Enhanced susceptibility to endotoxic shock and impaired STAT3 signaling in CD31-deficient mice
Enhanced susceptibility to endotoxic shock and impaired STAT3 signaling in CD31-deficient mice
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DOI：
10.1016/s0002-9440(10)62243-2
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发表时间：
2005-01-01
影响因子：
6
通讯作者：
Madri, JA
中科院分区：
文献类型：
--
作者：
Carrithers, M;Tandon, S;Madri, JA
血小板内皮细胞粘附分子-1（PECAM-1，CD 31）是一种在造血细胞和内皮细胞上表达的粘附分子，除了作为淋巴细胞和血小板信号传导的调节剂和中性粒细胞迁移的促进剂外，还介导细胞凋亡、细胞增殖和迁移，并维持内皮完整性。最近的数据表明，CD 31作为支架蛋白发挥作用，以调节信号转导和转录激活因子（STAT）家族的信号分子，特别是STAT 3和STAT 5的磷酸化。STAT 3调节对先天性免疫刺激如脂多糖（LPS）的急性期应答，并促进从LPS诱导的脓毒性休克中恢复。在这里，我们证明了CD 31缺陷小鼠在内毒素LPS诱导的休克期间存活率降低。与野生型对照相比，CD 31缺陷小鼠显示血管通透性增强;肝、肾和脾中凋亡细胞死亡增加;血清肿瘤坏死因子α（TNF-α）、干扰素γ（IFN γ）、MCP-1、MCP-5、sTNRF和IL-6水平升高。在体内和体外对LPS的反应中，来自敲除小鼠的脾细胞和内皮细胞具有降低的磷酸化STAT 3水平。这些结果表明，CD 31是必要的，以维持内皮细胞。完整性和预防败血性休克期间的细胞凋亡以及促进败血性休克期间存活的STAT 3介导的急性期应答。
Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31), an adhesion molecule expressed on hematopoietic and endothelial cells, mediates apoptosis, cell proliferation, and migration and maintains endothelial integrity in addition to its roles as a modulator of lymphocyte and platelet signaling and facilitator of neutrophil transmigration. Recent data suggest that CD31 functions as a scaffolding protein to regulate phosphorylation of the signal transducers and activators of transcription (STAT) family of signaling molecules, particularly STAT3 and STAT5. STAT3 regulates the acute phase response to innate immune stimuli such as lipopolysaccharide (LPS) and promotes recovery from LPS-induced septic shock. Here we demonstrate that CD31-deficient mice have reduced survival during endotoxic LPS-induced shock. As compared to wild-type controls, CD31-deficient mice showed enhanced vascular permeability; increased apoptotic cell death in liver, kidney, and spleen; and elevated levels of serum tumor necrosis factor a (TNF-alpha), interferon gamma (IFNgamma), MCP-1, MCP-5, sTNRF, and IL-6. In response to LPS in vivo and in vitro, splenocytes and endothelial cells from knockout mice had reduced levels of phosphorylated STAT3. These results suggest that CD31 is necessary for maintenance of endothelial. integrity and prevention of apoptosis during septic shock and for STAT3-mediated acute phase responses that promote survival during septic shock.