B cells is under the strict regulatory control of cytokines and that individual cytokines differentially regulate the development and activity of regulatory T cells and IL-10-producing regulatory B cells. PMID:24256319

  3. Lactobacillus acidophilus induces a slow but more sustained chemokine and cytokine response in naive foetal enterocytes compared to commensal Escherichia coli

    DEFF Research Database (Denmark)

    Zeuthen, Louise; Fink, Lisbeth Nielsen; Metzdorff, Stine B

    2010-01-01

    -positive Lactobacillus acidophilus NCFM, and expression of genes important for immune regulation was measured together with cytokine production. E. coli Nissle and L. acidophilus NCFM strongly induced chemokines and cytokines, but with different kinetics, and only E. coli Nissle induced down-regulation of Toll......, are highly responsive to stimulation with gut commensals, with L. acidophilus NCFM inducing a slower, but more sustained response than E. coli Nissle. E. coli may induce intestinal tolerance through very rapid up-regulation of chemokine and cytokine genes and down-regulation of Toll-like receptor 4, while...

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Effect of Malnutrition on the Expression of Cytokines Involved in Th1 Cell Differentiation

    Science.gov (United States)

    González-Torres, Cristina; González-Martínez, Haydeé; Miliar, Angel; Nájera, Oralia; Graniel, Jaime; Firo, Verónica; Alvarez, Catalina; Bonilla, Edmundo; Rodríguez, Leonor

    2013-01-01

    Malnutrition is a common cause of secondary immune deficiency and has been linked to an increased susceptibility to infection in humans. Malnutrition specifically affects T-cell-mediated immune responses. The aim of this study was to assess in lymphocytes from malnourished children the expression levels of IL-12, IL-18 and IL-21, molecules that induce the differentiation of T cells related to the immunological cellular response (Th1 response) and the production of cytokines related to the immunological cellular response (Th1 cytokines). We found that the expression levels of IL-12, IL-18 and IL-21 were significantly diminished in malnourished children compared to well-nourished children and were coincident with lower plasmatic levels of IL-2 and IFN-γ (Th1 cytokines). In this study, we show for the first time that the gene expression and intracellular production of cytokines responsible for Th1 cell differentiation (IL-12, IL-18 and IL-21) are diminished in malnourished children. As expected, this finding was related to lower plasmatic levels of IL-2 and IFN-γ. The decreased expression of Th1 cytokines observed in this study may contribute to the deterioration of the immunological Type 1 (cellular) response. We hypothesize that the decreased production of IL-12, IL-18 and IL-21 in malnourished children contributes to their inability to eradicate infections. PMID:23429441

  6. Inflammaging and Anti-Inflammaging: The Role of Cytokines in Extreme Longevity.

    Science.gov (United States)

    Minciullo, Paola Lucia; Catalano, Antonino; Mandraffino, Giuseppe; Casciaro, Marco; Crucitti, Andrea; Maltese, Giuseppe; Morabito, Nunziata; Lasco, Antonino; Gangemi, Sebastiano; Basile, Giorgio

    2016-04-01

    Longevity and aging are two sides of the same coin, as they both derive from the interaction between genetic and environmental factors. Aging is a complex, dynamic biological process characterized by continuous remodeling. One of the most recent theories on aging focuses on immune response, and takes into consideration the activation of subclinical, chronic low-grade inflammation which occurs with aging, named "inflammaging". Long-lived people, especially centenarians, seem to cope with chronic subclinical inflammation through an anti-inflammatory response, called therefore "anti-inflammaging". In the present review, we have focused our attention on the contrast between inflammaging and anti-inflammaging systems, by evaluating the role of cytokines and their impact on extreme longevity. Cytokines are the expression of a network involving genes, polymorphisms and environment, and are involved both in inflammation and anti-inflammation. We have described the role of IL-1, IL-2, IL-6, IL-12, IL-15, IL-18, IL-22, IL-23, TNF-α, IFN-γ as pro-inflammatory cytokines, of IL-1Ra, IL-4, IL-10, TGF-β1 as anti-inflammatory cytokines, and of lipoxin A4 and heat shock proteins as mediators of cytokines. We believe that if inflammaging is a key to understand aging, anti-inflammaging may be one of the secrets of longevity.

  7. Utility of cytokines to predict neonatal sepsis.

    Science.gov (United States)

    Ye, Qing; Du, Li-Zhong; Shao, Wen-Xia; Shang, Shi-Qiang

    2017-04-01

    Sepsis is an important cause of neonatal morbidity and mortality worldwide. Diagnosis and treatment of neonatal sepsis relies on clinical judgment and interpretation of nonspecific laboratory tests. In a prospective cohort, we measured inflammatory cytokines as a potential biomarker for neonatal sepsis. Serum inflammatory cytokine levels were evaluated in the early stage of neonatal sepsis and after antimicrobial treatment. Receiver operating characteristic curves assessed the diagnostic value of cytokines. We performed multiple logistic regression analysis to characterize the role of each cytokine independently for infants with culture proven sepsis. C-reactive protein, interleukin (IL)-6, IL-10 and IL-6/IL-10 levels were significantly elevated in neonatal sepsis when compared with the control group and there were 1.4 (95% confidence interval (CI): 1.2-1.5), 4.9 (95% CI: 4.6-5.1), 5.1 (95% CI: 4.5-5.6), and 10.2 (95% CI: 9.2-11.1) fold greater odds, respectively, to predict neonatal sepsis when increased. After effective treatment, median IL-6 (pretreatment value: 263.0 pg/ml and post-treatment value: 7.4 pg/ml) and IL-6/IL-10 levels (pretreatment value: 16.6 and post-treatment value: 1.4) significantly decreased. The areas under the curve for IL-6, IL-10, IL-6/IL-10 and C-reactive protein for differential diagnosis were 0.98, 0.82, 0.90, and 0.88, respectively. IL-6 and IL-6/IL-10 outperformed C-reactive protein to diagnose neonatal sepsis. Of the cytokines studied, IL-6 was the most sensitive, whereas IL-6/IL-10 was the most specific predictor of neonatal sepsis.

  8. Inflammatory cytokines as biomarkers in heart failure.

    Science.gov (United States)

    Ueland, Thor; Gullestad, Lars; Nymo, Ståle H; Yndestad, Arne; Aukrust, Pål; Askevold, Erik T

    2015-03-30

    Inflammation has been implicated in the pathogenesis of heart failure (HF). In addition to their direct involvement as mediators in the pathogenesis of HF, inflammatory cytokines and related mediators could also be suitable markers for risk stratification and prognostication in HF patients. Many reports have suggested that inflammatory cytokines may predict adverse outcome in these patients. However, most studies have been limited in sample size and lacking full adjustment with the most recent and strongest biochemical predictor such as NT-proBNP and high sensitivity troponins. Furthermore, a number of pre-analytical and analytical aspects of cytokine measurements may limit their use as biomarkers. This review focuses on technical, informative and practical considerations concerning the clinical use of inflammatory cytokines as prognostic biomarkers in HF. We focus on the predictive value of tumor necrosis factor (TNF) α, the TNF family receptors sTNFR1 and osteoprotegerin, interleukin (IL)-6 and its receptor gp130, the chemokines MCP-1, IL-8, CXCL16 and CCL21 and the pentraxin PTX-3 in larger prospective fully adjusted studies. No single inflammatory cytokine provides sufficient discrimination to justify the transition to everyday clinical use as a prognosticator in HF. However, while subjecting potential new HF markers to rigorous comparisons with "gold-standard" markers, such as NT-proBNP, using receiver operating characteristics (ROCs) and HF risk models, makes sense from a clinical standpoint, it may pose a threat to a broadening of mechanistic insight if the new markers are dismissed solely on account of lower statistical power. Copyright © 2014. Published by Elsevier B.V.

  9. Mental quality of life is related to a cytokine genetic pathway.

    Directory of Open Access Journals (Sweden)

    Dounya Schoormans

    Full Text Available BACKGROUND: Quality of life (QoL in patients with chronic disease is impaired and cannot be solely explained by disease severity. We explored whether genetic variability and activity contributes to QoL in patients with Marfan syndrome (MFS, a genetic connective tissue disorder. METHODOLOGY/PRINCIPAL FINDINGS: In 121 MFS patients, patient characteristics (i.e. demographics and MFS-related symptoms were assessed. Patients completed the SF-36 to measure QoL. In addition, transcriptome wide gene expression and 484 Single Nucleotide Polymorphysms (SNPs in cytokine genes were available. QoL was first analyzed and associated with patient characteristics. Patients' physical QoL was impaired and weakly related with age and scoliosis, whereas mental quality of life (MCS was normal. To explain a largely lacking correlation between disease severity and QoL, we related genome wide gene expression to QoL. Patients with lower MCS scores had high expression levels of CXCL9 and CXCL11 cytokine-related genes (p=0.001; p=0.002; similarly, patients with low vitality scores had high expression levels of CXCL9, CXCL11 and IFNA6 cytokine-related genes (p=0.02; p=0.02; p=0.04, independent of patient characteristics. Subsequently, we associated cytokine related SNPs to mental QoL (MCS and vitality. SNP-cluster in the IL4R gene showed a weak association with MCS and vitality (strongest association p=0.0017. Although overall mental QoL was normal, >10% of patients had low scores for MCS and vitality. Post-hoc analysis of systemic inflammatory mediators showed that patients with lowest MCS and vitality scores had high levels of CCL11 cytokine (p=0.03; p=0.04. CONCLUSIONS/SIGNIFICANCE: Variation in the cytokine genetic pathway and its activation is related to mental QoL. These findings might allow us to identify and, ultimately, treat patients susceptible to poor QoL.

  10. The role of the cytokine network in psychological stress.

    Science.gov (United States)

    Kim, Yong-Ku; Maes, Michael

    2003-06-01

    Although a considerable amount of evidence has shown that psychological stress alters peripheral and brain cytokines, the physiological significance of cytokine alteration in psychological stress remains to be elucidated. The aims of this review are to analyze the influence of acute and chronic psychological stresses on the cytokine network in animals and in humans, and to explore the pathophysiological implication of the cytokine changes in psychological stress. Acute psychological stress may increase proinflammatory cytokines both in animals and in humans, and increase T-helper-1 cell cytokines in humans. Investigations into the effect of chronic psychological stress on cytokine production in animals gives mixed results. However, in humans, academic exam stress or care-giver's stress appears to induce a shift in the Th1/Th2 cytokine balance toward a Th2 response and increase proinflammatory cytokines. Psychological stress-induced cytokines stimulate the activity of indoleamine 2,3 dioxygenase (IDO) and could induce serotonin depletion-related disorders such as depression in susceptible individuals. Psychological stress-induced production of cytokines may increase the risk for human diseases, such as cardiovascular disease and exacerbation of autoimmune diseases. Proinflammatory cytokines may also play a regulatory role in glucocorticoid resistance and may be involved in wound healing and skin barrier function alterations. Finally, psychological stress-induced production of cytokines may play a role in neurodegenerative changes in the brain.

  11. Catch and Release of Cytokines Mediated by Tumor Phosphatidylserine Converts Transient Exposure into Long-Lived Inflammation.

    Science.gov (United States)

    Oyler-Yaniv, Jennifer; Oyler-Yaniv, Alon; Shakiba, Mojdeh; Min, Nina K; Chen, Ying-Han; Cheng, Sheue-Yann; Krichevsky, Oleg; Altan-Bonnet, Nihal; Altan-Bonnet, Grégoire

    2017-06-01

    Immune cells constantly survey the host for pathogens or tumors and secrete cytokines to alert surrounding cells of these threats. In vivo, activated immune cells secrete cytokines for several hours, yet an acute immune reaction occurs over days. Given these divergent timescales, we addressed how cytokine-responsive cells translate brief cytokine exposure into phenotypic changes that persist over long timescales. We studied melanoma cell responses to transient exposure to the cytokine interferon γ (IFNγ) by combining a systems-scale analysis of gene expression dynamics with computational modeling and experiments. We discovered that IFNγ is captured by phosphatidylserine (PS) on the surface of viable cells both in vitro and in vivo then slowly released to drive long-term transcription of cytokine-response genes. This mechanism introduces an additional function for PS in dynamically regulating inflammation across diverse cancer and primary cell types and has potential to usher in new immunotherapies targeting PS and inflammatory pathways. Published by Elsevier Inc.

  12. Influence of host genetic variation on rubella-specific T cell cytokine responses following rubella vaccination.

    Science.gov (United States)

    Ovsyannikova, Inna G; Ryan, Jenna E; Vierkant, Robert A; O'Byrne, Megan M; Pankratz, V Shane; Jacobson, Robert M; Poland, Gregory A

    2009-05-26

    The variability of immune response modulated by immune response gene polymorphisms is a significant factor in the protective effect of vaccines. We studied the association between cellular (cytokine) immunity and HLA genes among 738 schoolchildren (396 males and 342 females) between the ages of 11 and 19 years, who received two doses of rubella vaccine (Merck). Cytokine secretion levels in response to rubella virus stimulation were determined in PBMC cultures by ELISA. Cell supernatants were assayed for Th1 (IFN-gamma, IL-2, and IL-12p40), Th2 (IL-4, IL-5, and IL-10), and innate/proinflammatory (TNF-alpha, GM-CSF, and IL-6) cytokines. We found a strong association between multiple alleles of the HLA-DQA1 (global p-value 0.022) and HLA-DQB1 (global p-value 0.007) loci and variations in rubella-specific IL-2 cytokine secretion. Additionally, the relationships between alleles of the HLA-A (global p-value 0.058), HLA-B (global p-value 0.035), and HLA-C (global p-value 0.023) loci and TNF-alpha secretion suggest the importance of HLA class I molecules in innate/inflammatory immune response. Better characterization of these genetic profiles could help to predict immune responses at the individual and population level, provide data on mechanisms of immune response development, and further inform vaccine development and vaccination policies.

