Stimulus-specific induction of a novel nuclear factor-kappaB regulator, IkappaB-zeta, via Toll/Interleukin-1 receptor is mediated by mRNA stabilization.
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.
Yamazaki
Soh
S
Department of Molecular and Cellular Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Muta
Tatsushi
T
Matsuo
Susumu
S
Takeshige
Koichiro
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003609:Dactinomycin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D020381:Interleukin-17 / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D016366:Open Reading Frames / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D013379:Substrate Specificity; D051193:Toll-Like Receptors; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D007375:Interleukin-1; D020381:Interleukin-17; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin