Induction of an epithelial integrin alphavbeta6 in human cytomegalovirus-infected endothelial cells leads to activation of transforming growth factor-beta1 and increased collagen production.
Induction of an epithelial integrin alphavbeta6 in human cytomegalovirus-infected endothelial cells leads to activation of transforming growth factor-beta1 and increased collagen production.
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DOI：
10.2353/ajpath.2008.070448
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发表时间：
2008-04
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通讯作者：
T. Tabata;H. Kawakatsu;E. Maidji;T. Sakai;K. Sakai;June Fang-Hoover;M. Aiba;D. Sheppard;L. Pereira
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文献类型：
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作者：
T. Tabata;H. Kawakatsu;E. Maidji;T. Sakai;K. Sakai;June Fang-Hoover;M. Aiba;D. Sheppard;L. Pereira
人巨细胞病毒（CMV）感染是免疫抑制个体发病的主要原因，先天性CMV感染是新生儿出生缺陷的主要原因。致病性病毒株感染改变细胞-细胞和细胞-基质相互作用，影响细胞外基质重塑和内皮细胞迁移。多功能细胞因子转化生长因子（TGF）-β 1调节细胞增殖、分化和细胞外基质重塑。TGF-β 1作为一种潜在的蛋白质复合物分泌，在与使细胞内效应物磷酸化的受体结合之前需要活化。TGF-β 1被整合素α v β 6激活，整合素α v β 6在上皮中由损伤和炎症强烈诱导，但以前在内皮细胞中未发现。在这里，我们报告说，CMV感染诱导整合素α v β 6在内皮细胞中的表达，导致TGF-β 1的激活，通过其受体ALK 5的信号传导，和其细胞内效应Smad 3的磷酸化。内皮细胞的感染也被发现通过依赖于TGF-β 1和整合素α v β 6的机制刺激胶原蛋白合成。免疫组织化学分析显示，在肺、唾液腺、子宫蜕膜和胎盘受损绒毛膜绒毛中CMV感染病灶附近的毛细血管中整合素α v β 6上调，表明其在体内内皮中的诱导和上皮中的上调。我们的研究结果表明，整合素α v β 6激活TGF-β 1有助于病理变化，并可能损害慢性感染CMV的组织中的内皮细胞功能。
Human cytomegalovirus (CMV) infection is a major cause of morbidity in immunosuppressed individuals, and congenital CMV infection is a leading cause of birth defects in newborns. Infection with pathogenic viral strains alters cell-cell and cell-matrix interactions, affecting extracellular matrix remodeling and endothelial cell migration. The multifunctional cytokine transforming growth factor (TGF)-beta1 regulates cell proliferation, differentiation, and extracellular matrix remodeling. Secreted as a latent protein complex, TGF-beta1 requires activation before binding to receptors that phosphorylate intracellular effectors. TGF-beta1 is activated by integrin alphavbeta6, which is strongly induced in the epithelium by injury and inflammation but has not previously been found in endothelial cells. Here, we report that CMV infection induces integrin alphavbeta6 expression in endothelial cells, leading to activation of TGF-beta1, signaling through its receptor ALK5, and phosphorylation of its intracellular effector Smad3. Infection of endothelial cells was also found to stimulate collagen synthesis through a mechanism dependent on both TGF-beta1 and integrin alphavbeta6. Immunohistochemical analysis showed integrin alphavbeta6 up-regulation in capillaries proximal to foci of CMV infection in lungs, salivary glands, uterine decidua, and injured chorionic villi of the placenta, demonstrating both its induction in endothelium and up-regulation in epithelium in vivo. Our results suggest that activation of TGF-beta1 by integrin alphavbeta6 contributes to pathological changes and may impair endothelial cell functions in tissues that are chronically infected with CMV.