  13. Levamisole induces interleukin-18 and shifts type 1/type 2 cytokine balance

    Science.gov (United States)

    Szeto, C-C; Gillespie, K M; Mathieson, P W

    2000-01-01

    Immune responses can be classified, according to the predominant cytokines involved, into type 1 (featuring interferon-γ, IFN-γ) and type 2 (featuring interleukin-4, IL-4); imbalance between type 1 and type 2 cytokine compartments has been implicated in many human diseases. Levamisole is a drug with an unknown mode of action that has been used to boost immunity in infectious diseases including leprosy, and in some cancers. To test the hypothesis that levamisole acts by inducing a shift to a type 1 immune response, we used Brown Norway (BN) rats, which are markedly biased to type 2 responses. BN rats treated with levamisole showed a dose-dependent rise in serum IFN-γ and fall in serum immunoglobulin E (IgE) level. Detailed analysis of cytokine gene expression showed upregulation of IFN-γ and downregulation of IL-4 messenger RNA. This coincided with marked upregulation of IL-18, a recently characterized cytokine with potent activity in stimulating IFN-γ production. IL-12 was not induced. Further, the type 2 response induced in BN rats by mercuric chloride was markedly attenuated when rats were pretreated with levamisole: there was a 2-log reduction in maximum serum IgE level and marked attenuation of IL-4 gene upregulation. These data indicate that levamisole acts by resetting the immune balance towards a type 1 response via induction of IL-18. Our findings provide a direction for development of more specific immunomodulating therapy. PMID:10886398

  14. Caries induced cytokine network in the odontoblast layer of human teeth

    Directory of Open Access Journals (Sweden)

    Horst Jeremy A

    2011-01-01

    Full Text Available Abstract Background Immunologic responses of the tooth to caries begin with odontoblasts recognizing carious bacteria. Inflammatory propagation eventually leads to tooth pulp necrosis and danger to health. The present study aims to determine cytokine gene expression profiles generated within human teeth in response to dental caries in vivo and to build a mechanistic model of these responses and the downstream signaling network. Results We demonstrate profound differential up-regulation of inflammatory genes in the odontoblast layer (ODL in human teeth with caries in vivo, while the pulp remains largely unchanged. Interleukins, chemokines, and all tested receptors thereof were differentially up-regulated in ODL of carious teeth, well over one hundred-fold for 35 of 84 genes. By interrogating reconstructed protein interaction networks corresponding to the differentially up-regulated genes, we develop the hypothesis that pro-inflammatory cytokines highly expressed in ODL of carious teeth, IL-1β, IL-1α, and TNF-α, carry the converged inflammatory signal. We show that IL1β amplifies antimicrobial peptide production in odontoblasts in vitro 100-fold more than lipopolysaccharide, in a manner matching subsequent in vivo measurements. Conclusions Our data suggest that ODL amplifies bacterial signals dramatically by self-feedback cytokine-chemokine signal-receptor cycling, and signal convergence through IL1R1 and possibly others, to increase defensive capacity including antimicrobial peptide production to protect the tooth and contain the battle against carious bacteria within the dentin.

  15. 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...

  16. Drug targets in the cytokine universe for autoimmune disease.

    Science.gov (United States)

    Liu, Xuebin; Fang, Lei; Guo, Taylor B; Mei, Hongkang; Zhang, Jingwu Z

    2013-03-01

    In autoimmune disease, a network of diverse cytokines is produced in association with disease susceptibility to constitute the 'cytokine milieu' that drives chronic inflammation. It remains elusive how cytokines interact in such a complex network to sustain inflammation in autoimmune disease. This has presented huge challenges for successful drug discovery because it has been difficult to predict how individual cytokine-targeted therapy would work. Here, we combine the principles of Chinese Taoism philosophy and modern bioinformatics tools to dissect multiple layers of arbitrary cytokine interactions into discernible interfaces and connectivity maps to predict movements in the cytokine network. The key principles presented here have important implications in our understanding of cytokine interactions and development of effective cytokine-targeted therapies for autoimmune disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Inflammasome-independent regulation of IL-1-family cytokines

    NARCIS (Netherlands)

    Netea, M.G.; Veerdonk, F.L. van de; Meer, J.W.M. van der; Dinarello, C.A.; Joosten, L.A.B.

    2015-01-01

    Induction, production, and release of proinflammatory cytokines are essential steps to establish an effective host defense. Cytokines of the interleukin-1 (IL-1) family induce inflammation and regulate T lymphocyte responses while also displaying homeostatic and metabolic activities. With the

  18. Cytokine expression profile over time in severely burned pediatric patients

    National Research Council Canada - National Science Library

    Finnerty, Celeste C; Herndon, David N; Przkora, Rene; Pereira, Clifford T; Oliveira, Hermes M; Queiroz, Dulciene M M; Rocha, Andreia M C; Jeschke, Marc G

    2006-01-01

    .... The massive release of cytokines is implicated in this hypermetabolic response. The aim of the present study was to compare cytokine expression profiles from severely burned children without signs of infections or inhalation injury (n = 19...

  19. Nerve growth factor: neurotrophin or cytokine?

    Science.gov (United States)

    Bonini, S; Rasi, G; Bracci-Laudiero, M L; Procoli, A; Aloe, L

    2003-06-01

    Nerve growth factor (NGF) is a neutrophin exerting an important role in the development and functions of the central and peripheral nervous system. However, it has recently been documented that several immune cells - such as mast cells, lymphocytes and eosinophils - produce, store and release NGF. Moreover, NGF high and low affinity receptors are widely expressed in the immune system, thus indicating the potential of responding to this neurotrophin through an autocrine mechanism. In fact, NGF influences development differentiation, chemotaxis and mediator release of inflammatory cells as well as fibroblast activation through a complex network influenced by other pro-inflammatory cytokines. Finally, NGF is increased in biological fluids of several allergic, immune and inflammatory diseases. Data reviewed suggest, therefore, that NGF might also be viewed as a (Th2?) cytokine with a modulatory role in allergic inflammation and tissue remodeling. Copyright 2003 S. Karger AG, Basel

  20. Rosacea: the Cytokine and Chemokine Network

    Science.gov (United States)

    Gerber, Peter Arne; Buhren, Bettina Alexandra; Steinhoff, Martin; Homey, Bernhard

    2013-01-01

    Rosacea is one of the most common dermatoses of adults. Recent studies have improved our understanding of the pathophysiology of rosacea. Current concepts suggest that known clinical trigger factors of rosacea such as UV radiation, heat, cold, stress, spicy food, and microbes modulate Toll-like receptor signaling, induce reactive oxygen species, as well as enhance antimicrobial peptide and neuropeptide production. Downstream of these events cytokines and chemokines orchestrate an inflammatory response that leads to the recruitment and activation of distinct leukocyte subsets and induces the characteristic histopathological features of rosacea. Here we summarize the current knowledge of the cytokine and chemokine network in rosacea and propose pathways that may be of therapeutic interest. PMID:22076326

  1. Cytokines and Other Mediators in Alopecia Areata

    Science.gov (United States)

    Gregoriou, Stamatis; Papafragkaki, Dafni; Kontochristopoulos, George; Rallis, Eustathios; Kalogeromitros, Dimitrios; Rigopoulos, Dimitris

    2010-01-01

    Alopecia areata, a disease of the hair follicles with multifactorial etiology and a strong component of autoimmune origin, has been extensively studied as far as the role of several cytokines is concerned. So far, IFN-γ, interleukins, TNF-α, are cytokines that are well known to play a major role in the pathogenesis of the disease, while several studies have shown that many more pathways exist. Among them, MIG, IP-10, BAFF, HLA antigens, MIG, as well as stress hormones are implicated in disease onset and activity. Within the scope of this paper, the authors attempt to shed light upon the complexity of alopecia areata underlying mechanisms and indicate pathways that may suggest future treatments. PMID:20300578

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  3. 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...

  4. Cytokines as Immunological Markers for Follow up of Disease ...

    African Journals Online (AJOL)

    Background: Cytokines play a major role in protection against Mycobacterium tuberculosis infection and regulate the immune responses at a cellular level. Cytokine profile determines clinical outcome of the disease and responses to treatment as well. A T helper 1 (Th1) cytokine interferon gamma (IFN-U) is one of the most ...

  5. Salivary cytokine levels in early gingival inflammation

    DEFF Research Database (Denmark)

    Belstrøm, Daniel; Damgaard, Christian; Könönen, Eija

    2017-01-01

    Salivary protein levels have been studied in periodontitis. However, there is lack of information on salivary cytokine levels in early gingival inflammation. The aim of this study was to determine salivary levels of vascular endothelial growth factor (VEGF), interleukin (IL)-8, monocyte chemoattr......Salivary protein levels have been studied in periodontitis. However, there is lack of information on salivary cytokine levels in early gingival inflammation. The aim of this study was to determine salivary levels of vascular endothelial growth factor (VEGF), interleukin (IL)-8, monocyte...... chemoattractant protein (MCP)-1, IL-1β, and IL-1 receptor antagonist (IL-1Ra) in gingival inflammation. Twenty-eight systemically and orally healthy nonsmokers abstained from oral hygiene protocols for 10 days. After that, self-performed cleaning was resumed for 14 days. Plaque and gingival indexes were measured......, and saliva samples were collected at days 1, 4, 7, 10, and 24. Salivary cytokines were detected with Luminex®-xMAP™. Salivary IL-1β, IL-1Ra, and VEGF levels decreased after 10 days' development of experimental gingivitis and reached baseline levels at the end of the 2-week resolution period. Salivary IL-8...

  6. Cytokines as Biomarkers in Rheumatoid Arthritis

    Science.gov (United States)

    Burska, Agata; Boissinot, Marjorie; Ponchel, Frederique

    2014-01-01

    RA is a complex disease that develops as a series of events often referred to as disease continuum. RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria) and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia. Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable. Monitoring biomarkers would be useful in predicting relapse. Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual. Increasing numbers of cytokines have been involved in RA pathology. Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology. We will review the current knowledge's relation to cytokine used as biomarker in RA. However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA. PMID:24733962

  7. Common studied polymorphisms do not affect plasma cytokine levels upon endotoxin exposure in humans

    DEFF Research Database (Denmark)

    Taudorf, Sarah; Krabbe, K.S.; Berg, R.M.

    2008-01-01

    The aim of this study was to investigate to what extent single nucleotide polymorphisms (SNPs) in promoter regions of genes of Toll-like receptor (TLR)-4, tumour necrosis factor (TNF)-alpha, interleukin (IL)-18, interferon (IFN)-gamma, IL-6 and IL-10 affect the cytokine response during a controlled......-607, IFN-gamma+874, IL-6-174, IL-10-592 and IL-10-1082) and endotoxin-induced changes in plasma levels of TNF-alpha, IL-6 and IL-10. IL-18 levels were unaffected by endotoxin. In conclusion, the investigated SNPs did not affect endotoxin-induced low-grade cytokine production of TNF-alpha, IL-6, IL-18 or IL......-10 in healthy young men. Previous reports of a major heritability factor in the inflammatory response may be due to other target genes or effects in older age groups or women Udgivelsesdato: 2008/4...

  8. In situ hybridization of cytokine mRNA using alkaline phosphatase-labelled oligodeoxynucleotide probes

    DEFF Research Database (Denmark)

    Clausen, Bettina Hjelm; Fenger, Christina; Finsen, B.

    2013-01-01

    In situ hybridization is a powerful tool for visualizing cellular gene expression in morphologically preserved brain tissue giving precise information on the regional expression of specific mRNA sequences in cells of diverse phenotype. Here, we describe a sensitive, simple, and robust method usin...... alkaline phosphatase (AP)-labelled oligodeoxynucleotide probes to detect cytokine mRNA in the acutely injured or inflamed mouse CNS....

  9. Can we design a better anti-cytokine therapy?

    Science.gov (United States)

    Drutskaya, Marina S; Efimov, Grigory A; Kruglov, Andrei A; Nedospasov, Sergei A

    2017-09-01

    Cytokine neutralization is successfully used for treatment of various autoimmune diseases and chronic inflammatory conditions. The complex biology of the two well-characterized proinflammatory cytokines TNF and IL-6 implicates unavoidable consequences when it comes to their global blockade. Because systemic cytokine ablation may result in unwanted side effects, efforts have been made to develop more specific cytokine inhibitors, which would spare the protective immunoregulatory functions of a given cytokine. In this article, we review current research and summarize new strategies for improved anti-TNF and anti-IL-6 biologics, which specifically target only selected parts of the signaling cascades mediated by these ligands. © Society for Leukocyte Biology.

  10. Extraction of mRNA from coagulated horse blood and analysis of inflammation-related cytokine responses to coagulation

    DEFF Research Database (Denmark)

    Bovbjerg, Kirsten Katrine Lindegaard; Heegaard, Peter M. H.; Skovgaard, Kerstin

    2010-01-01

    available. Here, a protocol for RNA extraction from highly clotted blood was optimized and the regulation of a number of cytokine genes compared to stabilized blood was studied. Whole blood samples from 10 clinically healthy horses were incubated for 24 hours at 37°C and RNA was extracted from...... (IL-1β), interleukin-1-receptor antagonist (IL-1ra), interleukin-15 (IL-15), and interleukin-8 (IL-8). These findings that a coagulation-induced inflammation-related cytokine response takes place in whole blood upon clotting. The extraction method provides reproducible and reliable results allowing......Coagulated blood is a rich source of mRNA that allows the study of the regulation of expression of cytokine and other genes. However, while several methods are available for isolation of RNA from whole blood and tissues, protocols for purification of mRNA from clotted blood are not generally...

  11. Differential effects of Th1 versus Th2 cytokines in combination with hypoxia on HIFs and angiogenesis in RA

    Science.gov (United States)

    2012-01-01

    Introduction Hypoxia and T-helper cell 1 (Th1) cytokine-driven inflammation are key features of rheumatoid arthritis (RA) and contribute to disease pathogenesis by promoting angiogenesis. The objective of our study was to characterise the angiogenic gene signature of RA fibroblast-like synoviocytes (FLS) in response to hypoxia, as well as Th1 and T-helper cell 2 (Th2) cytokines, and in particular to dissect out effects of combined hypoxia and cytokines on hypoxia inducible transcription factors (HIFs) and angiogenesis. Methods Human angiogenesis PCR arrays were used to screen cDNA from RA FLS exposed to hypoxia (1% oxygen) or dimethyloxalylglycine, which stabilises HIFs. The involvement of HIF isoforms in generating the angiogenic signature of RA FLS stimulated with hypoxia and/or cytokines was investigated using a DNA-binding assay and RNA interference. The angiogenic potential of conditioned media from hypoxia-treated and/or cytokine-treated RA FLS was measured using an in vitro endothelial-based assay. Results Expression of 12 angiogenic genes was significantly altered in RA FLS exposed to hypoxia, and seven of these were changed by dimethyloxalylglycine, including ephrin A3 (EFNA3), vascular endothelial growth factor (VEGF), adipokines angiopoietin-like (ANGPTL)-4 and leptin. These four proangiogenic genes were dependent on HIF-1 in hypoxia to various degrees: EFNA3 >ANGPTL-4 >VEGF >leptin. The Th1 cytokines TNFα and IL-1β induced HIF-1 but not HIF-2 transcription as well as activity, and this effect was additive with hypoxia. In contrast, Th2 cytokines had no effect on HIFs. IL-1β synergised with hypoxia to upregulate EFNA3 and VEGF in a HIF-1-dependent fashion but, despite strongly inducing HIF-1, TNFα suppressed adipokine expression and had minimal effect on EFNA3. Supernatants from RA FLS subjected to hypoxia and TNFα induced fewer endothelial tubules than those from FLS subjected to TNFα or hypoxia alone, despite high VEGF protein levels. The Th2

  12. Regulation of cytokines by small RNAs during skin inflammation

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    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.

