NDR 1 protein kinase promotes IL ‐17‐ and TNF ‐α‐mediated inflammation by competitively binding TRAF 3

Interleukin 17 ( IL ‐17) is an important inducer of tissue inflammation and is involved in numerous autoimmune diseases. However, how its signal transduction is regulated is not well understood. Here, we report that nuclear Dbf2‐related kinase 1 ( NDR 1) functions as a positive regulator of IL ‐17 signal transduction and IL ‐17‐induced inflammation. NDR 1 deficiency or knockdown inhibits the IL ‐17‐induced phosphorylation of p38, ERK 1/2, and p65 and the expression of chemokines and cytokines, whereas the overexpression of NDR 1 promotes IL ‐17‐induced signaling independent of its kinase activity. Mechanistically, NDR 1 interacts with TRAF 3 and prevents its binding to IL ‐17R, which promotes the formation of an IL ‐17R‐Act1‐ TRAF 6 complex and downstream signaling. Consistent with this, IL ‐17‐induced inflammation is significantly reduced in NDR 1‐ deficient mice, and NDR 1 deficiency significantly protects mice from MOG ‐induced experimental autoimmune encephalomyelitis ( EAE ) and 2,4,6‐trinitrobenzenesulfonic acid ( TNBS )‐induced colitis likely by its inhibition of IL ‐17‐mediated signaling pathway. NDR 1 expression is increased in the colons of ulcerative colitis ( UC ) patients. Taken together, these findings suggest that NDR 1 is involved in the development of autoimmune diseases.