Background/Purpose: IL-17A (IL-17) is a proinflammatory cytokine that contributes to the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA), multiple sclerosis (MS) and psoriasis. Despite limited homology with the toll-like receptors, IL-17 receptor subunits (IL-17RA and IL-17RC) do not recruit TLR-associated adaptors such as MyD88, but instead associate with the adaptor protein Act1/CIKS. Upon recruitment, Act1 activates pro-inflammatory signaling pathways including TRAF6/NF-kappaB, MAPK and CCAAT Enhancer Binding Proteins (C/EBP) Despite advances in identifying molecular events downstream of IL-17 signal transduction, mechanisms by which IL-17 signaling is constrained remain poorly understood. Ubiquitination is a central post-translational signaling mechanism involved in activation of inflammation, particularly the NF-kappaB pathway. Notably, both Act1 and Traf6 exhibit E3 ubiquitin ligase activity. Genome analysis has identified over 100 deubiquitinases (DUBs) in humans but their role in IL-17 signaling is unknown. Polymorphisms in the gene encoding the DUB A20 (Tnfaip3) are associated with autoimmune diseases including RA and psoriasis. A20 was originally defined as an inhibitor of the TNF signaling pathway. Here, we show that A20 also participates in downregulating the IL-17 signaling pathway.

Methods: IL-17 signaling was assessed in the stromal cell line ST2. Regulation of IL-17-induced genes was assessed by combinations of siRNA silencing, quantitative real-time RT-PCR (qPCR), immunoblotting and luciferase analyses. Association of receptor-associated proteins was determined by co-immunoprecipitation.

Results: IL-17 induced A20 expression, and transient knockdown of A20 resulted in increased IL-17-dependent proinflammatory target gene expression. Consistently, overexpression of A20 inhibits IL-17 target gene expression, which was associated with reduced NF-κB activity. Interestingly, A20 associated with IL-17RA at a motif that was previously linked to negative regulation of the IL-17 signaling pathway.

Conclusion: We show for the first time that A20 is an inhibitor of the IL-17 signaling pathway. This provides a new mechanistic explanation for the role of A20 in regulating autoimmune disease. Moreover, regulation of A20 could serve as a potential target for pharmacologic manipulation of inflammatory signaling in autoimmunity.

---

« Back to 2012 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-interleukin-17-signaling-via-de-ubiquitinatio/