  13. The Role of Cytokine in the Lupus Nephritis

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    Yasunori Iwata

    2011-01-01

    Full Text Available Lupus nephritis (LN is a major clinical manifestation of systemic lupus erythematosus (SLE. Although numerous abnormalities of immune system have been proposed, cytokine overexpression plays an essential role in the pathogenesis of LN. In the initial phase of the disease, the immune deposits and/or autoantibodies induce cytokine production in renal resident cells, leading to further inflammatory cytokine/chemokine expression and leukocyte infiltration and activation. Then, infiltrate leukocytes, such as macrophages (Mφ and dendritic cells (DCs, secrete a variety of cytokines and activate naïve T cells, leading the cytokine profile towards T helper (Th1, Th2, and/or Th17. Recent studies revealed these inflammatory processes in experimental animal models as well as human LN. The cytokine targeted intervention may have the therapeutic potentials for LN. This paper focuses on the expression of cytokine and its functional role in the pathogenesis of LN.

  14. Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms

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    Vladan P. Čokić

    2015-01-01

    Full Text Available The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34+ cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34+ cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs.

  15. STUDIES ON THE ROLE OF CYTOKINES POLYMORPHISM IN PATHOGENESIS OF CHRONIC URTICARIA

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    N. I. Baranova

    2015-01-01

    Full Text Available Fifty patients with chronic autoimmune urticaria (CAU and forty-eight patients with chronic idiopathic urticaria (CIU have been examined. Blood serum contents of IL-4, IL-10 and IL-17A, spontaneous and induced cytokine production in blood cells, as well as polymorphism of IL-4 (C-589T, IL-10 (G-1082A, IL-17A (G-197A cytokine genes has been studied. No differences have been detected when studying IL-4 levels, depending on genetic variants of IL-4 gene in patients with CAU and CIU. Increased IL-10 amounts in patients with CIU still did not show any correlations with IL-10 genotype (G-1082A. Increased IL-17A levels in patients with CAU were associated with homozygous genotype of AA in comparison to control group, and with heterozygous GA genotype, in comparison to CIU group. The revealed differences of cytokines` genes polymorphism in CAU and CIU provide a molecular-genetic evidence for different clinical forms of chronic urticaria. 

  16. Fetuin-A Induces Cytokine Expression and Suppresses Adiponectin Production

    Science.gov (United States)

    Wicke, Corinna; Machicao, Fausto; Fritsche, Andreas; Häring, Hans-Ulrich; Stefan, Norbert

    2008-01-01

    Background The secreted liver protein fetuin-A (AHSG) is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin. Methodology and Principal Findings Human monocytic THP1 cells and human in vitro differenttiated adipocytes as well as C57BL/6 mice were treated with fetuin-A. mRNA expression of the genes encoding inflammatory cytokines and the adipokine adiponectin (ADIPOQ) was assessed by real-time RT-PCR. In 122 subjects, plasma levels of fetuin-A, adiponectin and, in a subgroup, the multimeric forms of adiponectin were determined. Fetuin-A treatment induced TNF and IL1B mRNA expression in THP1 cells (p<0.05). Treatment of mice with fetuin-A, analogously, resulted in a marked increase in adipose tissue Tnf mRNA as well as Il6 expression (27- and 174-fold, respectively). These effects were accompanied by a decrease in adipose tissue Adipoq mRNA expression and lower circulating adiponectin levels (p<0.05, both). Furthermore, fetuin-A repressed ADIPOQ mRNA expression of human in vitro differentiated adipocytes (p<0.02) and induced inflammatory cytokine expression. In humans in plasma, fetuin-A correlated positively with high-sensitivity C-reactive protein, a marker of subclinical inflammation (r = 0.26, p = 0.01), and negatively with total- (r = −0.28, p = 0.02) and, particularly, high molecular weight adiponectin (r = −0.36, p = 0.01). Conclusions and Significance We provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin

  17. Fetuin-A induces cytokine expression and suppresses adiponectin production.

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    Anita M Hennige

    Full Text Available BACKGROUND: The secreted liver protein fetuin-A (AHSG is up-regulated in hepatic steatosis and the metabolic syndrome. These states are strongly associated with low-grade inflammation and hypoadiponectinemia. We, therefore, hypothesized that fetuin-A may play a role in the regulation of cytokine expression, the modulation of adipose tissue expression and plasma concentration of the insulin-sensitizing and atheroprotective adipokine adiponectin. METHODOLOGY AND PRINCIPAL FINDINGS: Human monocytic THP1 cells and human in vitro differenttiated adipocytes as well as C57BL/6 mice were treated with fetuin-A. mRNA expression of the genes encoding inflammatory cytokines and the adipokine adiponectin (ADIPOQ was assessed by real-time RT-PCR. In 122 subjects, plasma levels of fetuin-A, adiponectin and, in a subgroup, the multimeric forms of adiponectin were determined. Fetuin-A treatment induced TNF and IL1B mRNA expression in THP1 cells (p<0.05. Treatment of mice with fetuin-A, analogously, resulted in a marked increase in adipose tissue Tnf mRNA as well as Il6 expression (27- and 174-fold, respectively. These effects were accompanied by a decrease in adipose tissue Adipoq mRNA expression and lower circulating adiponectin levels (p<0.05, both. Furthermore, fetuin-A repressed ADIPOQ mRNA expression of human in vitro differentiated adipocytes (p<0.02 and induced inflammatory cytokine expression. In humans in plasma, fetuin-A correlated positively with high-sensitivity C-reactive protein, a marker of subclinical inflammation (r = 0.26, p = 0.01, and negatively with total- (r = -0.28, p = 0.02 and, particularly, high molecular weight adiponectin (r = -0.36, p = 0.01. CONCLUSIONS AND SIGNIFICANCE: We provide novel evidence that the secreted liver protein fetuin-A induces low-grade inflammation and represses adiponectin production in animals and in humans. These data suggest an important role of fatty liver in the pathophysiology of insulin resistance and

  18. Misregulation of suppressors of cytokine signaling in eosinophilic esophagitis.

    Science.gov (United States)

    Zafra, Ma Paz; Cancelliere, Natally; Rodríguez del Río, Pablo; Ruiz-García, Mónica; Estévez, Laura; Andregnette, Victoria; Sánchez-García, Silvia; Fiandor, Ana; Collantes, Elena; Sastre, Joaquín; Quirce, Santiago; Ibáñez, María Dolores; del Pozo, Victoria

    2013-08-01

    Several findings suggest that eosinophilic esophagitis (EoE) is strongly associated with atopy and allergen-driven, Th2-type immune responses, indicating the association of EoE with immune dysregulation. The objective of this study is to ascertain the molecular mechanism involved in EoE disease development a Th2 condition. 25 patients with diagnosis of EoE and 17 non-EoE controls were recruited by the gastroenterology and allergy departments from three different hospitals. Transcription analysis of suppressors of cytokine signaling 1, 3, 5 (SOCS), interleukin-5 (IL), IL-13, eotaxin (CCL26), eoataxin receptor (CCR3), and mitogen-activated protein kinase 1 (MAPK1) was performed in esophageal biopsies by real time PCR. Western blot of ERK esophageal protein and additional measures of IL-5 and VEGF levels in serum were performed. The esophagus of EoE patients expresses and synthesizes high levels of SOCS1 and SOCS3 proteins (P < 0.05), and these expression correlated with levels of IL-5, IL-13, CCL26, CCR3, and MAPK1 genes. In addition, we demonstrate the implication of the ERK pathway (P < 0.001). SOCS proteins probably contribute to EoE pathogenesis by directly or indirectly inducing the Th2 profile, as well as by promoting the production of Th2 cytokines. All these findings further enhance our understanding of the mechanism of EoE, and accumulating evidence suggests that EoE pathogenesis is likely to be due to misregulation of immunological pathways.

  19. Myokines (muscle-derived cytokines and chemokines) including ciliary neurotrophic factor (CNTF) inhibit osteoblast differentiation.

    Science.gov (United States)

    Johnson, Rachelle W; White, Jason D; Walker, Emma C; Martin, T John; Sims, Natalie A

    2014-07-01

    Muscle and bone are intimately linked by bi-directional signals regulating both muscle and bone cell gene expression and proliferation. It is generally accepted that muscle cells secrete factors (myokines) that influence adjacent bone cells, but these myokines are yet to be identified. We have previously shown that osteocyte-specific deletion of the co-receptor subunit utilized by IL-6 family cytokines, glycoprotein 130 (gp130), resulted in impaired bone formation in the trabecular bone, but enhanced periosteal expansion, suggesting a gp130-dependent periosteum-specific inhibition of osteoblast function, potentially induced by the local muscle fibres. We report here that differentiated primary calvarial osteoblasts cultured in myotube-conditioned media (CM) from myogenic C2C12 cells show reduced mRNA levels of genes associated with osteoblast differentiation. Alkaline phosphatase protein activity and all mRNA markers of osteoblast differentiation in the tested panel (runx2, osterix, alkaline phosphatase, parathyroid hormone (PTH) receptor, osteoprotegerin, osteocalcin, sclerostin) were reduced following culture with myotube CM. The exception was RANKL, which was significantly elevated in differentiated primary osteoblast cultures expressing osteocytic genes. A cytokine array of the C2C12 myotube-conditioned media identified TIMP-1 and MCP-1 as the most abundant myokines, but treatment with recombinant TIMP-1 or MCP-1 did not inhibit osteoblast gene expression. Rather, the IL-6 family cytokine ciliary neurotrophic factor (CNTF), which we found abundantly expressed by mouse muscle at the transcript and protein level, reduced osteoblast gene expression, although not to the same extent as the myotube-conditioned media. These data indicate that muscle cells secrete abundant TIMP-1, MCP-1, and CNTF, and that of these, only CNTF has the ability to suppress osteoblast function and gene expression in a similar manner to myotube-conditioned medium. This suggests that CNTF is

  20. Impaired Expression of Cytokines as a Result of Viral Infections with an Emphasis on Small Ruminant Lentivirus Infection in Goats

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    Justyna Jarczak

    2016-07-01

    Full Text Available Knowing about the genes involved in immunity, and being able to identify the factors influencing their expressions, helps in gaining awareness of the immune processes. The qPCR method is a useful gene expression analysis tool, but studies on immune system genes are still limited, especially on the caprine immune system. Caprine arthritis encephalitis, a disease caused by small ruminant lentivirus (SRLV, causes economic losses in goat breeding, and there is no therapy against SRLV. The results of studies on vaccines against other viruses are promising. Moreover, the Marker-Assisted Selection strategy against SRLV is possible, as has been shown in sheep breeding. However, there are still many gaps in our knowledge on the caprine immune response to infection. All types of cytokines play pivotal roles in immunity, and SRLV infection influences the expression of many cytokines in different types of cells. This information encouraged the authors to examine the results of studies conducted on SRLV and other viral infections, with an emphasis on the expression of cytokine genes. This review attempts to summarize the results of studies on the expression of cytokines in the context of the SRLV infection.

  1. Cytokine profile and pathology in human leishmaniasis

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    Ribeiro-de-Jesus A.

    1998-01-01

    Full Text Available The clinical spectrum of leishmaniasis and control of the infection are influenced by the parasite-host relationship. The role of cellular immune responses of the Th1 type in the protection against disease in experimental and human leishmaniasis is well established. In humans, production of IFN-g is associated with the control of infection in children infected by Leishmania chagasi. In visceral leishmaniasis, an impairment in IFN-g production and high IL-4 and IL-10 levels (Th2 cytokines are observed in antigen-stimulated peripheral blood mononuclear cells (PBMC. Moreover, IL-12 restores IFN-g production and enhances the cytotoxic response. IL-10 is the cytokine involved in down-regulation of IFN-g production, since anti-IL-10 monoclonal antibody (mAb restores in vitro IFN-g production and lymphoproliferative responses, and IL-10 abrogates the effect of IL-12. In cutaneous and mucosal leishmaniasis, high levels of IFN-g are found in L. amazonensis-stimulated PBMC. However, low or absent IFN-g levels were observed in antigen-stimulated PBMC from 50% of subjects with less than 60 days of disease (24 ± 26 pg/ml. This response was restored by IL-12 (308 ± 342 pg/ml and anti-IL-10 mAb (380 ± 245 pg/ml (P<0.05. Later during the disease, high levels of IFN-g and TNF-a are produced both in cutaneous and mucosal leishmaniasis. After treatment there is a decrease in TNF-a levels (366 ± 224 pg/ml before treatment vs 142 ± 107 pg/ml after treatment, P = 0.02. Although production of IFN-g and TNF-a might be involved in the control of parasite multiplication in the early phases of Leishmania infection, these cytokines might also be involved in the tissue damage seen in tegumentary leishmaniasis

  2. Tissue-engineered human psoriatic skin supplemented with cytokines as an in vitro model to study plaque psoriasis.

    Science.gov (United States)

    Pouliot-Bérubé, Claudia; Zaniolo, Karine; Guérin, Sylvain L; Pouliot, Roxane

    2016-09-01

    Psoriasis is a chronic inflammatory skin disease. To study its complex etiology, a psoriatic skin substitute model supplemented with a cytokine cocktail has been used. Reconstructed psoriatic skin substitutes were supplemented with a cocktail of four cytokines: TNF-α, IL-1α, IL-6 and IL-17A, to monitor their impact on gene expression by DNA microarray. Gene profiling analyses identified several deregulated genes reported as being also deregulated in psoriasis skin in vivo (S100A12, IL-8, DEFB4A and KYNU). The expression of those genes was dramatically increased compared with basal levels of controls (p < 0.005 to < 0.05). Psoriatic substitutes supplemented with a cocktail of TNF-α, IL-1α, IL-6 and IL-17A showed similar transcriptome alterations to those found in psoriasis.

  3. Cytokines in Alzheimer's disease and vascular dementia.

    Science.gov (United States)

    Angelopoulos, P; Agouridaki, H; Vaiopoulos, H; Siskou, E; Doutsou, K; Costa, V; Baloyiannis, S I

    2008-12-01

    The levels of interleukin 1beta, interleukin 6, and interleukin 10 were elevated in the serum of patients with dementia. No statistically significant correlation was recorded in the interleukin levels among patients with Alzheimer's disease and vascular dementia. Also, no significant correlation was observed in the interleukin levels in the serum and the severity of dementia. However, a significant correlation was found between IL-6 and tumor necrosis factor-alpha (TNF-alpha) levels and age. The levels of IL-1beta and IL-6 were positively correlated with hypertension, and IL-2 levels were negatively correlated. No correlation was found between depressive symptoms and levels of cytokines in the serum.

  4. Cytokines in the modulation of eosinophilia

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    Faccioli Lúcia H

    1997-01-01

    Full Text Available In this review we discuss our recently results showing interleukin 5 (IL-5 involvement in eosinophil migration and in the maintenance of eosinophilia in blood, bone marrow, lung and peritoneal cavity, in a visceral larva migrans syndrome model using guinea-pigs infected with Toxocara canis. We also describe the sequential release of TNF-alpha and IL-8 during the course of infection, and the interaction between these cytokines and IL-5 during infection. Finally we propose a new biological role for IL-5, at least in our model, as a modulator of IL-8 release and secretion.

