Crosstalk between inflammation and adhesion

我们研究了整合素信号通路的蛋白在炎症中的作用。Cas-L/HEF1/NEDD9是参与整合素信号转导的p130cas家族蛋白的一员。尽管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。我们首先展示了CaS-L蛋白在中性粒细胞中的表达。在脂多糖、肿瘤坏死因子和fMLP的刺激下，观察CaS-L的酪氨酸磷酸化。随着中性粒细胞的黏附，酪氨酸磷酸化增强。Cas-L基因缺陷小鼠的粒细胞对fMLP的反应增强迁移，CIZ是一种核质穿梭蛋白，与p130Cas结合，在转录水平上调节胶原蛋白和基质金属蛋白酶。我们筛选了新的CIZ结合伙伴。CIZ结合到细胞核中胶原蛋白的C-末端结构域，提示这种复合体对胶原蛋白的转录调控。我们将血清诱导的关节炎模型应用于CIZ缺陷小鼠。缺乏CIZ将关节炎严重程度降低到野生型小鼠的一半。CIZ缺乏可减少炎症细胞的侵袭和软骨的破坏。CIZ缺乏抑制了关节炎诱导的关节破骨细胞数量、尿脱氧吡啶酚和RANKL基因表达的增加。CIZ作为转录因子的靶点MMP3m RNA表达的增加与Adamts4、IL-1β和CXCL16mRNA的表达一起被CIZ缺乏抑制。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.