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.
Su
Jianmin
J
Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
Zhang
Tongli
T
Tyson
John
J
Li
Liwu
L
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D051550:I-kappa B Kinase / Q000378:metabolism; D007113:Immunity, Innate / Q000502:physiology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism
D016328:NF-kappa B; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse; D051550:I-kappa B Kinase