  5. Hypothyroidism and depression: Are cytokines the link?

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    Parimal S Tayde

    2017-01-01

    Full Text Available Context: Primary hypothyroidism has been thought of as an inflammatory condition characterized by raised levels of cytokines such as C-reactive protein (CRP, interleukin-6 (IL-6, and tumor necrosis factor-alpha (TNF-α. Depression is also well known to occur in hypothyroidism. Depression is also characterized by elevated inflammatory cytokines. We planned to study whether cytokines play an important part in linking these two conditions. Objectives: (1 To know the prevalence of depression in overt hypothyroidism due to autoimmune thyroid disease. (2 To correlate the levels of inflammatory markers with the occurrence of depression. (3 To study the effect of levothyroxine on inflammatory markers and depression. Materials and Methods: In this longitudinal, case–controlled study, 33 patients with autoimmune hypothyroidism (thyroid-stimulating hormone >10 uIU/ml were included with 33 age-, sex-, and body max index-matched healthy controls. Individuals were tested for Serum TNF-α, IL-6, high-sensitivity-CRP (hs-CRP. They were assessed for depression using Montgomery Asberg Depression Rating Scale (MADRS and World Health Organization Quality of Life (QOL Scale. Patients received L Thyroxine titrated to achieve euthyroidism and were reassessed for inflammatory markers and cognitive dysfunction. Results: Nineteen patients (57% had mild to moderate depression (MADRS >11. After 6 months of treatment, eight patients (42% had remission of depression with significant improvement in QOL scores (P < 0.05. TNF-α, IL-6, and hs-CRP were significantly elevated in patients compared with controls and reduced with therapy but did not reach baseline as controls. The change in inflammatory markers correlated with improvement in QOL scores in social and environmental domains (P < 0.01. Conclusions: Primary autoimmune hypothyroidism is an inflammatory state characterized by elevated cytokines which decline with LT4 therapy. It is associated with depression and poor

  6. Cytokine production capacity in depression and anxiety.

    Science.gov (United States)

    Vogelzangs, N; de Jonge, P; Smit, J H; Bahn, S; Penninx, B W

    2016-05-31

    Recent studies have suggested that immune function may be dysregulated in persons with depressive and anxiety disorders. Few studies examined the expression of cytokines in response to ex vivo stimulation of blood by lipopolysaccharide (LPS) to study the innate production capacity of cytokines in depression and anxiety. To investigate this, baseline data from the Netherlands Study of Depression and Anxiety (NESDA) were used, including persons (18-65 years; 66% women) with current (that is, past month; N=591) or remitted (N=354) DSM-IV depressive or anxiety disorders and healthy controls (N=297). Depressive and anxiety symptoms were measured by means of the Inventory of Depressive Symptomatology (IDS) and the Beck Anxiety Inventory (BAI). Using Multi-Analyte Profiling technology, plasma levels of 13 cytokines were assayed after whole blood stimulation by addition of LPS. Basal plasma levels of C-reactive protein, interleukin-6 and tumor necrosis factor-α were also available. A basal and a LPS summary index were created. Results show that LPS-stimulated inflammation was associated with increased odds of current depressive/anxiety disorders (odds ratio (OR)=1.28, P=0.009), as was the case for basal inflammation (OR=1.28, P=0.001). These associations were no longer significant after adjustment for lifestyle and health (OR=1.13, P=0.21; OR=1.07, P=0.45, respectively). After adjustment for lifestyle and health, interleukin-8 was associated with both remitted (OR=1.25, P=0.02) and current (OR=1.28, P=0.005) disorders. In addition, LPS-stimulated inflammation was associated with more severe depressive (β=0.129, P<0.001) and anxiety (β=0.165, P<0.001) symptoms, as was basal inflammation. Unlike basal inflammation, LPS-stimulated inflammation was still associated with (anxiety) symptom severity after adjustment for lifestyle and health (IDS: interleukin (IL)-8, MCP-1, MMP2; BAI: LPS index, IL-6, IL-8, IL-10, IL-18, MCP-1, MMP2, TNF-β). To conclude, lifestyle and health

  7. 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.

  8. Altered Expression of Pro-inflammatory Cytokines in Ovarian Follicles of Cows with Cystic Ovarian Disease.

    Science.gov (United States)

    Baravalle, M E; Stassi, A F; Velázquez, M M L; Belotti, E M; Rodríguez, F M; Ortega, H H; Salvetti, N R

    2015-01-01

    A growing body of evidence suggests that ovulation shares many of the features of an inflammatory reaction and that cytokines play many diverse and important roles in reproductive biology. The aim of this study was to examine the expression of the pro-inflammatory cytokines interleukin (IL)-1α, IL-6 and tumour necrosis factor (TNF)-α in ovarian cells from cows with cystic ovarian disease (COD) as compared with that in ovarian structures from regularly cycling cows. Expression of genes encoding IL-1α, IL-6 and TNF-α was detected by real-time polymerase chain reaction in follicular cells from ovaries from healthy cows and cows with COD with no significant differences. However, immunohistochemistry showed increased expression of IL-1α, IL-6 and TNF-α in cystic follicles, suggesting that this expression may be related to the persistence of follicular cysts. The effect of COD was evident for IL-1α and TNF-α, and a follicular structure-disease interaction was observed in the expression of all the cytokines evaluated. Thus, altered expression of these proinflammatory cytokines may be related to ovulation failure and development of follicular cysts. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Cytokine polymorphisms are associated with daytime napping in adults living with HIV.

    Science.gov (United States)

    Byun, Eeeseung; Gay, Caryl L; Portillo, Carmen J; Pullinger, Clive R; Aouizerat, Bradley E; Lee, Kathryn A

    2017-04-01

    Daytime napping longer than one hour has been associated with an increased risk for all-cause mortality. Associations between cytokine polymorphisms and daytime napping in chronic illnesses such as HIV, however, have not been well described. The purpose of this study was to examine cytokine polymorphisms associated with long daytime napping in adults living with HIV. A cross-sectional analysis was conducted using a convenience sample of 257 adults living with HIV. Daytime napping was assessed with wrist actigraphy data collected over three days. Participants categorized as long nappers (≥60 min) were compared to short nappers and non-nappers (napping was associated with 12 SNPs from seven genes: 1) IFNG rs2069728; 2) IL1B rs1143642, rs1143627, and rs16944; 3) IL2 rs2069763; 4) IL6 rs4719714, rs1554606, and rs2069845; 5) IL17A rs3819024 and rs8193036; 6) NFKB1 rs4648110; and 7) NFKB2 rs1056890. Cytokine genetic variations may have a role in physiological regulation of daytime napping as well as nocturnal sleep. Cytokine polymorphisms associated with long daytime napping could help identify adults with HIV who may benefit from targeted therapeutic interventions. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. The Possible Role of the Novel Cytokines IL-35 and IL-37 in Inflammatory Bowel Disease

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    Yanmei Li

    2014-01-01

    Full Text Available Interleukin- (IL- 35 and IL-37 are newly discovered immune-suppressing cytokines. They have been described in inflammatory diseases such as collagen-induced arthritis and asthma. However, their expressions in inflammatory bowel disease (IBD patients have not been yet explored. Our aim was to evaluate serum and inflamed mucosal levels in IBD patients. In 20 ulcerative colitis (UC patients, 7 Crohn’s disease (CD patients, and 15 healthy subjects, cytokine levels in serum were determined using ELISA and mucosal expression studies were performed by immunohistochemistry, quantitative real-time PCR, and Western blot. The results showed that serums IL-35 and IL-37 levels were significantly decreased in UC and CD patients compared with healthy subjects. The cytokines levels correlated inversely with UC activity. IL-35 was expressed in infiltrating immune cells while IL-37 in intestinal epithelial cells as well as inflammatory cells. IBD patients had significantly higher Ebi3, p35 (two subunits of IL-35, and IL-37b gene expressions; IL-35 and IL-37 protein expressions were higher in IBD patients compared with controls. The study showed that serums IL-35 and IL-37 might be potentially novel biomarkers for IBD. Intestinal IL-35 and IL-37 proteins are upregulated, suggesting that regulating the expression of the two cytokines may provide a new possible target for the treatment of IBD.

  11. Inflammatory Cytokines Stimulate Bone Morphogenetic Protein-2 Expression and Release from Pancreatic Beta Cells

    DEFF Research Database (Denmark)

    Urizar, Adriana Ibarra; Friberg, Josefine; Christensen, Dan Ploug

    2016-01-01

    The proinflammatory cytokines interleukin-1 beta (IL-1β) and interferon gamma (IFN-γ) play important roles in the progressive loss of beta-cell mass and function during development of both type 1 and type 2 diabetes. We have recently showed that bone morphogenetic protein (BMP)-2 and -4 are expre......The proinflammatory cytokines interleukin-1 beta (IL-1β) and interferon gamma (IFN-γ) play important roles in the progressive loss of beta-cell mass and function during development of both type 1 and type 2 diabetes. We have recently showed that bone morphogenetic protein (BMP)-2 and -4...... 6- and 3-fold in isolated islets of Langerhans from neonatal rat and human. Downstream target genes of the BMP pathway were also increased by cytokine treatment and could be reversed by neutralization of endogenous BMP activity. Nuclear factor kappa B- (NFκB) binding sites were identified in the rat...... BMP-2 promoter, and reporter assays verified the role of NFκB in cytokine-induced BMP-2 expression. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays confirmed NFκB binding to BMP-2 promoter upon IL-1β stimulation in beta cells. In conclusion, we suggest that NFκ...

  12. Identification of activated cytokine pathways in the blood of systemic lupus erythematosus, myositis, rheumatoid arthritis, and scleroderma patients.

    Science.gov (United States)

    Higgs, Brandon W; Zhu, Wei; Richman, Laura; Fiorentino, David F; Greenberg, Steven A; Jallal, Bahija; Yao, Yihong

    2012-02-01

    To develop genomic signatures of seven cytokines involved in the pathogenesis of rheumatic diseases such as systemic lupus erythematosus (SLE), dermatomyositis (DM), polymyositis (PM), rheumatoid arthritis (RA), or systemic scleroderma (SSc) that could potentially help identify patients likely to respond to therapies that target these individual cytokines. Over-expressed transcripts in the whole blood (WB) were identified from 262 SLE, 44 DM, 33 PM, 38 SSc and 89 RA subjects and compared to 24 healthy subjects using Affymetrix arrays. Cytokine-inducible gene signatures such as type I interferon (IFN), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-10, IL-13, IL-17, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were assessed in the WB of these subjects to identify subpopulations showing activation of specific cytokine pathways. Significant activation of the type I IFN pathway in a population of five diseases studied was universally observed. The TNF-α and IL-1β pathways were activated in subgroups of PM and RA subjects, respectively, with another subgroup of RA subjects showing activation of the IL-13 pathway. The GM-CSF pathway was activated in a subgroup of SSc subjects and the IL-17 pathway was activated in subgroups of all diseases except SLE. A novel gene expression measurement of activated cytokines in five different rheumatic diseases is presented. Characterizing the cytokine pathways most activated in specific patient subpopulations has the potential to help target the appropriate patient populations for corresponding anti-cytokine therapies. © 2011 The Authors. International Journal of Rheumatic Diseases © 2011 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd.

  13. Autoantibodies against the calcium-sensing receptor and cytokines in autoimmune polyglandular syndromes types 2, 3 and 4.

    Science.gov (United States)

    Kemp, E Helen; Kahaly, George J; Porter, Julie A; Frommer, Lara; Weetman, Anthony P

    2018-01-01

    The frequency of autoimmunity against the parathyroid glands in patients with polyglandular autoimmunity that is not due to autoimmune polyendocrine syndrome type 1 (APS1) is unclear. To investigate this, this study aimed to determine the prevalence of autoantibodies against parathyroid autoantigens, calcium-sensing receptor (CaSR) and NACHT leucine-rich-repeat protein 5 (NALP5), in a large group of patients with non-APS1 polyendocrine autoimmunity. Possible occult APS1 was investigated by cytokine autoantibody measurement and AIRE gene analysis. Subjects were 178 patients with APS2, 3 or 4, and 80 healthy blood donors. Autoantibodies against the CaSR, NALP5 and cytokines were measured by immunoprecipitation, radioligand binding assays or ELISA, respectively. Four patient samples (2.2%), but none of the controls, were positive for CaSR autoantibodies. NALP5 autoantibodies were not detected in any participant. Eleven patients (6.2%) had cytokine autoantibodies, but none of the control samples was positive. None of the patients with cytokine autoantibodies had any known or novel mutations in the AIRE gene. The low prevalence of CaSR autoantibodies indicate a very low level of subclinical parathyroid autoimmunity in APS types 2, 3 and 4. In addition, autoantibodies against cytokines constitute an uncommon feature of non-APS1 polyglandular autoimmunity. © 2017 John Wiley & Sons Ltd.

  14. Effects of Low-Level Laser Therapy on M1-Related Cytokine Expression in Monocytes via Histone Modification

    Directory of Open Access Journals (Sweden)

    Chia-Hsin Chen

    2014-01-01

    Full Text Available Low-level laser therapy (LLLT has been used in the treatment of radiotherapy-induced oral mucositis and allergic rhinitis. However, the effects of LLLT on human monocyte polarization into M1 macrophages are unknown. To evaluate the effects of LLLT on M1-related cytokine and chemokine production and elucidate the mechanism, the human monocyte cell line THP-1 was treated with different doses of LLLT. The expression of M1-related cytokines and chemokines (CCL2, CXCL10, and TNF-α was determined by ELISA and real-time PCR. LLLT-associated histone modifications were examined by chromatin immunoprecipitation (ChIP assays. Mitochondrial involvement in the LLLT-induced M1-related cytokine expression was evaluated by quantitative real-time PCR. Flow cytometry was used to detect the cell surface markers for monocyte polarization. The results showed that LLLT (660 nm significantly enhanced M1-related cytokine and chemokine expression in mRNA and protein levels. Mitochondrial copy number and mRNA levels of complex I-V protein were increased by LLLT (1 J/cm2. Activation of M1 polarization was concomitant with histone modification at TNF-α gene locus and IP-10 gene promoter area. This study indicates that LLLT (660 nm enhanced M1-related cytokine and chemokine expression via mitochondrial biogenesis and histone modification, which may be a potent immune-enhancing agent for the treatment of allergic diseases.

