Activated IL-1R1 Signaling Pathway Induces Th17 Cell Differentiation in Patients with Relapsing Remitting Multiple Sclerosis (83.18)

Abstract

Abstract BACKGROUND: IL-1β plays a crucial role in the development of human Th17 cells. However, its mechanisms of action are still not completely elucidated. Recent has study discovered that Th17 cells are characterized by IL-1R1 expression. RESULTS: Our study has revealed that IL-1R1 and IL-1R2 gene expression is significantly increased in both naïve and memory CD4+ T-cells derived from patients with relapsing-remitting multiple sclerosis (RRMS) in comparison to matched healthy controls. IL-1R1 expression is up-regulated in the in vitro differentiated Th17 cells in comparison to the Th1 and Th2 cell subsets. IL-17A production was induced by IL-1β. This induction was blocked by IL-1R antagonist in the naïve CD4+cells cultured in the presence of Th17 polarizing cytokines. When IL-1R1 gene expression was silenced using siRNA, human naïve CD4+ T-cells cultured in the presence of Th17 polarizing cytokines had a significantly decreased expression of IL-21, IL-22, IL-23R, IRF4, RORC, IL-17A and IL-17F genes, confirming that IL-1R1 signaling induces Th17 cell differentiation. IRF4 gene expression silencing, similarly inhibited Th17 cell differentiation in the presence of IL-1b, indicating that IL-1R1 signals upstream of IRF4. CONCLUSION: Our study has identified that IL-1R1-mediated signaling pathway may be constitutively activated, leading to an increased Th17 cell expansion and autoimmune response in patients with RR MS.