Induction of an epithelial integrin αVβ6 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, Lenore Pereira

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)

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)-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 αvβ6, 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 αvβ6 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 αvβ6. Immunohistochemical analysis showed integrin αvβ6 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 upregulation in epithelium in vivo. Our results suggest that activation of TGF-β1 by integrin αvβ6 contributes to pathological changes and may impair endothelial cell functions in tissues that are chronically infected with CMV.

Original languageEnglish
Pages (from-to)1127-1140
Number of pages14
JournalAmerican Journal of Pathology
Volume172
Issue number4
DOIs
Publication statusPublished - 04-2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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