  15. Effects of low-level laser therapy on M1-related cytokine expression in monocytes via histone modification.

    Science.gov (United States)

    Chen, Chia-Hsin; Wang, Chau-Zen; Wang, Yan-Hsiung; Liao, Wei-Ting; Chen, Yi-Jen; Kuo, Chang-Hung; Kuo, Hsuan-Fu; Hung, Chih-Hsing

    2014-01-01

    Low-level laser therapy (LLLT) has been used in the treatment of radiotherapy-induced oral mucositis and allergic rhinitis. However, the effects of LLLT on human monocyte polarization into M1 macrophages are unknown. To evaluate the effects of LLLT on M1-related cytokine and chemokine production and elucidate the mechanism, the human monocyte cell line THP-1 was treated with different doses of LLLT. The expression of M1-related cytokines and chemokines (CCL2, CXCL10, and TNF-α) was determined by ELISA and real-time PCR. LLLT-associated histone modifications were examined by chromatin immunoprecipitation (ChIP) assays. Mitochondrial involvement in the LLLT-induced M1-related cytokine expression was evaluated by quantitative real-time PCR. Flow cytometry was used to detect the cell surface markers for monocyte polarization. The results showed that LLLT (660 nm) significantly enhanced M1-related cytokine and chemokine expression in mRNA and protein levels. Mitochondrial copy number and mRNA levels of complex I-V protein were increased by LLLT (1 J/cm(2)). Activation of M1 polarization was concomitant with histone modification at TNF-α gene locus and IP-10 gene promoter area. This study indicates that LLLT (660 nm) enhanced M1-related cytokine and chemokine expression via mitochondrial biogenesis and histone modification, which may be a potent immune-enhancing agent for the treatment of allergic diseases.

  16. Macrophage cytokines: Involvement in immunity and infectious diseases

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    Guillermo eArango Duque

    2014-10-01

    Full Text Available The evolution of macrophages has made them primordial for both development and immunity. Their functions range from the shaping of body plans to the ingestion and elimination of apoptotic cells and pathogens. Cytokines are small soluble proteins that confer instructions and mediate communication among immune and non-immune cells. A portfolio of cytokines is central to the role of macrophages as sentries of the innate immune system that mediate the transition from innate to adaptive immunity. In concert with other mediators, cytokines bias the fate of macrophages into a spectrum of inflammation-promoting ‘classically activated’, to anti-inflammatory or ‘alternatively activated’ macrophages. Deregulated cytokine secretion is implicated in several disease states ranging from chronic inflammation to allergy. Macrophages release cytokines via a series of beautifully orchestrated pathways that are spatiotemporally regulated. At the molecular level, these exocytic cytokine secretion pathways are coordinated by multi-protein complexes that guide cytokines from their point of synthesis to their ports of exit into the extracellular milieu. These trafficking proteins, many of which were discovered in yeast and commemorated in the 2013 Nobel Prize in Physiology or Medicine, coordinate the organelle fusion steps that are responsible for cytokine release. This review discusses the functions of cytokines secreted by macrophages, and summarizes what is known about their release mechanisms. This information will be used to delve into how selected pathogens subvert cytokine release for their own survival.

  17. Macrophage cytokines: involvement in immunity and infectious diseases.

    Science.gov (United States)

    Arango Duque, Guillermo; Descoteaux, Albert

    2014-01-01

    The evolution of macrophages has made them primordial for both development and immunity. Their functions range from the shaping of body plans to the ingestion and elimination of apoptotic cells and pathogens. Cytokines are small soluble proteins that confer instructions and mediate communication among immune and non-immune cells. A portfolio of cytokines is central to the role of macrophages as sentries of the innate immune system that mediate the transition from innate to adaptive immunity. In concert with other mediators, cytokines bias the fate of macrophages into a spectrum of inflammation-promoting "classically activated," to anti-inflammatory or "alternatively activated" macrophages. Deregulated cytokine secretion is implicated in several disease states ranging from chronic inflammation to allergy. Macrophages release cytokines via a series of beautifully orchestrated pathways that are spatiotemporally regulated. At the molecular level, these exocytic cytokine secretion pathways are coordinated by multi-protein complexes that guide cytokines from their point of synthesis to their ports of exit into the extracellular milieu. These trafficking proteins, many of which were discovered in yeast and commemorated in the 2013 Nobel Prize in Physiology or Medicine, coordinate the organelle fusion steps that are responsible for cytokine release. This review discusses the functions of cytokines secreted by macrophages, and summarizes what is known about their release mechanisms. This information will be used to delve into how selected pathogens subvert cytokine release for their own survival.

  18. The Cross-talk between Tristetraprolin and Cytokines in Cancer.

    Science.gov (United States)

    Guo, Jian; Wang, Hao; Jiang, Shiyi; Xia, Jiazeng; Jin, Shimao

    2017-11-24

    Cytokines are small secreted proteins serving as vital mediators that mediate the host immune responses. Transcription and post-transcription play a critical role in cytokine expression through the regulation of message RNA (mRNA) cytoplasmic localization, translation initiation and decay. Researches have been conducted to reveal regulatory mechanisms of cytokines production in cells involved in cancer. AU-rich element (ARE) can regulate the degradation and translation of mRNA by connecting with specific ARE binding proteins. It is now clear that tristetraprolin (TTP), as the most common ARE binding protein, negatively regulates many aspects of the cytokines through binding to the AREs in the 3'-untranslated region (3'UTR) of mRNA. Furthermore, some certain cytokines have an impact on TTP expression and function. Therefore, the cross-regulation between cytokines and TTP has come into sight. The complicated regulatory networks between cytokines and TTP are closely related to tumorigenesis. In this review, we summarize specific regulatory mechanisms of cytokine mRNAs. We focus on how TTP negatively regulates inflammatory and oncogenic cytokines expression after combining with AREs, we also pay attention to some cytokines mediating the expression of TTP and their cross-talk in various cancers in detail. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice.

    Science.gov (United States)

    Chen, Yong; Boettger, Michael K; Reif, Andreas; Schmitt, Angelika; Uçeyler, Nurcan; Sommer, Claudia

    2010-03-02

    Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1beta), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1beta. The increase of the anti-inflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1beta, and IL-10 following CFA, overall corroborating the inhibitor data. These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression.

  20. Ex Vivo Innate Immune Cytokine Signature of Enhanced Risk of Relapsing Brucellosis

    Science.gov (United States)

    Feldman, Kristyn E.; Loriaux, Paul M.; Saito, Mayuko; Tuero, Iskra; Villaverde, Homarh; Siva, Tenaya; Gotuzzo, Eduardo; Gilman, Robert H.; Hoffmann, Alexander; Vinetz, Joseph M.

    2013-01-01

    Background Brucellosis, a zoonotic infection caused by one of the Gram-negative intracellular bacteria of the Brucella genus, is an ongoing public health problem in Perú. While most patients who receive standard antibiotic treatment recover, 5–40% suffer a brucellosis relapse. In this study, we examined the ex vivo immune cytokine profiles of recovered patients with a history of acute and relapsing brucellosis. Methodology/Principal Findings Blood was taken from healthy control donors, patients with a history of acute brucellosis, or patients with a history of relapsing brucellosis. Peripheral blood mononuclear cells were isolated and remained in culture without stimulation or were stimulated with a panel of toll-like receptor agonists or heat-killed Brucella melitensis (HKBM) isolates. Innate immune cytokine gene expression and protein secretion were measured by quantitative real-time polymerase chain reaction and a multiplex bead-based immunoassay, respectively. Acute and relapse patients demonstrated consistently elevated cytokine gene expression and secretion levels compared to controls. Notably, these include: basal and stimulus-induced expression of GM-CSF, TNF-α, and IFN-γ in response to LPS and HKBM; basal secretion of IL-6, IL-8, and TNF-α; and HKBM or Rev1-induced secretion of IL-1β, IL-2, GM-CSF, IFN-Υ, and TNF-α. Although acute and relapse patients were largely indistinguishable by their cytokine gene expression profiles, we identified a robust cytokine secretion signature that accurately discriminates acute from relapse patients. This signature consists of basal IL-6 secretion, IL-1β, IL-2, and TNF-α secretion in response to LPS and HKBM, and IFN-γ secretion in response to HKBM. Conclusions/Significance This work demonstrates that informative cytokine variations in brucellosis patients can be detected using an ex vivo assay system and used to identify patients with differing infection histories. Targeted diagnosis of this signature may

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

    Directory of Open Access Journals (Sweden)

    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

  2. Cytokine and anti-cytokine therapies in prevention or treatment of fibrosis in IBD

    Science.gov (United States)

    Jacob, Noam; Targan, Stephan R

    2016-01-01

    The frequency of fibrosing Crohn’s disease (CD) is significant, with approximately 40% of CD patients with ileal disease developing clinically apparent strictures throughout their lifetime. Although strictures may be subdivided into fibrotic, inflammatory, or mixed forms, despite immunosuppressive therapy in CD patients in the form of steroids or immunomodulators, the frequency of fibrostenosing complications has still remained significant. A vast number of genetic and epigenetic variables are thought to contribute to fibrostenosing disease, including those that affect cytokine biology, and therefore highlight the complexity of disease, but also shed light on targetable pathways. Exclusively targeting fibrosis may be difficult, however, because of the relatively slow evolution of fibrosis in CD, and the potential adverse effects of inhibiting pathways involved in tissue repair and mucosal healing. Acknowledging these caveats, cytokine-targeted therapy has become the mainstay of treatment for many inflammatory conditions and is being evaluated for fibrotic disorders. The question of whether anti-cytokine therapy will prove useful for intestinal fibrosis is, therefore, acutely relevant. This review will highlight some of the current therapeutics targeting cytokines involved in fibrosis. PMID:27536363

  3. Anti-cytokine autoantibodies in autoimmune diseases

    Science.gov (United States)

    Cappellano, Giuseppe; Orilieri, Elisabetta; Woldetsadik, Abiy D; Boggio, Elena; Soluri, Maria F; Comi, Cristoforo; Sblattero, Daniele; Chiocchetti, Annalisa; Dianzani, Umberto

    2012-01-01

    An overview of the current literature is showing that autoantibodies (AutoAbs) against cytokines are produced in several pathological conditions, including autoimmune diseases, but can also be detected in healthy individuals. In autoimmune diseases, these AutoAbs may also be prognostic markers, either negative (such as AutoAbs to IL-8 and IL-1α in rheumatoid arthritis) or positive (such as AutoAbs to IL-6 in systemic sclerosis and those to osteopontin in rheumatoid arthritis). They may have neutralizing activity and influence the course of the physiological and pathological immune responses. High levels of AutoAbs against cytokines may even lead to immunodeficiency, such as those to IL-17 in autoimmune polyendocrine syndrome type I or those to IFN-γ in mycobacterial infections. Their role in human therapy may be exploited not only through passive immunization but also through vaccination, which may improve the costs for long lasting treatments of autoimmune diseases. Detection and quantification of these AutoAbs can be profoundly influenced by the technique used and standardization of these methods is needed to increase the value of their analysis. PMID:23885320

  4. Angiogenic Factors and Cytokines in Diabetic Retinopathy

    Science.gov (United States)

    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

  5. Cytokine ratios in chronic periodontitis and type 2 diabetes mellitus.

    Science.gov (United States)

    Acharya, Anirudh B; Thakur, Srinath; Muddapur, M V; Kulkarni, Raghavendra D

    Chronic periodontitis may influence systemic cytokines in type 2 diabetes. This study aimed to evaluate the cytokine ratios in type 2 diabetes with, and without chronic periodontitis. Gingival status, periodontal, glycemic parameters and serum cytokines were evaluated in participants grouped as healthy, chronic periodontitis, and type 2 diabetes with, and without chronic periodontitis. Cytokine ratios showed significant differences in type 2 diabetes and chronic periodontitis, were highest in participants having both type 2 diabetes and chronic periodontitis, with a statistically significant cut-off point and area under curve by receiver operating characteristic. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  6. PORCINE CYTOKINE RESPONSES TO PAMP-STRUCTURES IN VITRO

    DEFF Research Database (Denmark)

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

    antigen-presentation. Different PAMPs will activate different signalling pathways, resulting in specific cytokine signatures, which will influence the orientation of a developing immune response. In the pig, the range of antibodies available for cytokine-detection is limited, and so cytokines are often......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 inductive...

  7. Cytokines profile and peripheral blood mononuclear cells morphology in Rett and autistic patients.

    Science.gov (United States)

    Pecorelli, Alessandra; Cervellati, Franco; Belmonte, Giuseppe; Montagner, Giulia; Waldon, PhiAnh; Hayek, Joussef; Gambari, Roberto; Valacchi, Giuseppe

    2016-01-01

    A potential role for immune dysfunction in autism spectrum disorders (ASD) has been well established. However, immunological features of Rett syndrome (RTT), a genetic neurodevelopmental disorder closely related to autism, have not been well addressed yet. By using multiplex Luminex technology, a panel of 27 cytokines and chemokines was evaluated in serum from 10 RTT patients with confirmed diagnosis of MECP2 mutation (typical RTT), 12 children affected by classic autistic disorder and 8 control subjects. The cytokine/chemokine gene expression was assessed by real time PCR on mRNA of isolated peripheral blood mononuclear cells (PBMCs). Moreover, ultrastructural analysis of PBMCs was performed using transmission electron microscopy (TEM). Significantly higher serum levels of interleukin-8 (IL-8), IL-9, IL-13 were detected in RTT compared to control subjects, and IL-15 shows a trend toward the upregulation in RTT. In addition, IL-1β and VEGF were the only down-regulated cytokines in autistic patients with respect to RTT. No difference in cytokine/chemokine profile between autistic and control groups was detected. These data were also confirmed by ELISA real time PCR. At the ultrastructural level, the most severe morphological abnormalities were observed in mitochondria of both RTT and autistic PBMCs. In conclusion, our study shows a deregulated cytokine/chemokine profile together with morphologically altered immune cells in RTT. Such abnormalities were not quite as evident in autistic subjects. These findings indicate a possible role of immune dysfunction in RTT making the clinical features of this pathology related also to the immunology aspects, suggesting, therefore, novel possible therapeutic interventions for this disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Proinflammatory and Anti-Inflammatory Cytokines Mediated by NF-κB Factor as Prognostic Markers in Mammary Tumors

    Directory of Open Access Journals (Sweden)

    Gustavo Rodrigues Martins

    2016-01-01

    Full Text Available Inflammation results in the production of cytokines, such as interleukin- (IL- 4 and IL-10 with immunosuppressive properties or IL-6 and TNF-α with procarcinogenic activity. Furthermore, NF-κB is the major link between inflammation and tumorigenesis. This study verified the interaction between active inflammatory cytokines in the tumor microenvironment and serum of female dogs with mammary tumors and their correlation with the clinicopathological characteristics and overall survival. Measurement of gene expression was performed by qPCR and protein levels by ELISA/Luminex. High gene and protein expression levels of NF-κB, IL-6, and TNF-α were found in association with characteristics that reflect worse prognosis and a negative correlation between TNF-α protein expression and survival time was observed (p<0.05. In contrast, high gene and protein expression levels of IL-4 and IL-10 were associated with characteristics of better prognosis and an increased level of IL-4 and a longer survival time of animals were obtained (p<0.05. In addition, there was a positive correlation between TNF-α and IL-6 expression in association with NF-κB. The results show a significant correlation of these cytokines with tumor development, associated with NF-κB expression and cytokines promodulation, showing that these biological factors could be used as predictive and prognostic markers in breast cancer.

