Published online before print March 18, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070448

Accepted for publication January 14, 2008.

Article

Induction of an Epithelial Integrin v6 in Human Cytomegalovirus-Infected Endothelial Cells Leads to Activation of Transforming Growth Factor-1 and Increased Collagen Production

Takako Tabata^*, Hisaaki Kawakatsu, Ekaterina Maidji^*, Takao Sakai, Keiko Sakai, June Fang-Hoover^*, Motohiko Aiba, Dean Sheppard, and Lenore Pereira^*@

From the Department of Cell and Tissue Biology,* and the Lung Biology Center, University of California, San Francisco, San Francisco, California; the Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; and the Department of Pathology, Tokyo Women's Medical School, Tokyo, Japan

^@ To whom correspondence should be addressed. E-mail: lenore.pereira{at}ucsf.edu.

	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)-1 regulates cell proliferation, differentiation, and extracellular matrix remodeling. Secreted as a latent protein complex, TGF-1 requires activation before binding to receptors that phosphorylate intracellular effectors. TGF-1 is activated by integrin v6, 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 v6 expression in endothelial cells, leading to activation of TGF-1, 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-1 and integrin v6. Immunohistochemical analysis showed integrin v6 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-1 by integrin v6 contributes to pathological changes and may impair endothelial cell functions in tissues that are chronically infected with CMV.