Title: The Functional Mechanisms of IL-17 Family Cytokines

Presenter: Prof. Qian Youcun

University: Institute of Health Sciences, SIBS, CAS

Time: 10:00-11:30, January 10, 2013

Venue: Room A102, Institute of Microbiology, Chinese Academy of Sciences

Abstract: Interleukin-17A (IL-17A or IL-17), produced by Th17 cells as well as innate immune cells, not only plays a critical role in host defense against infections but also contributes to the inflammatory pathogenesis of autoimmune diseases. Its functional mechanisms remain incompletely understood. Here we identify a novel mechanism for IL-17 through regulation of miR-23b expression during autoimmune pathogenesis. miR-23b was commonly downregulated in inflammatory lesions of humans with lupus or rheumatoid arthritis, as well as in the mouse models of lupus, rheumatoid arthritis or multiple sclerosis, where IL-17 was upregulated. IL-17 downregulated miR-23b expression in primary stromal cells and was essential for the downregulation of miR-23b during autoimmune pathogenesis. In turn, miR-23b suppressed IL-17-, TNF-α or IL-1β-induced NF-κB activation and inflammatory cytokine expression by targeting TAB2, TAB3 and IKK-α and, consequently, repressed autoimmune inflammation. Thus, IL-17 contributes to autoimmune pathogenesis by suppressing miR-23b expression in radio-resistant resident cells and promoting proinflammatory cytokine expression.

IL-17 family contains six cytokines (IL-17A to IL-17F). IL-17A and IL-17F are critical for host defense against bacterial infections while IL-17E (also named IL-25) is essential for Th2 mediated biology. The function of the other cytokines is not well understood. Here we found that IL-17C is the cytokine for the orphan receptor, Interleukin 17 receptor E (IL-17RE), and plays an essential role in host mucosal defense against bacterial infection. IL-17C activated downstream signaling through IL-17RE-IL-17RA complex for the induction of genes encoding antibacterial peptides as well as proinflammatory molecules. IL-17C was upregulated in colon epithelial cells during infection with Citrobacter rodentium and acted in synergy with IL-22 to induce the expression of antibacterial peptides in colon epithelial cells. Loss of IL-17C-mediated signaling in IL-17RE-deficient mice led to lower expression of genes encoding antibacterial molecules, greater bacterial burden and early mortality during infection. Together our data identify IL-17RE as a receptor of IL-17C that regulates early innate immunity to intestinal pathogens.