Induction of an epithelial integrin alphavbeta6 in human cytomegalovirus-infected endothelial cells leads to activation of transforming growth factor-beta1 and increased collagen production.
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.
Tabata
Takako
T
Department of Cell and Tissue Biology, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0640, USA.
Kawakatsu
Hisaaki
H
Maidji
Ekaterina
E
Sakai
Takao
T
Sakai
Keiko
K
Fang-Hoover
June
J
Aiba
Motohiko
M
Sheppard
Dean
D
Pereira
Lenore
L
D030301:Activin Receptors, Type II / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D003587:Cytomegalovirus / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000378:metabolism* / Q000821:virology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D004847:Epithelial Cells / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008907:Mink; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014471:Umbilical Veins / Q000473:pathology / Q000821:virology; D015854:Up-Regulation; D014779:Virus Replication
D000951:Antigens, Neoplasm; D039641:Integrin beta Chains; D016023:Integrins; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C073878:integrin alphavbeta6; C072170:integrin beta6; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human