Identification of interleukin-1 receptor-associated kinase 1 as a critical component that induces post-transcriptional activation of I?B-?

I?B-?, an essential inflammatory regulator, is specifically induced by Toll-like receptor ligands or interleukin (IL)-1 beta by post-transcriptional activation mediated via a 165-nucleotide element in I B- mRNA. Here, we analyzed the Toll-like receptorIL-1 receptor signaling components involved in the post-transcriptional regulation of I?B-? with mutated estrogen receptor [ER(T2)] fusion proteins. Upon 4-hydroxytamoxifen treatment, the ER(T2) fusion proteins with IL-1 receptor-associated kinase (IRAK)1 and IRAK4 elicited specific activation of a reporter gene for the post-transcriptional regulation of I?B-?. The tumor necrosis factor receptor-associated factor (TRAF)6ER(T2) protein activated nuclear factor-?B, but not post-transcriptional regulation, indicating that activation of IRAK1/4, but not of TRAF6, is sufficient to activate the 165-nucleotide element-mediated post-transcriptional mechanism. Interestingly, the post-transcriptional mechanism was not activated in TRAF6-deficient cells, indicating an essential role for TRAF6. Thus, the signaling pathway leading to nuclear factor-?B activation and the post-transcriptional activation bifurcates at IRAK1, suggesting a new pathway activated by IRAK1.