  9. Development and validation of quantitative PCR assays to measure cytokine transcript levels in the Florida manatee (Trichechus manatus latirostris)

    Science.gov (United States)

    Ferrante, Jason; Hunter, Margaret; Wellehan, James F.X.

    2018-01-01

    Cytokines have important roles in the mammalian response to viral and bacterial infections, trauma, and wound healing. Because of early cytokine production after physiologic stresses, the regulation of messenger RNA (mRNA) transcripts can be used to assess immunologic responses before changes in protein production. To detect and assess early immune changes in endangered Florida manatees (Trichechus manatus latirostris), we developed and validated a panel of quantitative PCR assays to measure mRNA transcription levels for the cytokines interferon (IFN)-γ; interleukin (IL)-2, -6, and -10; tumor necrosis factor-α, and the housekeeping genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and β-actin (reference genes). Assays were successfully validated using blood samples from free-ranging, apparently healthy manatees from the east and west coasts of central Florida. No cytokine or housekeeping gene transcription levels were significantly different among age classes or sexes. However, the transcription levels for GAPDH, IL-2, IL-6, and IFN-γ were significantly higher (Ptrauma and novel or ongoing environmental stressors.

  10. Cytokines and Angiogenesis in the Corpus Luteum

    Directory of Open Access Journals (Sweden)

    António M. Galvão

    2013-01-01

    Full Text Available In adults, physiological angiogenesis is a rare event, with few exceptions as the vasculogenesis needed for tissue growth and function in female reproductive organs. Particularly in the corpus luteum (CL, regulation of angiogenic process seems to be tightly controlled by opposite actions resultant from the balance between pro- and antiangiogenic factors. It is the extremely rapid sequence of events that determines the dramatic changes on vascular and nonvascular structures, qualifying the CL as a great model for angiogenesis studies. Using the mare CL as a model, reports on locally produced cytokines, such as tumor necrosis factor α (TNF, interferon gamma (IFNG, or Fas ligand (FASL, pointed out their role on angiogenic activity modulation throughout the luteal phase. Thus, the main purpose of this review is to highlight the interaction between immune, endothelial, and luteal steroidogenic cells, regarding vascular dynamics/changes during establishment and regression of the equine CL.

  11. Cytokine secretion and NK cell activity in human ADAM17 deficiency

    Science.gov (United States)

    Chavkin, Maor; Schmiedel, Dominik; Wong, Eitan; Werner, Marion; Yaacov, Barak; Averbuch, Diana; Molho-Pessach, Vered; Stepensky, Polina; Kaynan, Noa; Bar-On, Yotam; Seidel, Einat; Yamin, Rachel; Sagi, Irit; Elpeleg, Orly; Mandelboim, Ofer

    2015-01-01

    Genetic deficiencies provide insights into gene function in humans. Here we describe a patient with a very rare genetic deficiency of ADAM17. We show that the patient's PBMCs had impaired cytokine secretion in response to LPS stimulation, correlating with the clinical picture of severe bacteremia from which the patient suffered. ADAM17 was shown to cleave CD16, a major NK killer receptor. Functional analysis of patient's NK cells demonstrated that his NK cells express normal levels of activating receptors and maintain high surface levels of CD16 following mAb stimulation. Activation of individual NK cell receptors showed that the patient's NK cells are more potent when activated directly by CD16, albeit no difference was observed in Antibody Depedent Cytotoxicity (ADCC) assays. Our data suggest that ADAM17 inhibitors currently considered for clinical use to boost CD16 activity should be cautiously applied, as they might have severe side effects resulting from impaired cytokine secretion. PMID:26683521

  12. Evaluation by hierarchical clustering of multiple cytokine expression after phytohemagglutinin stimulation

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    Yang Chunhe

    2016-01-01

    Full Text Available The hierarchical clustering method has been used for exploration of gene expression and proteomic profiles; however, little research into its application in the examination of expression of multiplecytokine/chemokine responses to stimuli has been reported. Thus, little progress has been made on how phytohemagglutinin(PHA affects cytokine expression profiling on a large scale in the human hematological system. To investigate the characteristic expression pattern under PHA stimulation, Luminex, a multiplex bead-based suspension array, was performed. The data set collected from human peripheral blood mononuclear cells (PBMC was analyzed using the hierarchical clustering method. It was revealed that two specific chemokines (CCL3 andCCL4 underwent significantly greater quantitative changes during induction of expression than other tested cytokines/chemokines after PHA stimulation. This result indicates that hierarchical clustering is a useful tool for detecting fine patterns during exploration of biological data, and that it can play an important role in comparative studies.

  13. Production of fibrogenic cytokines by interleukin-2-treated peripheral blood leukocytes

    DEFF Research Database (Denmark)

    Kovacs, E J; Brock, B; Silber, I E

    1993-01-01

    OBJECTIVE: To assess the production of fibrogenic cytokines by interleukin-2 (IL-2)-stimulated peripheral blood leukocytes and to examine their ability to stimulate the production of connective tissue. METHODS: Culture medium from human peripheral blood leukocytes incubated with or without IL-2...... was tested for induction of fibroblast proliferation, collagen synthesis, and expression of cytokine genes. RESULTS: Supernatants from IL-2-treated peripheral blood leukocytes induced six times more fibroblast proliferation than medium from leukocytes cultured without IL-2. The expression of type I...... procollagen and fibronectin messenger RNAs was increased in human fibroblasts in response to leukocyte supernatants. Unstimulated leukocytes expressed minimal levels of transforming growth factor-beta or platelet-derived growth factor B chain messenger RNAs, but could be greatly enhanced by IL-2 treatment...

  14. Modulation of Cytokine and Cytokine Receptor/Antagonist by Treatment with Doxycycline and Tetracycline in Patients with Dengue Fever

    Directory of Open Access Journals (Sweden)

    J. E. Z. Castro

    2011-01-01

    Full Text Available Dengue virus infection can lead to dengue fever (DF or dengue hemorrhagic fever (DHF. Disease severity has been linked to an increase in various cytokine levels. In this study, we evaluated the effectiveness of doxycycline and tetracycline to modulate serum levels of IL-6, IL-1B, and TNF and cytokine receptor/receptor antagonist TNF-R1 and IL-1RA in patients with DF or DHF. Hospitalized patients were randomized to receive standard supportive care or supportive care combined with doxycycline or tetracycline therapy. Serum cytokine and cytokine receptor/antagonist levels were determined at the onset of therapy and after 3 and 7 days. Cytokine and cytokine receptor/antagonist levels were substantially elevated at day 0. IL-6, IL-1β, and TNF remained at or above day 0 levels throughout the study period in untreated patients. Treatment with tetracycline or doxycycline resulted in a significant decline in cytokine levels. Similarly, IL-1RA and TNF-R1 serum concentrations were elevated at baseline and showed a moderate increase among untreated patients. Both drugs resulted in a significant rise in IL-1Ra levels by day 3 in patients. In contrast, treatment did not affect a similar result for TNF-R1. When compared to the control group, however, a significant rise post-treatment was seen upon intragroup analysis. Further analysis demonstrated that doxycycline was significantly more effective at modulating cytokine and cytokine receptor/antagonist levels than tetracycline.

  15. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling.

    Science.gov (United States)

    Jahani-Asl, Arezu; Yin, Hang; Soleimani, Vahab D; Haque, Takrima; Luchman, H Artee; Chang, Natasha C; Sincennes, Marie-Claude; Puram, Sidharth V; Scott, Andrew M; Lorimer, Ian A J; Perkins, Theodore J; Ligon, Keith L; Weiss, Samuel; Rudnicki, Michael A; Bonni, Azad

    2016-06-01

    EGFRvIII-STAT3 signaling is important in glioblastoma pathogenesis. Here, we identified the cytokine receptor OSMR as a direct target gene of the transcription factor STAT3 in mouse astrocytes and human brain tumor stem cells (BTSCs). We found that OSMR functioned as an essential co-receptor for EGFRvIII. OSMR formed a physical complex with EGFRvIII, and depletion of OSMR impaired EGFRvIII-STAT3 signaling. Conversely, pharmacological inhibition of EGFRvIII phosphorylation inhibited the EGFRvIII-OSMR interaction and activation of STAT3. EGFRvIII-OSMR signaling in tumors operated constitutively, whereas EGFR-OSMR signaling in nontumor cells was synergistically activated by the ligands EGF and OSM. Finally, knockdown of OSMR strongly suppressed cell proliferation and tumor growth of mouse glioblastoma cells and human BTSC xenografts in mice, and prolonged the lifespan of these mice. Our findings identify OSMR as a critical regulator of glioblastoma tumor growth that orchestrates a feed-forward signaling mechanism with EGFRvIII and STAT3 to drive tumorigenesis.

  16. Cytokine-rich autologous serum system for cartilaginous tissue engineering.

    Science.gov (United States)

    Isogai, Noritaka; Nakagawa, Yumiko; Suzuki, Koji; Yamada, Ryo; Asamura, Shinichi; Hayakawa, Sumio; Munakata, Hiroshi

    2008-06-01

    Animal serum used for tissue engineering approaches has unacceptable risk for contamination with infectious agents. In this study, a cytokine-rich autologous serum (CRAS) system was developed. Canine auricular chondrocytes were cultured in medium supplemented with either fetal bovine serum (FBS) or autologous canine serum, alone or supplemented with basic fibroblast growth factor (b-FGF). Cell proliferative capacity was higher in the CRAS cultures than in those cultured in FBS, with greater expression of aggrecan and type II collagen in the b-FGF-supplemented CRAS group. The chondrocytes were seeded onto an ear-shaped biodegradable polymer (poly-L-lactide:epsilon-caprolactone, 50:50) and cultured in a Bioflow reactor for 1 week, using the 3 different culture media indicated above, and subsequently implanted into nude mice. The best outcome (cartilage gene expression and morphologic properties) was seen with tissue-engineered constructs precultured in the b-FGF-supplemented CRAS media. These findings indicate a clinically realizable approach for tissue engineering of cartilaginous structures.

  17. Microarray analysis of rat sensory ganglia after local inflammation implicates novel cytokines in pain.

    Directory of Open Access Journals (Sweden)

    Judith A Strong

    Full Text Available Inflammation plays a role in neuropathic pain conditions as well as in pain induced solely by an inflammatory stimulus. Robust mechanical hyperalgesia and allodynia can be induced by locally inflaming the L5 dorsal root ganglion (DRG in rat. This model allows investigation of the contribution of inflammation per se to chronic pain conditions. Most previous microarray studies of DRG gene expression have investigated neuropathic pain models. To examine the role of inflammation, we used microarray methods to examine gene expression 3 days after local inflammation of the L5 DRG in rat. We observed significant regulation in a large number of genes (23% of observed transcripts, and examined 221 (3% with a fold-change of 1.5-fold or more in more detail. Immune-related genes were the largest category in this group and included members of the complement system as well as several pro-inflammatory cytokines. However, these upregulated cytokines had no prior links to peripheral pain in the literature other than through microarray studies, though most had previously described roles in CNS (especially neuroinflammatory conditions as well as in immune responses. To confirm an association to pain, qPCR studies examined these cytokines at a later time (day 14, as well as in two different versions of the spinal nerve ligation pain model including a version without any foreign immunogenic material (suture. Cxcl11, Cxcl13, and Cxcl14 were found to be significantly upregulated in all these conditions, while Cxcl9, Cxcl10, and Cxcl16 were upregulated in at least two of these conditions.

  18. CYTOKINE - The Official Journal of the International Cytokine Society. Volume 11, Number 11

    Science.gov (United States)

    1999-12-09

    through upregulation of IFN-y production.1 Another phagocyte-derived cytokine displaying a potent IFN-y- inducing activity, provisionally called IGIF... antimicrobial activity and disrupt the cytoplasmic membrane of microorganisms. We observed that human ß-defensins (HBDs) were also chemotactic for immature...Collection, Braunschweig, Germany Dennis L. Stevens (Pathogenesis) VA Medical Center, Boise, USA Anne Tanner (Oral & Dental Bacteriology & Infection

  19. Diverse inflammatory cytokines induce selectin ligand expression on murine CD4 T cells via p38 alpha MAP kinase1

    Science.gov (United States)

    Ebel, Mark E.; Awe, Olufolakemi; Kaplan, Mark H.; Kansas, Geoffrey S.

    2015-01-01

    Selectins are glycan-binding adhesion molecules which mediate the initial steps of leukocyte recognition of endothelium. Cytokines control numerous aspects of CD4 T helper differentiation, but how cytokines control induction of ligands for E- and P-selectin on T helper subsets remains poorly understood. Among 20 cytokines that affect T helper cell differentiation, we identified six, IL-12, IL-18, IL-27, IL-9, IL-25 and TGFβ1, that induce expression of selectin ligands on murine CD4 T cells above the low levels associated with TCR engagement. Collectively, these six cytokines could potentially account for selectin ligand expression on all of the currently defined non-sessile T helper lineages, including Th1, Th2, Th9, Th17 and Treg. Induction of selectin ligand expression by each of these six cytokines was almost completely inhibited by pharmacologic inhibition of p38 MAPK, but not other MAPKs, or by conditional genetic deletion of p38 alpha MAPK. Analysis of the expression of key glycosyltransferase genes revealed that p38 alpha signaling was selectively required for induction of Fut7 and Gcnt1, but not for induction of St3gal4 or St3gal6. Constitutively active MKK6, an immediate upstream activator of p38 MAPK, induced selectin ligand expression equivalent to that of cytokines, and this induction was completely dependent on expression of p38 alpha. Our results identify the repertoire of cytokines responsible for selectin ligand induction on CD4 T cells and provide a mechanistic link between T helper development and T cell migration. PMID:25941329

  20. Methylation of insulin DNA in response to proinflammatory cytokines during the progression of autoimmune diabetes in NOD mice.

