Identification of interleukin‐1 receptor‐associated kinase 1 as a critical component that induces post‐transcriptional activation of IκB‐ζ

IκB‐ζ, an essential inflammatory regulator, is specifically induced by Toll‐like receptor ligands or interleukin (IL)‐1β by post‐transcriptional activation mediated via a 165‐nucleotide element in IκB‐ζ mRNA. Here, we analyzed the Toll‐like receptor–IL‐1 receptor signaling components involved in the post‐transcriptional regulation of IκB‐ζ 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 IκB‐ζ. The tumor necrosis factor receptor‐associated factor (TRAF)6–ER(T2) protein activated nuclear factor‐κB, 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‐κB activation and the post‐transcriptional activation bifurcates at IRAK1, suggesting a new pathway activated by IRAK1.