IkappaBNS inhibits induction of a subset of Toll-like receptor-dependent genes and limits inflammation.
Toll-like receptor (TLR)-mediated immune responses are downregulated by several mechanisms that affect signaling pathways. However, it remains elusive how TLR-mediated gene expression is differentially modulated. Here, we show that IkappaBNS, a TLR-inducible nuclear IkappaB protein, negatively regulates induction of a subset of TLR-dependent genes through inhibition of NF-kappaB activity. IkappaBNS-deficient macrophages and dendritic cells show increased TLR-mediated expression of genes such as IL-6 and IL-12p40, which are induced late after TLR stimulation. In contrast, IkappaBNS-deficient cells showed normal induction of genes that are induced early or induced via IRF-3 activation. LPS stimulation of IkappaBNS-deficient macrophages prolonged NF-kappaB activity at the specific promoters, indicating that IkappaBNS mediates termination of NF-kappaB activity at selective gene promoters. Moreover, IkappaBNS-deficient mice are highly susceptible to LPS-induced endotoxin shock and intestinal inflammation. Thus, IkappaBNS regulates inflammatory responses by inhibiting the induction of a subset of TLR-dependent genes through modulation of NF-kappaB activity.
Kuwata
Hirotaka
H
Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Matsumoto
Makoto
M
Atarashi
Koji
K
Morishita
Hideaki
H
Hirotani
Tomohiro
T
Koga
Ritsuko
R
Takeda
Kiyoshi
K
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D003106:Colon / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000235:genetics; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D021122:Protein Subunits / Q000037:antagonists & inhibitors* / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D015854:Up-Regulation; D000093242:Interleukin-6 Inhibitors
D018664:Interleukin-12; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D021122:Protein Subunits; D011506:Proteins; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D000093242:Interleukin-6 Inhibitors; C454819:Nfkbid protein, mouse