    Science.gov (United States)

    Rui, Jinxiu; Deng, Songyan; Lebastchi, Jasmin; Clark, Pamela L; Usmani-Brown, Sahar; Herold, Kevan C

    2016-05-01

    Type 1 diabetes is caused by the immunological destruction of pancreatic beta cells. Preclinical and clinical data indicate that there are changes in beta cell function at different stages of the disease, but the fate of beta cells has not been closely studied. We studied how immune factors affect the function and epigenetics of beta cells during disease progression and identified possible triggers of these changes. We studied FACS sorted beta cells and infiltrating lymphocytes from NOD mouse and human islets. Gene expression was measured by quantitative real-time RT-PCR (qRT-PCR) and methylation of the insulin genes was investigated by high-throughput and Sanger sequencing. To understand the role of DNA methyltransferases, Dnmt3a was knocked down with small interfering RNA (siRNA). The effects of cytokines on methylation and expression of the insulin gene were studied in humans and mice. During disease progression in NOD mice, there was an inverse relationship between the proportion of infiltrating lymphocytes and the beta cell mass. In beta cells, methylation marks in the Ins1 and Ins2 genes changed over time. Insulin gene expression appears to be most closely regulated by the methylation of Ins1 exon 2 and Ins2 exon 1. Cytokine transcription increased with age in NOD mice, and these cytokines could induce methylation marks in the insulin DNA by inducing methyltransferases. Similar changes were induced by cytokines in human beta cells in vitro. Epigenetic modification of DNA by methylation in response to immunological stressors may be a mechanism that affects insulin gene expression during the progression of type 1 diabetes.

  1. Overexpression of the Cytokine BAFF and Autoimmunity Risk.

    Science.gov (United States)

    Steri, Maristella; Orrù, Valeria; Idda, M Laura; Pitzalis, Maristella; Pala, Mauro; Zara, Ilenia; Sidore, Carlo; Faà, Valeria; Floris, Matteo; Deiana, Manila; Asunis, Isadora; Porcu, Eleonora; Mulas, Antonella; Piras, Maria G; Lobina, Monia; Lai, Sandra; Marongiu, Mara; Serra, Valentina; Marongiu, Michele; Sole, Gabriella; Busonero, Fabio; Maschio, Andrea; Cusano, Roberto; Cuccuru, Gianmauro; Deidda, Francesca; Poddie, Fausto; Farina, Gabriele; Dei, Mariano; Virdis, Francesca; Olla, Stefania; Satta, Maria A; Pani, Mario; Delitala, Alessandro; Cocco, Eleonora; Frau, Jessica; Coghe, Giancarlo; Lorefice, Lorena; Fenu, Giuseppe; Ferrigno, Paola; Ban, Maria; Barizzone, Nadia; Leone, Maurizio; Guerini, Franca R; Piga, Matteo; Firinu, Davide; Kockum, Ingrid; Lima Bomfim, Izaura; Olsson, Tomas; Alfredsson, Lars; Suarez, Ana; Carreira, Patricia E; Castillo-Palma, Maria J; Marcus, Joseph H; Congia, Mauro; Angius, Andrea; Melis, Maurizio; Gonzalez, Antonio; Alarcón Riquelme, Marta E; da Silva, Berta M; Marchini, Maurizio; Danieli, Maria G; Del Giacco, Stefano; Mathieu, Alessandro; Pani, Antonello; Montgomery, Stephen B; Rosati, Giulio; Hillert, Jan; Sawcer, Stephen; D'Alfonso, Sandra; Todd, John A; Novembre, John; Abecasis, Gonçalo R; Whalen, Michael B; Marrosu, Maria G; Meloni, Alessandra; Sanna, Serena; Gorospe, Myriam; Schlessinger, David; Fiorillo, Edoardo; Zoledziewska, Magdalena; Cucca, Francesco

    2017-04-27

    Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).

  2. A psychoneuroimmunological review on cytokines involved in antidepressant treatment response.

    Science.gov (United States)

    Janssen, Debbie G A; Caniato, Riccardo N; Verster, Joris C; Baune, Bernhard T

    2010-04-01

    The literature exploring the role that cytokine functioning plays in the pathogenesis and treatment of depressive illness is reviewed. The review focuses on the influence of antidepressants on cytokines, and on how treatment response might be affected by genetic variants of cytokines. The authors systematically reviewed the scientific literature on the subject over the last 20 years, searching PubMed, PsychInfo, and Cochrane databases. Antidepressants modulate cytokine functioning, and these mechanisms appear to directly influence treatment outcome in depression. Antidepressants appear to normalize serum levels of major inflammatory cytokines, including interleukin (IL)-1beta, IL-6, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma). Antidepressants are postulated to modulate cytokine functioning through their effects on intracellular cyclic adenosyl monophosphate (cAMP), serotonin metabolism, the hypothalamo-pituitary-adrenocortical (HPA) axis or through a direct action on neurogenesis. Preliminary research shows that cytokine genotypes and functioning may be able to help predict antidepressant treatment response. Current literature demonstrates an association between antidepressant action and cytokine functioning in major depression. Improved understanding of the specific pharmacologic and pharmacogenetic mechanisms is needed. Such knowledge may serve to enhance our understanding of depression, leading to promising new directions in the pathology, nosology, and treatment of depression. Copyright (c) 2010 John Wiley & Sons, Ltd.

  3. Cytokines: abnormalities in major depression and implications for pharmacological treatment.

    LENUS (Irish Health Repository)

    O'Brien, Sinead M

    2012-02-03

    The role of cytokines in depression was first considered when the cytokine interferon resulted in "sickness behaviour", the symptoms of which are similar to those of major depression. The latter is associated with an increase in pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). These cytokines are potent modulators of corticotropin-releasing hormone (CRH) which produces heightened hypothalamic-pituitary-adrenal axis (HPA) activity characterized by increases in ACTH and cortisol, both of which are reported elevated in major depression. Antidepressant treatment has immunomodulatory effects with increases in the production of IL-10, which is an anti-inflammatory cytokine. This review based on a Medline search from 1980-2003, focuses on the evidence available of cytokine changes in acute stress, chronic stress and major depression. It examines the effects of antidepressant treatment on immune parameters in both animal models and clinical trials. We suggest that future antidepressants may target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.

  4. Effects of coagulation factors and inflammatory cytokines on ...

    African Journals Online (AJOL)

    be closely related to the high levels of coagulation factors and inflammatory cytokines in the blood. Keywords: Coagulation factor, Inflammatory cytokines, Acute myocardial infarction, C-reactive protein,. Tumor necrosis factor-α, ... addition, the systemic inflammation response has been documented in patients with AMI, and.

  5. Cytokine Levels in the Serum of Healthy Subjects

    Directory of Open Access Journals (Sweden)

    Giulio Kleiner

    2013-01-01

    Full Text Available Growing knowledge about the cytokine network response has led to a better comprehension of mechanisms of pathologies and to the development of new treatments with biological drugs, able to block specific molecules of the immune response. Indeed, when the cytokine production is deregulated, diseases often occur. The understanding of the physiological mechanism of the cytokine network would be useful to better comprehend pathological conditions. Moreover, since the immune system and response change their properties with development, differences in patients' age should be taken into account, both in physiological and in pathological conditions. In this study, we analyzed the profile of 48 cytokines and chemokines in the serum of healthy subjects, comparing adults (≥18 years with young children and children (1–6 and 7–17 years. We found that a certain number of cytokines were not being produced in healthy subjects; others showed a constant serum level amongst the groups. Certain cytokines exhibited a downward or an upward trend with increasing age. The remaining cytokines were up- or downregulated in the group of the children with respect to the other groups. In conclusion, we drew some kinds of guidelines about the physiological production of cytokines and chemokines, underling the difference caused by aging.

  6. Cytokine expression & TGF-beta signaling in cervical cancer

    NARCIS (Netherlands)

    Kloth, Judith Nathalie

    2009-01-01

    Immune surveillance is of utmost importance in preventing cervical carcinogenesis. Cytokines play a central role in directing and fine tuning the immune response. In cancer, cytokines can either be involved in stimulating the anti-tumor immune response or in tumor growth and progression. The studies

  7. 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.

  8. Cytokines and the Risk of Preterm Delivery in Twin Pregnancies

    DEFF Research Database (Denmark)

    Rode, Line; Klein, Katharina; Larsen, Helle

    2012-01-01

    To estimate the association between cytokine levels in twin pregnancies and risk of spontaneous preterm delivery, including the effect of progesterone treatment.......To estimate the association between cytokine levels in twin pregnancies and risk of spontaneous preterm delivery, including the effect of progesterone treatment....

  9. Identification of overexpressed cytokines as serum biomarkers of ...

    African Journals Online (AJOL)

    Hepatic inflammation is the stimulator to activate hepatic stellate cells (HSCs) and triggers fibrogenesis. Cytokines are produced during liver inflammation and maybe considered as liver fibrosis biomarker. The aim of this study was to investigate whether cytokines can be used as reliable biomarkers of liver fibrosis using ...

  10. Inflammatory cytokines and risk of coronary heart disease

    DEFF Research Database (Denmark)

    Kaptoge, Stephen; Seshasai, Sreenivasa Rao Kondapally; Gao, Pei

    2014-01-01

    Because low-grade inflammation may play a role in the pathogenesis of coronary heart disease (CHD), and pro-inflammatory cytokines govern inflammatory cascades, this study aimed to assess the associations of several pro-inflammatory cytokines and CHD risk in a new prospective study, including meta...

  11. Modulation of cytokine production profiles in splenic dendritic cells ...

    African Journals Online (AJOL)

    We examined the role of splenic dendritic cells in immune response to Toxoplasma gondii infection in SAG1 (P30+) transgenic mice by investigating the kinetics of intracellular cytokines expression of IL-4, IL-10, IL-12 and IFN-γ by intracellular cytokine staining (ICS) using flow cytometry, and compared the results to those of ...

  12. Spironolactone inhibits production of proinflammatory cytokines by human mononuclear cells

    DEFF Research Database (Denmark)

    Hansen, Peter Riis; Rieneck, Klaus; Bendtzen, Klaus

    2004-01-01

    The mineralocorticoid receptor antagonist spironolactone (SPIR) reduces the mortality and morbidity in patients with congestive heart failure (CHF). Overexpression of proinflammatory cytokines contribute to the development and progression of CHF.......The mineralocorticoid receptor antagonist spironolactone (SPIR) reduces the mortality and morbidity in patients with congestive heart failure (CHF). Overexpression of proinflammatory cytokines contribute to the development and progression of CHF....

  13. The cytokines cardiotrophin-like cytokine/cytokine-like factor-1 (CLC/CLF) and ciliary neurotrophic factor (CNTF) differ in their receptor specificities.

    Science.gov (United States)

    Tormo, Aurélie Jeanne; Letellier, Marie-Claude; Lissilaa, Rami; Batraville, Laurie-Anne; Sharma, Mukut; Ferlin, Walter; Elson, Greg; Crabé, Sandrine; Gauchat, Jean-François

    2012-12-01

    Ciliary neurotrophic factor (CNTF) and cardiotrophin-like cytokine (CLC) are two cytokines with neurotrophic and immunomodulatory activities. CNTF is a cytoplasmic factor believed to be released upon cellular damage, while CLC requires interaction with a soluble cytokine receptor, cytokine-like factor 1 (CLF), to be efficiently secreted. Both cytokines activate a receptor complex comprising the cytokine binding CNTF receptor α (CNTFRα) and two signaling chains namely, leukemia inhibitory factor receptor β (LIFRβ) and gp130. Human CNTF can recruit and activate an alternative receptor in which CNTFRα is substituted by IL-6Rα. As both CNTF and CLC have immune-regulatory activities in mice, we compared their ability to recruit mouse receptors comprising both gp130 and LIFRβ signaling chains and either IL-6Rα or IL-11Rα which, unlike CNTFRα, are expressed by immune cells. Our results indicate that 1) mouse CNTF, like its human homologue, can activate cells expressing gp130/LIFRβ with either CNTFRα or IL-6Rα and, 2) CLC/CLF is more restricted in its specificity in that it activates only the tripartite CNTFR. Several gp130 signaling cytokines influence T helper cell differentiation. We therefore investigated the effect of CNTF on CD4 T cell cytokine production. We observed that CNTF increased the number of IFN-γ producing CD4 T cells. As IFN-γ is considered a mediator of the therapeutic effect of IFN-β in multiple sclerosis, induction of IFN-γ by CNTF may contribute to the beneficial immunomodulatory effect of CNTF in mouse multiple sclerosis models. Together, our results indicate that CNTF activates the same tripartite receptors in mouse and human cells and further validate rodent models for pre-clinical investigation of CNTF and CNTF derivatives. Furthermore, CNTF and CLC/CLF differ in their receptor specificities. The receptor α chain involved in the immunomodulatory effects of CLC/CLF remains to be identified. Crown Copyright © 2012. Published by

  14. Unique Cytokine Signature in the Plasma of Patients with Fibromyalgia

    Directory of Open Access Journals (Sweden)

    Jamie Sturgill

    2014-01-01

    Full Text Available Fibromyalgia (FMS is a chronic pain syndrome with a complex but poorly understood pathogenesis affecting approximately 10 million adults in the United States. The lack of a clear etiology of FMS has limited the effective diagnosis and treatment of this debilitating condition. The objective of this secondary data analysis was to examine plasma cytokine levels in women with FMS using the Bio-Plex Human Cytokine 17-plex Assay. Post hoc analysis of plasma cytokine levels was performed to evaluate patterns that were not specified a priori. Upon examination, patients with FMS exhibited a marked reduction in TH2 cytokines such as IL-4, IL-5, and IL-13. The finding of this pattern of altered cytokine milieu not only supports the role of inflammation in FMS but also may lead to more definitive diagnostic tools for clinicians treating FMS. The TH2 suppression provides strong evidence of immune dysregulation in patients with FMS.

  15. Cytokines in Bipolar Disorder: Paving the Way for Neuroprogression

    Directory of Open Access Journals (Sweden)

    Izabela Guimarães Barbosa

    2014-01-01

    Full Text Available Bipolar disorder (BD is a severe, chronic, and recurrent psychiatric illness. It has been associated with high prevalence of medical comorbidities and cognitive impairment. Its neurobiology is not completely understood, but recent evidence has shown a wide range of immune changes. Cytokines are proteins involved in the regulation and the orchestration of the immune response. We performed a review on the involvement of cytokines in BD. We also discuss the cytokines involvement in the neuroprogression of BD. It has been demonstrated that increased expression of cytokines in the central nervous system in postmortem studies is in line with the elevated circulating levels of proinflammatory cytokines in BD patients. The proinflammatory profile and the immune imbalance in BD might be regarded as potential targets to the development of new therapeutic strategies.

  16. Characterization and potential clinical applications of autoantibodies against cytokines

    DEFF Research Database (Denmark)

    de Lemos Rieper, Carina; Galle, Pia; Hansen, Morten Bagge

    2009-01-01

    Autoantibodies recognizing cytokines arise in certain patients during the course of therapy with recombinant cytokines, although they may arise spontaneously as well. They are typically high avidity and in vitro neutralizing IgG antibodies present in picomolar to nanomolar concentrations....... Methodology is therefore critical. Quantitative studies based on sound methodology strongly indicate that nanomolar levels of cytokine autoantibodies are likely to be involved in a number of "new" syndromes such as acquired immune deficiencies, lung diseases, and certain age-related manifestations....... There are many ways in which the autoantibodies could be naturally induced, and they have been experimentally induced with ease. Therefore, a new therapeutic concept of inducing cytokine autoantibodies via anti-cytokine vaccination is currently rapidly emerging....

