The interleukin-1 receptor-associated kinase M selectively inhibits the alternative, instead of the classical NFkappaB pathway.

The innate immunity signaling process is controlled by numerous positive and negative regulators. The interleukin-1 receptor-associated kinase M (IRAK-M) is one of the negative regulators that contribute to the attenuation of NFkappaB activation. The molecular mechanism involved, however, is poorly defined. In this report, we observed that IRAK-M selectively suppresses the NIK-IKKalpha-mediated alternative NFkappaB pathway. Deletion of IRAK-M led to NIK stabilization, favored the formation of the IKKalpha/IKKalpha homodimer instead of the IKKalpha/IKKbeta heterodimer, and enhanced RelB nuclear distribution. In contrast, p65 nuclear localization and phosphorylation was not affected by IRAK-M deficiency. IRAK-M-deficient cells exhibited increased expression of selected cytokines such as IL-6 and GM-CSF, as well as quickened resynthesis of IkappaBalpha. The increased expression of IL-6 and GM-CSF was ablated when RelB expression was knocked down using specific siRNA. We also demonstrated that the observed inhibitory effect of IRAK-M was primarily limited to the TLR2 ligand, instead of TLR4. Taken together, our findings suggest that IRAK-M negatively regulates the alternative NFkappaB pathway in a ligand-specific manner.