Ablation of IL-17A leads to severe colitis in IL-10-deficient mice: implications of myeloid-derived suppressor cells and NO production
INTERNATIONAL IMMUNOLOGY
Authors: Tachibana, Masashi; Watanabe, Nobumasa; Koda, Yuzo; Oya, Yukako; Kaminuma, Osamu; Katayama, Kazufumi; Fan, Zifei; Sakurai, Fuminori; Kawabata, Kenji; Hiroi, Takachika; Mizuguchi, Hiroyuki
Abstract
IL-10 is an immune regulatory cytokine and its genetic defect leads to gastrointestinal inflammation in humans and mice. Moreover, the IL-23/T(h)17 axis is known to be involved in these inflammatory disorders. IL-17A, a representative cytokine produced by T(h)17 cells, has an important role for the pathological process of inflammatory diseases. However, the precise function of IL-17A in inflammatory bowel disease (IBD) remains controversial. In this study, we evaluated the effect of IL-17A on colitis in IL-10-deficient (Il10(-/-)) mice. Mice lacking both IL-10 and IL-17A (Il10(-/-)Il17a(-/-)) suffered from fatal wasting and manifested more severe colitis compared with Il10(-/-)Il17a(+/-) mice. Moreover, we found that CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) accumulated in the bone marrow, spleen and peripheral blood of Il10(-/-)Il17a(-/-) mice. These MDSCs highly expressed inducible nitric oxide synthase (iNOS) (Nos2) and suppressed the T-cell response in vitro in a NOS-dependent manner. In correlation with these effects, the concentration of nitric oxide was elevated in the serum of Il10(-/-)Il17a(-/-) mice. Surprisingly, the severe colitis observed in Il10(-/-)Il17a(-/-) mice was ameliorated in Il10(-/-)Il17a(-/-)Nos2(-/-) mice. Our findings suggest that IL-17A plays suppressive roles against spontaneous colitis in Il10(-/-) mice in an iNOS-dependent manner and inhibits MDSC differentiation and/or proliferation.
IL17A polymorphism and elevated IL17A serum levels are associated with oral lichen planus
ORAL DISEASES
Authors: Gueiros, L. A.; Arao, T.; Souza, T.; Vieira, C. L.; Gomez, R. S.; Almeida, O. P.; Lodi, G.; Leao, J. C.
Abstract
ObjectiveThe aim of this study was to evaluate the association of IL17A G197A polymorphism and serum levels with oral lichen planus (OLP) susceptibility and clinical presentation. Subjects and MethodsEighty-three individuals diagnosed with OLP and 99 healthy controls (C) were consecutively recruited. All participants had desquamating oral mucosal cells collected and DNA isolated for IL17A (G197A) genotyping. Blood samples of 42 OLP individuals and 23 healthy controls were collected for evaluation of IL17A serum levels. ResultsIL17A G197A genotypes were associated with an increased chance of having OLP (GA/AAxGG, OR=3.44, 95% CI=1.87-6.33, p<.001). Overall A carriers (GA or AA) were more common in OLP (38.1%) than in C (20.2%; OR=2.43, 95% CI=1.53-3.87, p<.001). Serum levels of IL17A were higher among patients with OLP than in healthy controls (reticular, p=.0003; erosive, p<.001), but no difference was found among the disease types. ConclusionsIL17A G197A is associated with a higher susceptibility of developing OLP and these patients seem to present a considerable increase in IL17A serum levels. These findings suggest that Th17 cells, and IL17A in particular, may play a pivotal role in OLP pathogenesis.