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Crosstalk between inflammation and adhesion

炎症和粘连之间的串扰

基本信息

批准号：
18591079
负责人：
NAKAMOTO Tetsuya
金额：
$ 2.57万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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-18591079/
关键词：
immunology Signal Transduction inflammatory cells cell adhesion

项目摘要

We investigated how proteins of integrin signaling pathway are involved in inflammation.Cas-L/Hef1/Nedd9 is a member of p 130cas family proteins that are involved in integrin signaling. Although the roles of Cas-L in lymphocytes are reported, its expression in granulocytes was not known. We first showed the expression of Cas-L protein in neutrophils. Tyrosine phosphorylation of Cas-L was observed with the stimulation by LPS, TNF, or fMLP. The tyrosine phosphorylation was enhanced with the adhesion of neutrophils. Granulocytes from Cas-L deficient mice showed enhanced migration in response to fMLP.CIZ is a nucleo-cytoplasmic shuttling protein that binds to p 130Cas and transcriptionally regulates collagens and matrix metalloproteinases. We screened for new binding partners of CIZ. CIZ binds to the C-terminal domain of collagens in the nucleus, suggesting the transcriptional regulation of collagens by this complex.We applied the serum-induced arthritis model to CIZ-deficient mice. CIZ deficiency reduced arthritis severity to half of that in wild-type mice. CIZ deficiency reduced inflammatory cell invasion and cartilage destruction. CIZ deficiency suppressed the arthritis-induced increase in the number of osteoclasts in the joint, urinary deoxypyridinoline, and mRNA expression of RANKL. Arthritis-induced increase of mRNA expression of MMP-3, a target of CIZ as a transcription factor, was decreased by CIZ deficiency together with the mRNA expression of Adamts4, IL-1β, and CXCL16. These results suggest that CIZ plays pivotal roles in the induction of inflammatory genes.

我们研究了整合素信号通路中的蛋白质如何参与炎症反应，Cas-L/Hef 1/Nedd 9是整合素信号通路中p130 cas家族的成员。虽然Cas-L在淋巴细胞中的作用已有报道，但其在粒细胞中的表达尚不清楚。我们首次发现Cas-L蛋白在中性粒细胞中表达。在LPS、TNF或fMLP刺激下观察到Cas-L的酪氨酸磷酸化。随着中性粒细胞的粘附，酪氨酸磷酸化增强。来自Cas-L缺陷小鼠的粒细胞显示响应于fMLP的增强的迁移。CIZ是核质穿梭蛋白，其结合p130 Cas并转录调节胶原和基质金属蛋白酶。我们筛选了新的CIZ结合伴侣。CIZ与细胞核中胶原蛋白的C-末端结构域结合，表明胶原蛋白的转录由该复合物调节。CIZ缺乏将关节炎的严重程度降低至野生型小鼠的一半。CIZ缺乏减少炎性细胞侵袭和软骨破坏。CIZ缺乏抑制关节炎诱导的关节破骨细胞数量增加、尿脱氧吡啶啉和RANKL mRNA表达。关节炎诱导的MMP-3（CIZ作为转录因子的靶点）mRNA表达的增加与Adamts 4、IL-1β和CXCL 16的mRNA表达一起被CIZ缺乏降低。这些结果表明，CIZ在炎症基因的诱导中起着关键作用。