TY - JOUR
T1 - IκBNS inhibits induction of a subset of toll-like receptor-dependent genes and limits inflammation
AU - Kuwata, Hirotaka
AU - Matsumoto, Makoto
AU - Atarashi, Koji
AU - Morishita, Hideaki
AU - Hirotani, Tomohiro
AU - Koga, Ritsuko
AU - Takeda, Kiyoshi
N1 - Funding Information:
We thank Y. Yamada, K. Takeda, M. Otsu, and N. Kinoshita for technical assistance; M. Yamamoto and S. Akira for providing us with reagents, P. Lee for critical reading of the manuscript, and M. Kurata for secretarial assistance. This work was supported by grants from the Special Coordination Funds of the Ministry of Education, Culture, Sports, Science and Technology; the Uehara Memorial Foundation; the Mitsubishi Foundation; the Takeda Science Foundation; the Tokyo Biochemical Research Foundation; the Kowa Life Science Foundation; the Osaka Foundation for Promotion of Clinical Immunology; and the Sankyo Foundation of Life Science.
PY - 2006/1
Y1 - 2006/1
N2 - 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 IκBNS, a TLR-inducible nuclear IκB protein, negatively regulates induction of a subset of TLR-dependent genes through inhibition of NF-κB activity. IκBNS-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, IκBNS-deficient cells showed normal induction of genes that are induced early or induced via IRF-3 activation. LPS stimulation of IκBNS-deficient macrophages prolonged NF-κB activity at the specific promoters, indicating that IκBNS mediates termination of NF-κB activity at selective gene promoters. Moreover, IκBNS-deficient mice are highly susceptible to LPS-induced endotoxin shock and intestinal inflammation. Thus, IκBNS regulates inflammatory responses by inhibiting the induction of a subset of TLR-dependent genes through modulation of NF-κB activity.
AB - 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 IκBNS, a TLR-inducible nuclear IκB protein, negatively regulates induction of a subset of TLR-dependent genes through inhibition of NF-κB activity. IκBNS-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, IκBNS-deficient cells showed normal induction of genes that are induced early or induced via IRF-3 activation. LPS stimulation of IκBNS-deficient macrophages prolonged NF-κB activity at the specific promoters, indicating that IκBNS mediates termination of NF-κB activity at selective gene promoters. Moreover, IκBNS-deficient mice are highly susceptible to LPS-induced endotoxin shock and intestinal inflammation. Thus, IκBNS regulates inflammatory responses by inhibiting the induction of a subset of TLR-dependent genes through modulation of NF-κB activity.
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U2 - 10.1016/j.immuni.2005.11.004
DO - 10.1016/j.immuni.2005.11.004
M3 - Article
C2 - 16413922
AN - SCOPUS:30444456370
SN - 1074-7613
VL - 24
SP - 41
EP - 51
JO - Immunity
JF - Immunity
IS - 1
ER -
