Published online before print March 18, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2008.070448v1 172/4/1127    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tabata, T. Articles by Pereira, L. Search for Related Content PubMed PubMed Citation Articles by Tabata, T. Articles by Pereira, L.

(American Journal of Pathology. 2008;172:1127-1140.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070448

Induction of an Epithelial Integrin vβ6 in Human Cytomegalovirus-Infected Endothelial Cells Leads to Activation of Transforming Growth Factor-β1 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

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)-β1 regulates cell proliferation, differentiation, and extracellular matrix remodeling. Secreted as a latent protein complex, TGF-β1 requires activation before binding to receptors that phosphorylate intracellular effectors. TGF-β1 is activated by integrin vβ6, 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 vβ6 expression in endothelial cells, leading to activation of TGF-β1, 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-β1 and integrin vβ6. Immunohistochemical analysis showed integrin vβ6 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-β1 by integrin vβ6 contributes to pathological changes and may impair endothelial cell functions in tissues that are chronically infected with CMV.