IκBNS inhibits induction of a subset of toll-like receptor-dependent genes and limits inflammation
IκBNS inhibits induction of a subset of toll-like receptor-dependent genes and limits inflammation
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DOI：
10.1016/j.immuni.2005.11.004
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发表时间：
2006-01-01
期刊：
影响因子：
32.4
通讯作者：
Takeda, K
中科院分区：
文献类型：
--
作者：
Kuwata, H;Matsumoto, M;Takeda, K
toll样受体（TLR）介导的免疫反应被影响信号通路的几种机制下调。然而，tlr介导的基因表达是如何被差异调节的尚不清楚。在这里，我们发现I kappa BNS是一种tlr诱导的核I kappa B蛋白，通过抑制NF-kappa B活性负向调节tlr依赖性基因亚群的诱导。I kappa bns缺陷巨噬细胞和树突状细胞显示TLR介导的IL-6和IL-12p40等基因表达增加，这些基因是TLR刺激后晚期诱导的。相比之下，I kappa bns缺陷细胞对早期诱导或通过IRF-3激活诱导的基因表现出正常的诱导。LPS刺激I kappa BNS缺陷巨噬细胞可延长特异性启动子NF-kappa B活性，表明I kappa BNS介导了选择性基因启动子NF-kappa B活性的终止。此外，I kappa bns缺陷小鼠极易发生lps诱导的内毒素休克和肠道炎症。因此，I kappa BNS通过调节NF-kappa B活性，抑制tlr依赖性基因亚群的诱导，从而调节炎症反应。
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 I kappa BNS, a TLR-inducible nuclear I kappa B protein, negatively regulates induction of a subset of TLR-dependent genes through inhibition of NF-kappa B activity. I kappa BNS-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, I kappa BNS-deficient cells showed normal induction of genes that are induced early or induced via IRF-3 activation. LPS stimulation of I kappa BNS-deficient macrophages prolonged NF-kappa B activity at the specific promoters, indicating that I kappa BNS mediates termination of NF-kappa B activity at selective gene promoters. Moreover, I kappa BNS-deficient mice are highly susceptible to LPS-induced endotoxin shock and intestinal inflammation. Thus, I kappa BNS regulates inflammatory responses by inhibiting the induction of a subset of TLR-dependent genes through modulation of NF-kappa B activity.