Stimulus-specific induction of a novel nuclear factor-kappaB regulator, IkappaB-zeta, via Toll/Interleukin-1 receptor is mediated by mRNA stabilization

Abstract

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