Stimulus-specific induction of a novel nuclear factor-κB regulator, IκB-ζ, via toll/interleukin-1 receptor is mediated by mRNA stabilization

We have recently identified an inducible nuclear factor-κB (NF-κB) regulator, IκB-ζ, which is induced by microbial ligands for Toll-like receptors such as lipopolysaccharide and the proinflammatory cytokine interleukin (IL)-1β but not by tumor necrosis factor (TNF)-α. In the present study, we examined mechanisms for stimulus-specific induction of IκK-ζ. The analysis of the IκB-ζ promoter revealed an essential role for an NF- κB·binding sequence in transcriptional activation. The activation, however, did not account for the Toll-like receptor/IL-1 receptor-specific induction of IκB-ζ, because the promoter analysis and nuclear run-on analysis indicated that its transcription was similarly induced by TNF-α. To examine post-transcriptional regulation, we analyzed the decay of IκB-ζ mRNA, and we found that it was specifically stabilized by lipopolysaccharide or IL-1β but not by TNF-α. Furthermore, we found that costimulation with TNF-α and another proinflammatory cytokine, IL-17, elicited the IκB-ζ induction. Stimulation with IL-17 alone did not induce IκB-ζ but stabilized its mRNA. Therefore, IκB-ζ induction requires both NF-κB activation and stimulus-specific stabilization of its mRNA. Because IκB-ζ is essential for expression of a subset of NF-κB target genes, the stimulus-specific induction of IκB-ζ may be of great significance in regulation of inflammatory reactions.