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      The IL-17A G-197A and IL-17F 7488T/C polymorphisms are associated with increased risk of cancer in Asians: a meta-analysis


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          Interleukin-17 (IL-17) is a family of emerged pro-inflammatory cytokines. The IL-17A and IL-17F are two important members of IL-17 family. Previous studies have shown that the functional IL-17A G-197A and IL-17F 7488T/C polymorphisms may contribute to susceptibility to cancer but the results were inconclusive. This meta-analysis was performed to determine the exact association between IL-17 polymorphisms and cancer risk.


          Online databases were searched to identify eligible case–control studies. Pooled odds ratios (ORs) and confidence intervals (CIs) were calculated by fixed-effect models or random-effect models. Publication bias was detected by Egger’s test and Begg’s test.


          Nine eligible case–control studies of IL-17A G-197A and seven studies of IL-17F 7488T/C, including 3,181 cases and 4,005 controls, were identified. Pooled analysis suggested the variant IL-17A-197A allele was associated with increased risk cancer (GA/AA vs GG, OR =1.27, 95% CI: 1.15, 1.41, P heterogeneity =0.374; and A vs G, OR =1.30, 95% CI: 1.17, 1.45, P heterogeneity =0.021). For IL-17F 7488T/C, the homozygote 7488CC genotype significantly increased risk of cancer (CC vs TC/TT, OR =1.36, 95% CI: 0.97, 1.91, P heterogeneity =0.875; and CC vs TT, OR =1.39, 95% CI: 1.03, 1.88, P heterogeneity =0.979), especially for gastric cancer.


          The variant IL-17A-197A allele and IL-17F 7488CC genotype were associated with increased risk of cancer, especially for gastric cancer.

          Most cited references19

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          Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17.

          The C-type lectin dectin-1 binds to yeast and signals through the kinase Syk and the adaptor CARD9 to induce production of interleukin 10 (IL-10) and IL-2 in dendritic cells (DCs). However, whether this pathway promotes full DC activation remains unclear. Here we show that dectin-1-Syk-CARD9 signaling induced DC maturation and the secretion of proinflammatory cytokines, including IL-6, tumor necrosis factor and IL-23, but little IL-12. Dectin-1-activated DCs 'instructed' the differentiation of CD4+ IL-17-producing effector T cells (T(H)-17 cells) in vitro, and a dectin-1 agonist acted as an adjuvant promoting the differentiation of T(H)-17 and T helper type 1 cells in vivo. Infection with Candida albicans induced CARD9-dependent T(H)-17 responses to the organism. Our data indicate that signaling through Syk and CARD9 can couple innate to adaptive immunity independently of Toll-like receptor signals and that CARD9 is required for the development of T(H)-17 responses to some pathogens.
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            Th17 cell differentiation: the long and winding road.

            The characterization of the new lineage of IL-17-producing CD4+ T helper (Th17) cells has revolutionized our current understanding of T cell-mediated immunity. Over the past five years, there have been many twists and turns as the pathways that lead to Th17 cell differentiation have been elucidated. Not least of these was the discovery that TGF-beta is a crucial cytokine for Th17 cell development, suggesting that Th17 and regulatory T cell subsets share reciprocal developmental pathways during the pathogenesis or control of inflammation. This review aims to bring together the observations that have formed current opinion on factors that promote and contain Th17 cell development, in both mouse and man. Unresolved controversies in this field are also discussed: For example, IL-23 is absolutely required for disease pathogenesis in many models of Th17-cell-mediated autoimmunity, yet its role in Th17 cell development is relatively unclear.
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              Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines.

              IL-17 is a cytokine produced by CD4 T cells that activates the production of inflammatory mediators by synoviocytes. To study the contribution of soluble factors in the interaction between T cells and synoviocytes in rheumatoid arthritis (RA), we looked at the effect of IL-17 on these cells in the presence of cytokines classified as pro (IL-1)- and anti-inflammatory (IL-4, IL-13, IL-10). Both human rIL-1beta and rIL-17 induced IL-6 and leukemia inhibitory factor (LIF) production by synovial fibroblasts in a dose-dependent manner. After 7 days of culture, optimal concentrations of IL-1beta increased IL-6 (33-fold) and LIF (10-fold) production by synoviocytes, while IL-17 showed a lesser effect on IL-6 (17-fold) and LIF (4-fold) production. Using low concentrations of IL-17 and IL-1beta in combination, a synergistic effect was observed on the production of IL-6, whereas an additive effect was observed for LIF production. Production of biologically active IL-17 was demonstrated in RA synovium supernatants with the use of a blocking anti-IL-17 Ab. Both IL-4 and IL-13 had a modest stimulatory effect on IL-1- and IL-17-induced production of IL-6, but inhibited that of LIF. In contrast, IL-10 had a limited inhibitory effect on IL-6 production and no effect on that of LIF. These findings indicate that low levels of cytokines produced by monocytes (IL-1) and T cells (IL-17) can act together on synoviocytes. Thus, some RA synovium T cells producing IL-17 can activate mesenchymal cells leading to an increased proinflammatory pattern sensitive to Th2 cytokine regulation.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                24 September 2015
                : 9
                : 5159-5168
                [1 ]Department of Gastroenterology, China-Japan Friendship Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
                [2 ]Center for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
                [3 ]Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China
                Author notes
                Correspondence: Shiyu Du, Department of Gastroenterology, China-Japan Friendship Hospital, 2 Yinghua Dongjie, Chaoyang, Beijing 100029, People’s Republic of China, Tel +86 10 8420 5504, Fax +86 10 8420 5504, Email dushiyu1975@ 123456126.com

                These authors contributed equally to this work

                © 2015 Wang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                interleukin-17,gene polymorphism,gastric cancer,risk,meta-analysis


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