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Analyses on Mechanisms for Multistep Transcriptional Regulation via Inducible Factors

诱导因子多步转录调控机制分析

基本信息

批准号：
18370056
负责人：
MUTA Tatsushi
金额：
$ 11.21万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18370056/
关键词：
regulation of expression gene infectious disease immunology signal transduction transcriptional regulation innate immunity induction of expression

项目摘要

IκB-ζ, which was discovered by the head investigator, is a key molecule playing dual roles in regulation of inflammatory reactions. IκB-ζ is induced by various microbial substances stimulating the innate immune system and is essential for transcription of secondary response genes such as interleukin (IL)-6, IL-12, and the transcription factor C/EBP-δ and suppresses those of primary response genes represented by tumor necrosis factor (TNF)-α. In the present study, we investigated mechanisms for transcriptional regulation by IκB-ζ. We found that both an NF-κB binding site and a C/EBP binding site in the promoter region are essential for the transcriptional activation by IκB-ζ in the human β-defensin 2 and neutrophil gelatinase-associated lipocalin genes. On the other hand, IκB-ζ inhibited transcription of a promoter harboring canonical NF-κB binding sites. These results indicated that IκB-ζ induced on stimulation forms a complex with NF-κB and binds to the promoters harboring an NF-κB binding site and a C/EBP sites, where it activates transcription. Induction of IκB-ζ is induced by IL-1β stimulation as well as LPS, but not by TNF-α. We have analyzed mechanisms for IκB-ζ induction and have shown that IκB-ζ mRNA is specifically stabilized upon LPS/IL-1β stimulation. In the present study, we searched for an element in the IκB-ζ mRNA that is essential for the post-transcriptional regulation, and found that a 165-nucleotide sequence in the 3'-untranslated region is essential and sufficient for the regulation. We furthermore examined induction of IκB-ζ in B cells and found that it is induced upon stimulation of B cell antigen receptor. We also found that the induction was inhibited by co-stimulation of the inhibitory Fc receptor. These results strongly suggest that IκB-ζ plays a critical role in the adaptive immune system.

IκB-κ B是本课题组组长发现的在炎症反应调控中起双重作用的关键分子。IκB-κ B由刺激先天免疫系统的各种微生物物质诱导，对于次级应答基因（如白细胞介素（IL）-6，IL-12和转录因子C/EBP-δ）的转录至关重要，并抑制以肿瘤坏死因子（TNF）-α为代表的初级应答基因的转录。在本研究中，我们研究了IκB-β的转录调控机制。我们发现启动子区的NF-κB结合位点和C/EBP结合位点对于IκB-κ B激活人β-防御素2和中性粒细胞明胶酶相关脂质运载蛋白基因的转录是必需的。另一方面，IκB-κ B抑制了含有典型NF-κB结合位点的启动子的转录。这些结果表明，在刺激时诱导的IκB-β与NF-κB形成复合物，并结合到具有NF-κB结合位点和C/EBP位点的启动子上，在那里它激活转录。IL-1β刺激和LPS均可诱导IκB-κ B的诱导，但TNF-α不能诱导IκB的诱导。我们已经分析了IκB-β诱导的机制，并表明IκB-β mRNA在LPS/IL-1β刺激后特异性稳定。在本研究中，我们在IκB-κ B mRNA中寻找转录后调控所必需的元件，并发现3 '非翻译区的165个核苷酸序列是必需的，并且足以进行调控。我们进一步检查了IκB-κ B在B细胞中的诱导，发现它是在刺激B细胞抗原受体后诱导的。我们还发现，诱导抑制抑制性Fc受体的共刺激抑制。这些结果有力地表明IκB-κ B在适应性免疫系统中起着关键作用。