Characterization of the IL -18 receptor and SIGIRR, members of the IL -1 /Toll receptor superfamily

The Toll/IL-1 receptor superfamily, highly conserved from Drosophila to humans, plays crucial roles in the immune response. Two recently identified members of this superfamily are the IL-18R and SIGIRR. IL-18, a pleitropic cytokine produced by activated macrophages, plays significant roles in the immune response, inducing the secretion of IFNgamma, TNFalpha and IL-2, enhancing NK cell activity and potentiating the differentiation of Th1 cells. The intracellular signal transduction pathways through which IL-18 functions have not been thoroughly defined. Utilizing a mutant cell line, I1A, which lacks the IRAK protein and has low or no expression of the other known IRAK family members, we find that IRAK is essential for the activation of NF-kappaB and JNK in response to IL-18. Furthermore the death domain, but not the kinase activity of IRAK, is necessary for NFkappaB activation. Interestingly, the N-proximal undetermined region of IRAK is necessary for NFkappaB activation, but not for JNK activation in response to IL-18, indicating that IRAK maybe at a branchpoint in IL-18 signaling. In addition to IRAK, we implicate two other components in IL-18 signaling, TAK1 (TGFbeta activated kinase 1) and its activator and substrate TAB1. A dominant negative mutant of TAK1 inhibits IL-18-mediated NFkappaB activation, while stimulation with IL-18 leads to the phosphorylation of TAB1. Finally, analysis of IL-18 signaling in several different IL-1-unresponsive mutant cell lines suggests that the IL-1- and IL-18-mediated pathways are similar, but not identical.;Besides the IL-18R, SIGIRR another member of the Toll/IL-1 R superfamily has been analyzed. SIGIRR, a novel receptor that does not induce the production of inflammatory cytokines, instead negatively modulates responses. Through construction of a SIGIRR-null mouse, SIGIRR was found to play significant roles in the immune response. Inflammation is enhanced in SIGIRR-null mice as measured by enhanced chemokine induction after IL-1 injection and a reduced threshold for lethal endotoxin challenge. Cells from SIGIRR-null mice show enhanced activation in response to either IL-1 or certain Toll ligands. Finally, biochemical analysis indicates that SIGIRR binds to the Toll/IL-1R signaling components in a ligand-dependent manner. Our data reveals that SIGIRR functions as a biologically important modulator of Toll/IL-1R signaling.