It was then shown that culture of T cells from IL-1R1-deficient m

It was then shown that culture of T cells from IL-1R1-deficient mice which cannot

respond to IL-1β, exhibited substantially less IL-17 bias than WT T cells when co-cultured with R258W CD11b+ cells. Similar results were obtained when T cells were co-cultured with supernatants of R258W KI APC. Taken together, these findings indicate that the KI APCs act on differentiating CD4+ T cells to favor Th17-cell differentiation via IL-1β, providing that the T cells have undergone initial Th17-inductive steps. It should be noted, however, that as there was residual Th17-cell bias in the studies using IL-1R1−/− cells, other factors secreted by APC from R258W KI mice may also play a role in inducing beta-catenin inhibitor Th17-cell differentiation 9. Parallel studies of T-cell differentiation directed by APC from A350V and L351P KI mice were

conducted with antigen-specific T cells. It was found that these APC exhibited a normal capacity to induce T cells to differentiate into any type of T-cell lineage under subset-specific conditions, and exhibited only a modest bias toward IL-17 under neutral conditions. This result was consistent with the fact that skin inflammation in these mice did not show an IL-17 cytokine bias. This discrepancy may be due to the fact that these in vitro studies were not conducted under conditions that allowed initial Th17-cell induction and thus did not assess IL-1β effects at an appropriate phase of T-cell differentiation 9, 10. The mechanism underlying the Th17-cell CT99021 bias in the inflammasome-associated inflammation noted above for R258W KI mice is not fully understood. Previous studies have shown that IL-1β together with TNF-α can augment TGF-β/IL-6-induced Th17-cell differentiation and that in fact IL-6 induces IL-1R1 expression on T cells 24, 25. In addition, IL-1β has been shown to upregulate factors that induce/enhance IL-17 transcription, such as RORγt and IRF-4 24, 26; however, Phosphatidylinositol diacylglycerol-lyase the molecular mechanism underlying this upregulation is not known. As for the fact that the inflammasome-associated

inflammation is marked by decreased IFN-γ as well as increased IL-17 production, it may be due to the fact that IL-1β downregulates IL-6-induced STAT-1 activation and thereby inhibits T-bet transcription 27. Additionally, it was observed that the inflamed tissue of the KI mice exhibited decreased IL-12Rβ2 expression and that treatment of mice with anti-IL-1R1 reversed this effect. Thus, IL-1β may inhibit IL-12p70 induction of STAT-4 activation, the essential initial step in Th1-cell development 28. Given the well-known propensity of IL-17 to induce a neutrophil-rich inflammation 29, 30, the Th17-cell bias inherent in inflammasome activity may be a major reason why neutrophils are a major component of autoinflammation in CAPS.

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