Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta.
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.
Yamamoto
Masahiro
M
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita Osaka, Japan.
Yamazaki
Soh
S
Uematsu
Satoshi
S
Sato
Shintaro
S
Hemmi
Hiroaki
H
Hoshino
Katsuaki
K
Kaisho
Tsuneyasu
T
Kuwata
Hirotaka
H
Takeuchi
Osamu
O
Takeshige
Koichiro
K
Saitoh
Tatsuya
T
Yamaoka
Shoji
S
Yamamoto
Naoki
N
Yamamoto
Shunsuke
S
Muta
Tatsushi
T
Takeda
Kiyoshi
K
Akira
Shizuo
S
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
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