Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta.
Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IkappaBzeta.
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发表时间：
2004
期刊：
影响因子：
64.8
通讯作者：
Masahiro Yamamoto;S. Yamazaki;S. Uematsu;Shintaro Sato;H. Hemmi;K. Hoshino;T. Kaisho;H. Kuwata;O. Takeuchi;K. Takeshige;T. Saitoh;S. Yamaoka;N. Yamamoto;Shunsuke Yamamoto;T. Muta;K. Takeda;S. Akira
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作者：
Masahiro Yamamoto;S. Yamazaki;S. Uematsu;Shintaro Sato;H. Hemmi;K. Hoshino;T. Kaisho;H. Kuwata;O. Takeuchi;K. Takeshige;T. Saitoh;S. Yamaoka;N. Yamamoto;Shunsuke Yamamoto;T. Muta;K. Takeda;S. Akira
Toll样受体(Toll-like Receptor，TLRs)识别微生物成分，触发针对病原体的炎症和免疫反应。IkappaBzeta(又称Mail和INAP)是一种含有Ankyrin重复序列的核蛋白，与IkappaB家族成员Bcl3高度同源(参考文献1-6)。IkappaBzeta的转录在TLR配体和白介素1(IL-1)的刺激下迅速被诱导。在这里，我们表明IkappaBzeta对于TLR/IL-1R信号通路中激活的基因子集的表达是必不可少的。IkappaBzeta缺陷细胞对多种TLR配体和IL-1的反应表现出严重的IL-6生成障碍，但对肿瘤坏死因子-α的反应不明显。内源性IkappaBzeta与核因子-kappaB的p50亚基特异性结合，并在刺激下被募集到IL-6启动子的核因子-kappaB结合部位。此外，NF-kappaB1/p50缺陷小鼠对TLR/IL-1R配体的反应与IkappaBzeta缺陷小鼠相似。在IkappaBzeta缺乏的巨噬细胞中，内毒素诱导的其他基因如IL12b和CSF2的表达也被取消。鉴于内毒素诱导的IkappaBzeta转录发生在这些基因的转录之前，一些TLR/IL-1R介导的反应可能在至少两个步骤的基因表达过程中被调节，这需要诱导的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.