Crosstalk between inflammation and adhesion

我们研究了整合素信号通路蛋白在炎症中的作用。Cas-L/Hef1/Nedd9是参与整合素信号传导的p130cas家族蛋白的成员。虽然报道了casl在淋巴细胞中的作用，但其在粒细胞中的表达尚不清楚。我们首先在中性粒细胞中发现了casl蛋白的表达。在LPS、TNF或fMLP的刺激下，观察到酪氨酸磷酸化的casl。酪氨酸磷酸化随着中性粒细胞的粘附而增强。casl缺陷小鼠的粒细胞对fMLP的迁移反应增强。CIZ是一种核细胞质穿梭蛋白，与p130cas结合并转录调节胶原和基质金属蛋白酶。我们筛选了新的自贸区绑定伙伴。CIZ结合到胶原细胞核的c端结构域，表明该复合物对胶原的转录调节。我们采用血清诱导的cz缺陷小鼠关节炎模型。缺乏CIZ可以将关节炎的严重程度降低到野生型小鼠的一半。CIZ缺乏减少炎症细胞侵袭和软骨破坏。CIZ缺乏抑制关节炎引起的关节破骨细胞数量、尿脱氧吡啶啉和RANKL mRNA表达的增加。关节炎引起的MMP-3 mRNA表达升高，以及Adamts4、IL-1β和CXCL16 mRNA表达降低，而MMP-3是CIZ的转录因子靶点。这些结果表明，CIZ在炎症基因的诱导中起着关键作用。

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.