Vitronectin Inhibits Neutrophil Apoptosis through Activation of Integrin-Associated Signaling Pathways
Vitronectin Inhibits Neutrophil Apoptosis through Activation of Integrin-Associated Signaling Pathways
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DOI：
10.1165/rcmb.2011-0187oc
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发表时间：
2012-06-01
影响因子：
6.4
通讯作者：
Abraham, Edward
中科院分区：
文献类型：
--
作者：
Bae, Hong-Beom;Zmijewski, Jaroslaw W.;Abraham, Edward
玻连蛋白以大浓度存在于血清和细胞外基质中。虽然玻连蛋白是已知的调节中性粒细胞粘附和趋化性，并有助于嗜中性粒细胞相关的促炎过程中，细胞凋亡的作用尚未得到证实。在目前的研究中，我们发现，中性粒细胞表现出更快的进展，自发或TNF-相关的凋亡诱导配体诱导的细胞凋亡时，孵育玻连蛋白的条件下比玻连蛋白存在。天然玻连蛋白延迟中性粒细胞凋亡的能力不被玻连蛋白生长调节蛋白B结构域所概括。相反，在含有玻连蛋白的培养物中加入环[Arg-Gly-Asp-D-Phe-Val]肽导致增强的中性粒细胞凋亡，表明玻连蛋白的RGD基序（Arg-Gly-Asp基序）负责玻连蛋白的抗凋亡作用。添加β（1）、β（3）或β（5）整合素抗体，但不添加β（2）或β（4）整合素抗体，可逆转玻连蛋白减少中性粒细胞凋亡的能力。玻连蛋白增强中性粒细胞活力的能力依赖于磷脂酰肌醇3激酶和细胞外信号调节激酶1/2激酶的激活，但不依赖于p38激酶。与对照小鼠相比，LPS处理的转基因玻连蛋白缺陷小鼠的肺中存在凋亡的中性粒细胞数量增加。这些结果证明了玻连蛋白的一种新的抗凋亡功能。
Vitronectin is present in large concentrations in serum and the extracellular matrix. Although vitronectin is known to modulate neutrophil adhesion and chemotaxis, and to contribute to neutrophil-associated proinflammatory processes, a role in apoptosis has not been demonstrated. In the present studies, we found that neutrophils demonstrated more rapid progression to spontaneous or TNF-related apoptosis-inducing ligand-induced apoptosis when incubated under vitronectin-free conditions than when vitronectin was present. The ability of native vitronectin to delay neutrophil apoptosis was not recapitulated by the vitronectin somatomedin B domain. In contrast, inclusion of the cyclo[Arg-Gly-Asp-D-Phe-Val] peptide in cultures containing vitronectin resulted in enhanced neutrophil apoptosis, showing that the vitronectin RGD motif ( Arg-Gly-Asp motif) was responsible for the antiapoptotic effects of vitronectin. Addition of antibodies to beta(1), beta(3), or beta(5), but not to beta(2) or beta(4) integrins, reversed the ability of vitronectin to diminish neutrophil apoptosis. The ability of vitronectin to enhance neutrophil viability was dependent on activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2 kinases, but not on the p38 kinase. Increased numbers of apoptotic neutrophils were present in the lungs of LPS-treated transgenic vitronectin-deficient mice, as compared with control mice. These results demonstrate a novel antiapoptotic function for vitronectin.