  17. Role of IL-38 and Its Related Cytokines in Inflammation

    Directory of Open Access Journals (Sweden)

    Xianli Yuan

    2015-01-01

    Full Text Available Interleukin- (IL- 38 is a recently discovered cytokine and is the tenth member of the IL-1 cytokine family. IL-38 shares structural features with IL-1 receptor antagonist (IL-1Ra and IL-36Ra. IL-36R is the specific receptor of IL-38, a partial receptor antagonist of IL-36. IL-38 inhibits the production of T-cell cytokines IL-17 and IL-22. IL-38 also inhibits the production of IL-8 induced by IL-36γ, thus inhibiting inflammatory responses. IL-38-related cytokines, including IL-1Ra and IL-36Ra, are involved in the regulation of inflammation and immune responses. The study of IL-38 and IL-38-related cytokines might provide new insights for developing anti-inflammatory treatments in the near future.

  18. Citoquinas en tuberculosis Cytokines in tuberculosis

    Directory of Open Access Journals (Sweden)

    Jaime I. Rodríguez

    1997-04-01

    Full Text Available La tuberculosis continúa siendo un modelo inmunológico para estudiar las infecciones intracelulares. Entenderlos complejos mecanismos de interacción de la micobacteria con el sistema inmune del hospedero permitirá un manejo más racional de los fenómenos clínicos que se presentan en la enfermedad. Las citoquinas desempeñan un papel fundamental tanto en el desarrollo de los mecanismos de inmunidad protectora como en el daño tisular presente en esta enfermedad. La estimulación in vitro de linfocitos de sujetos sanos tuberculino positivos con antígenos específicos induce preferencial mente un patrón de citoquinas tipo I (1'IL-2, 1'IFN-y, ~IL-4, ~IL-5, mientras que en la mayoría de los pacientes no se presenta este patrón. Las citoquinas tipo I conducen a la activación de los macrófagos que a su vez inhiben la replicación de las micobacterias. En el ratón, los macrófagos activados inhiben la micobacteria por medio del óxido nítrico; en los humanos la producción de óxido nítrico por los macrófagos no está plenamente demostrada. Recientemente se ha demostrado que la infección con M. tuberculosis puede inducir apoptosis en los macrófagos infectados. La apoptosis depende de la producción del Factor de Necrosis Tumoral a y de óxido nítrico. Paradójicamente, ellipoarabinomanán manosilado (ManLAM presente en la pared de las micobacterias inhibe la apoptosis. Estos hallazgos muestran un nuevo fenómeno en la interacción micobacteriamacrófago el cual debe estar finamente regulado tanto en el microorganismo como en el hospedero. Tuberculosis continues to be a model to study the immunological aspects of intracellular infections. A better understanding of the mycobacteria.host interaction would allow a more rational approach to the clinical problems of this disease. Cytokines playa key role in the development of protective immunity as well as in the tissue injury that occurs during the disease. In vitro stimulation with

  19. Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs

    Directory of Open Access Journals (Sweden)

    Silvia Leoncini

    2015-01-01

    Full Text Available An involvement of the immune system has been suggested in Rett syndrome (RTT, a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2 or, more rarely, cyclin-dependent kinase-like 5 (CDKL5. To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg response, as well as chemokines, were investigated in MECP2- (MECP2-RTT (n=16 and CDKL5-Rett syndrome (CDKL5-RTT (n=8, before and after ω-3 polyunsaturated fatty acids (PUFAs supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4 were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

  20. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

    DEFF Research Database (Denmark)

    Ortis, Fernanda; Naamane, Najib; Flamez, Daisy

    2010-01-01

    OBJECTIVE: Cytokines contribute to pancreatic beta-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified by the cy......OBJECTIVE: Cytokines contribute to pancreatic beta-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified...... by the cytokines interleukin (IL)-1beta + interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha + IFN-gamma in primary rat beta-cells. RESEARCH DESIGN AND METHODS: Fluorescence-activated cell sorter-purified rat beta-cells were exposed to IL-1beta + IFN-gamma or TNF-alpha + IFN-gamma for 6 or 24 h......-cells, with temporal differences in the number of genes modulated by IL-1beta + IFNgamma or TNF-alpha + IFN-gamma. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression...

  1. Involvement of cytokines in slow wave sleep.

    Science.gov (United States)

    Krueger, James M; Clinton, James M; Winters, Bradley D; Zielinski, Mark R; Taishi, Ping; Jewett, Kathryn A; Davis, Christopher J

    2011-01-01

    Cytokines such as tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL1β) play a role in sleep regulation in health and disease. TNFα or IL1β injection enhances non-rapid eye movement sleep. Inhibition of TNFα or IL1β reduces spontaneous sleep. Mice lacking TNFα or IL1β receptors sleep less. In normal humans and in multiple disease states, plasma levels of TNFα covary with EEG slow wave activity (SWA) and sleep propensity. Many of the symptoms induced by sleep loss, for example, sleepiness, fatigue, poor cognition, enhanced sensitivity to pain, are elicited by injection of exogenous TNFα or IL1β. IL1β or TNFα applied unilaterally to the surface of the cortex induces state-dependent enhancement of EEG SWA ipsilaterally, suggesting greater regional sleep intensity. Interventions such as unilateral somatosensory stimulation enhance localized sleep EEG SWA, blood flow, and somatosensory cortical expression of IL1β and TNFα. State oscillations occur within cortical columns. One such state shares properties with whole animal sleep in that it is dependent on prior cellular activity, shows homeostasis, and is induced by TNFα. Extracellular ATP released during neuro- and gliotransmission enhances cytokine release via purine type 2 receptors. An ATP agonist enhances sleep, while ATP antagonists inhibit sleep. Mice lacking the P2X7 receptor have attenuated sleep rebound responses after sleep loss. TNFα and IL1β alter neuron sensitivity by changing neuromodulator/neurotransmitter receptor expression, allowing the neuron to scale its activity to the presynaptic neurons. TNFα's role in synaptic scaling is well characterized. Because the sensitivity of the postsynaptic neuron is changed, the same input will result in a different network output signal and this is a state change. The top-down paradigm of sleep regulation requires intentional action from sleep/wake regulatory brain circuits to initiate whole-organism sleep. This raises unresolved

  2. Genetic analysis of inflammation, cytokine mRNA expression and disease course of relapsing experimental autoimmune encephalomyelitis in DA rats

    DEFF Research Database (Denmark)

    Lorentzen, J C; Andersson, M; Issazadeh-Navikas, Shohreh

    1997-01-01

    -MHC genes were decisive since a high incidence of SPR-EAE only occurred in rats with DA non-MHC genes. Analysis of cytokine mRNA expression and infiltrating cells in the spinal cords of congenic strains revealed that the av1 haplotype associated with a high CD4/CD8 ratio and expression of m......Genetic analysis of experimental autoimmune encephalomyelitis (EAE) can provide clues to the etiology of multiple sclerosis (MS). Identifying the susceptibility genes of DA rats may be particularly rewarding since they are prone to develop a remarkably MS-like chronic and demyelinating disease...

  3. Machine Learning-Based Gene Prioritization Identifies Novel Candidate Risk Genes for Inflammatory Bowel Disease.

    Science.gov (United States)

    Isakov, Ofer; Dotan, Iris; Ben-Shachar, Shay

    2017-09-01

    The inflammatory bowel diseases (IBDs) are chronic inflammatory disorders, associated with genetic, immunologic, and environmental factors. Although hundreds of genes are implicated in IBD etiology, it is likely that additional genes play a role in the disease process. We developed a machine learning-based gene prioritization method to identify novel IBD-risk genes. Known IBD genes were collected from genome-wide association studies and annotated with expression and pathway information. Using these genes, a model was trained to identify IBD-risk genes. A comprehensive list of 16,390 genes was then scored and classified. Immune and inflammatory responses, as well as pathways such as cell adhesion, cytokine-cytokine receptor interaction, and sulfur metabolism were identified to be related to IBD. Scores predicted for IBD genes were significantly higher than those for non-IBD genes (P genes had a high prediction score (>0.8). A literature review of the genes, excluding those used to train the model, identified 67 genes without any publication concerning IBD. These genes represent novel candidate IBD-risk genes, which can be targeted in future studies. Our method successfully differentiated IBD-risk genes from non-IBD genes by using information from expression data and a multitude of gene annotations. Crucial features were defined, and we were able to detect novel candidate risk genes for IBD. These findings may help detect new IBD-risk genes and improve the understanding of IBD pathogenesis.

  4. 1, 25(OH)₂D₃ inhibits hepatocellular carcinoma development through reducing secretion of inflammatory cytokines from immunocytes.

    Science.gov (United States)

    Guo, Jian; Ma, Zhenhua; Ma, Qingyong; Wu, Zheng; Fan, Ping; Zhou, Xiaojie; Chen, Lulu; Zhou, Shuang; Goltzman, David; Miao, Dengshun; Wu, Erxi

    2013-01-01

    Epidemiological and clinical studies have indicated that low vitamin D activity is not only associated with an increased cancer risk and a more aggressive tumor growth, but also connected with an aggravated liver damage caused by chronic inflammation. Meanwhile, increasing evidence has demonstrated that 1,25(OH)₂D₃ (the most biologically active metabolite of vitamin D) can inhibit inflammatory response in some chronic inflammatory associated cancer, which is considered to have the anti-tumor potency. However, the interaction between 1,25(OH)₂D₃ and inflammation during hepatocellular carcinoma (HCC) initiation and progression is not yet clear. Here, we report an anti-tumorigenesis effect of 1,25(OH)₂D₃ via decreasing inflammatory cytokine secretion in HCC and hypothesize the possible underlying mechanism. Firstly, we show that the enhanced tumor growth is associated with elevated inflammatory cytokine IL-6 and TNF-α in 1α(OH)ase gene-knockout mice. Secondly, 1,25(OH)₂D₃ can inhibit vitamin D receptor (VDR) shRNA interfered tumor cell growth through decreasing inflammatory cytokine secretion in vitro and in vivo. Finally, using p27(kip1) gene knock-out mouse model, we demonstrate that the effect of 1,25(OH)₂D₃ in inhibiting immune cell related inflammatory cytokine secretion, exerts in a p27(kip1) gene dependent way. Collectively, 1,25(OH)₂D₃ inhibits HCC development through up-regulating the expression of p27(kip1) in immune cell and reducing inflammatory cytokine production.

  5. 1, 25(OH)2D3 Inhibits Hepatocellular Carcinoma Development Through Reducing Secretion of Inflammatory Cytokines from Immunocytes

    Science.gov (United States)

    Guo, Jian; Ma, Zhenhua; Ma, Qingyong; Wu, Zheng; Fan, Ping; Zhou, Xiaojie; Chen, Lulu; Zhou, Shuang; Goltzman, David; Miao, Dengshun; Wu, Erxi

    2014-01-01

    Epidemiological and clinical studies have indicated that low vitamin D activity is not only associated with an increased cancer risk and a more aggressive tumor growth, but also connected with an aggravated liver damage caused by chronic inflammation. Meanwhile, increasing evidence has demonstrated that 1,25(OH)2D3 (the most biologically active metabolite of vitamin D) can inhibit inflammatory response in some chronic inflammatory associated cancer, which is considered to have the anti-tumor potency. However, the interaction between 1,25(OH)2D3 and inflammation during hepatocellular carcinoma (HCC) initiation and progression is not yet clear. Here, we report an anti-tumorigenesis effect of 1,25(OH)2D3 via decreasing inflammatory cytokine secretion in HCC and hypothesize the possible underlying mechanism. Firstly, we show that the enhanced tumor growth is associated with elevated inflammatory cytokine IL-6 and TNF-α in 1α(OH)ase gene-knockout mice. Secondly, 1,25(OH)2D3 can inhibit vitamin D receptor (VDR) shRNA interfered tumor cell growth through decreasing inflammatory cytokine secretion in vitro and in vivo. Finally, using p27kip1 gene knock-out mouse model, we demonstrate that the effect of 1,25(OH)2D3 in inhibiting immune cell related inflammatory cytokine secretion, exerts in a p27kip1 gene dependent way. Collectively, 1,25(OH)2D3 inhibits HCC development through up-regulating the expression of p27kip1 in immune cell and reducing inflammatory cytokine production. PMID:23992309

  6. IL-1beta-induced chemokine and Fas expression are inhibited by suppressor of cytokine signalling-3 in insulin-producing cells

    DEFF Research Database (Denmark)

    Jacobsen, M L B; Rønn, S G; Bruun, C

    2008-01-01

    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...

  7. Role of Cytokines and Toll-Like Receptors in the Immunopathogenesis of Guillain-Barré Syndrome

    Directory of Open Access Journals (Sweden)

    Kishan Kumar Nyati

    2014-01-01

    Full Text Available Guillain-Barré syndrome (GBS is an autoimmune disease of the peripheral nervous system, mostly triggered by an aberrant immune response to an infectious pathogen. Although several infections have been implicated in the pathogenesis of GBS, not all such infected individuals develop this disease. Moreover, infection with a single agent might also lead to different subtypes of GBS emphasizing the role of host factors in the development of GBS. The host factors regulate a broad range of inflammatory processes that are involved in the pathogenesis of autoimmune diseases including GBS. Evidences suggest that systemically and locally released cytokines and their involvement in immune-mediated demyelination and axonal damage of peripheral nerves are important in the pathogenesis of GBS. Toll-like receptors (TLRs link innate and adaptive immunity through transcription of several proinflammatory cytokines. TLR genes may increase susceptibility to microbial infections; an attenuated immune response towards antigen and downregulation of cytokines occurs due to mutation in the gene. Herein, we discuss the crucial role of host factors such as cytokines and TLRs that activate the immune response and are involved in the pathogenesis of the disease.

  8. Neuroendocrine effects of cytokines in the rat.

    Science.gov (United States)

    Rivier, C

    1993-01-01

    The necessity ot maintain and/or restore homeostasis is an essential feature of mammals. This requires complex interactions between body cells, such as those from the immune and neuroendocrine systems, and in particular implies that the occurrence of immune activation be conveyed to the brain. It is now widely recognized that following infection, injury or inflammation, some immune cells (particularly macrophages) produce polypeptides called cytokines, interleukins or lymphokines /48/. These proteins provide the basis for intercellular communication between leukocytes (hence the name "interleukins") and mediate the immunoinflammatory responses (in particular T and B lymphocyte proliferation) /4,177/. In addition, interleukins (IL) can enter the general circulation and reach cells of the neuroendocrine axes, a phenomenon which represents one arm of the bidirectional communication links between the immune and the endocrine systems /25/. The early events which take place after presentation of an antigen (the so-called "acute-phase response" /89/) include metabolic and endocrine changes, such as changes in the circulating levels of insulin, TSH, GH, LH and ACTH, as well as adrenal and gonadal steroids /7,14/. This article reviews our present state of knowledge with regard to the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes of the rod