title: Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta.
abstract: Toll-like receptors (TLRs) recognize microbial components and trigger the inflammatory and immune responses against pathogens. IkappaBzeta (also known as MAIL and INAP) is an ankyrin-repeat-containing nuclear protein that is highly homologous to the IkappaB family member Bcl-3 (refs 1-6). Transcription of IkappaBzeta is rapidly induced by stimulation with TLR ligands and interleukin-1 (IL-1). Here we show that IkappaBzeta is indispensable for the expression of a subset of genes activated in TLR/IL-1R signalling pathways. IkappaBzeta-deficient cells show severe impairment of IL-6 production in response to a variety of TLR ligands as well as IL-1, but not in response to tumour-necrosis factor-alpha. Endogenous IkappaBzeta specifically associates with the p50 subunit of NF-kappaB, and is recruited to the NF-kappaB binding site of the IL-6 promoter on stimulation. Moreover, NF-kappaB1/p50-deficient mice show responses to TLR/IL-1R ligands similar to those of IkappaBzeta-deficient mice. Endotoxin-induced expression of other genes such as Il12b and Csf2 is also abrogated in IkappaBzeta-deficient macrophages. Given that the lipopolysaccharide-induced transcription of IkappaBzeta occurs earlier than transcription of these genes, some TLR/IL-1R-mediated responses may be regulated in a gene expression process of at least two steps that requires inducible IkappaBzeta.
authors.affiliation: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Soh
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sato
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hemmi
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Hoshino
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kuwata
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Takeshige
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Saitoh
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamaoka
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Muta
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007700:Kinetics; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015850:Interleukin-6; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12