Induction of an Epithelial Integrin αvβ6 in Human Cytomegalovirus-Infected Endothelial Cells Leads to Activation of Transforming Growth Factor-β1 and Increased Collagen Production

Department of Cell and Tissue Biology, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0640, USA.
American Journal Of Pathology (Impact Factor: 4.59). 05/2008; 172(4):1127-40. DOI: 10.2353/ajpath.2008.070448
Source: PubMed


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.

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Available from: Ekaterina Maidji, Jun 26, 2014
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    • "Increased release of IL-10 in cancers, conferring a more invasive phenotype [102] [103] [104] [105] [106] [107] [108] HCMV encodes an IL-10 homolog (cmv-IL-10) that shares human IL-10 immunomodulatory properties [114] [115] [116] [117] [118] Expression of TGF Overexpression of TGF promoted tumor-immune escape and was associated with tumor progression with worse prognosis. [128] [129] [130] [131] [134] [135] [136] HCMV induced transcription and release of TGF [138] [139] [140] "
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    ABSTRACT: CYTOMEGALOVIRUS (CMV) AND THE HUMAN TUMOR CELL SHARE THE SAME OBJECTIVES: escape the recognition and destruction by the immune system and establish a state of immune tolerance conducive for their development. For early tumor development, the escape of the first lines of defense of the immune surveillance is a critical step which determines survival or destruction. The presence of CMV on the tumor site and its involvement in carcinogenesis as initiator or promoter is increasingly documented. In this article, we highlight the similarity between mechanisms used by tumors and CMV to circumvent the immune defenses and evade from immune surveillance. We suggest that CMV and tumors help one another for their common objective. CMV gets shelter in immunologically poor environment of the tumor cells. In return CMV, by acting directly on the cancer cell and/or on the tumor microenvironment, provides the tumor cell the ways to promote its immune escape and development of immune tolerance.
    The Open Virology Journal 06/2011; 5:60-9. DOI:10.2174/1874357901105010060
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    • "Virus infection has also been shown to contribute to TGF-β activation and expression of extracellular matrix components in endothelial cells. Infection of endothelial cells with cytomegalovirus (CMV) upregulated integrin-β6 followed by activation of the TGF-β pathway and expression of collagen IV [36]. Those observations are intriguing in view that EMT in alveolar epithelial cells is induced by linking TGF-β and β-catenin signaling through integrins [13], [37]. "
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    PLoS ONE 10/2009; 4(10):e7559. DOI:10.1371/journal.pone.0007559 · 3.23 Impact Factor
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    North American Journal of Medical Sciences 09/2009; 1(4):200-4. DOI:10.4297/najms.2009.4200
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