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: 4.6). 05/2008; 172(4):1127-40. DOI: 10.2353/ajpath.2008.070448
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Ekaterina Maidji, Jun 26, 2014
  • Source
    [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    ABSTRACT: To defend against pulmonary infections, lung epithelial cells are equipped with complex innate immunity closely linked to inflammation. Dysregulated innate immunity/inflammation leads to self-perpetuating lung injury. The CpG motif in bacterial DNA is one of the factors involved in bacterial infection-associated inflammation. Bacterial DNA and synthetic CpG oligonucleotide (ODN) induced CCN1 secretion from lung epithelial cells, functioning as a potential "braking" signal to prevent uncontrolled inflammatory responses. CpG ODN-induced endoplasmic reticulum (ER) stress resulted in Src-Y527 phosphorylation (pY527) and Src/CCN1 vWF domain dissociation. Src-Y527 activated caveolin-1 (cav-1) phosphorylation at Y14 and then modulated CCN1 secretion via pCav-1 interaction with the CCN1 IGFbp domain. Functionally, secreted CCN1 promoted anti-inflammatory cytokine interleukin (IL)-10 release from epithelial cells via integrin αVβ6-PKC, and this subsequently suppressed tumor necrosis factor (TNF)-α, macrophage inflammatory protein 2 (MIP-2)-2 secretion and neutrophil infiltration in the lungs. Collectively, bacterial DNA/CpG ODN-stimulated CCN1 secretion via the BiP/GRP78-Src(Y527)-JNK-Cav-1(Y14) pathway and CpG-induced CCN1 conferred anti-inflammatory roles. Our studies suggested a novel paradigm by which the lung epithelium maintains innate immune homeostasis after bacterial infection.Mucosal Immunology advance online publication, 9 July 2014; doi:10.1038/mi.2014.62.
    Mucosal Immunology 07/2014; 8(2). DOI:10.1038/mi.2014.62 · 7.54 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human cytomegalovirus is the leading non-genetic cause of congenital malformation in developed countries. Congenital CMV may result in fetal and neonatal death or development of serious clinical sequelae. In this review, we identified evidence-based interventions for prevention of congenital CMV at the primary level (prevention of maternal infection), secondary level (risk reduction of fetal infection and disease) and tertiary level (risk reduction of infected neonates being affected by CMV). A systematic review of existing literature revealed 24 eligible studies that met the inclusion criteria. Prevention of maternal infection using hygiene and behavioural interventions reduced maternal seroconversion rates during pregnancy. However, evidence suggested maternal adherence to education on preventative behaviours was a limiting factor. Treatment of maternal CMV infection with hyperimmune globulin (HIG) showed some evidence for efficacy in prevention of fetal infection and fetal/neonatal morbidity with a reasonable safety profile. However, more robust clinical evidence is required before HIG therapy can be routinely recommended. Limited evidence also existed for the safety and efficacy of established CMV antivirals (valaciclovir, ganciclovir and valganciclovir) to treat neonatal consequences of CMV infection, but toxicity and lack of randomised clinical trial data remain major issues. In the absence of a licensed CMV vaccine or robust clinical evidence for anti-CMV therapeutics, patient education and behavioural interventions that emphasise adherence remain the best preventative strategies for congenital CMV. There is a strong need for further data on the use of HIG and other antivirals in pregnancy, as well as the development of less toxic, novel, antiviral agents. Copyright © 2014 John Wiley & Sons, Ltd.
    Reviews in Medical Virology 11/2014; 24(6). DOI:10.1002/rmv.1814 · 5.76 Impact Factor