Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice

Interleukin (IL)-18 is functionally similar to IL-12. in mediating T helper cell type 1 (Th1) response and natural killer (NK) cell activity bur is re lated to IL-1 in protein structure and signaling, including recruitment of IL-1 receptor-associated kinase (IRAK) to the receptor and activation of c- Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-kappa B. The role of IRAK in IL-18-induced responses was studied in IRAK-deficient mice. Signifi cant defects in JNK induction and partial impairment in NF-kappa D activati on were found ill IRAK-deficient Th1 cells, resulting in a dramatic decreas e in interferon (IFN)-gamma mRNA expression. In vivo Th1 response to Propio nibacterium acnes and lipopolysaccharide ill IFN-gamma production and induc tion of NK cytotoxicity by IL-18 were severely impaired in IRAK-deficient m ice. IFN-gamma production by activated NK cells in an acute murine cytomega lovirus infection was significantly reduced despite normal induction of NK cytotoxicity. These results demonstrate that IRAK plays all important role in IL-18-induced signaling and function.