LRRFIP1 negatively regulates IL-17 signalling by binding to CIKS

Interleukin-17 (IL-17), the signature cytokine produced by T helper 17 (Th17) cells, plays crucial roles in host defense against microbial organisms and in the development of inflammatory diseases. IL-17 promotes the expression of cytokines and proteins involved in inflammatory responses, via the induction of gene transcription and post-transcription stabilization of mRNA. These functions are mediated by CIKS, an adaptor protein that is recruited to the receptor after IL-17 stimulation. We shows here that LRRFIP1 isoform 3 is a new CIKS interactor. Overexpression of LRRFIP1 isoform 3 blocks the IL-17 induced gene expression, via down-regulation of NF-?B and AP-1. Accordingly, down-regulation of LRRFIP1 enhanced the expression of cxcl1 and il-6 after IL-17 stimulation. LRRFIP 1 isoform 3 exerts this function by interfering with the recruitment of CIKS to the cytoplasmic domain of the IL-17 receptor. Collectively our finding defines a new mechanism regulating the inflammatory response.