Integrin alphavbeta8-mediated activation of transforming growth factor-beta inhibits human airway epithelial proliferation in intact bronchial tissue.
Transforming growth factor (TGF)-beta is a potent multifunctional cytokine that is an essential regulator of epithelial proliferation. Because TGF-beta is expressed almost entirely in a latent state in vivo, a major source of regulation of TGF-beta function is its activation. A subset of integrins, alphavbeta8 and alphavbeta6, which are expressed in the human airway, has recently been shown to activate latent TGF-beta in vitro, suggesting a regulatory role for integrins in TGF-beta function in vivo. Here we have developed a novel, biologically relevant experimental model of human airway epithelium using intact human bronchial tissue. We have used this model to determine the function of integrin-mediated activation of TGF-beta in the airway. In human bronchial fragments cultured in vitro, authentic epithelial-stromal interactions were maintained and integrin and TGF-beta expression profiles correlated with profiles found in normal lung. In addition, in this model, we found that either the integrin alphavbeta8 or TGF-beta could inhibit airway epithelial cell proliferation. Furthermore, we found that one mechanism of integrin-alphavbeta8-dependent inhibition of cell proliferation was through activation of TGF-beta because anti-beta8 antibody blocked the majority (76%) of active TGF-beta released from bronchial fragments. These data provide compelling evidence for a functional role for integrin-mediated activation of TGF-beta in control of human airway epithelial proliferation in vivo.
Fjellbirkeland
Lars
L
Department of Anatomic Pathology and Lung Biology Center, San Francisco General Hospital, University of California at San Francisco/Mt. Zion Cancer Center, San Francisco, California 94110, USA.
Cambier
Stephanie
S
Broaddus
V Courtney
VC
Hill
Arthur
A
Brunetta
Paul
P
Dolganov
Gregory
G
Jablons
David
D
Nishimura
Stephen L
SL
D000368:Aged; D000369:Aged, 80 and over; D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology*; D046508:Culture Techniques; D005260:Female; D020869:Gene Expression Profiling; D006706:Homeostasis; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007633:Keratins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016023:Integrins; D019394:Ki-67 Antigen; D016212:Transforming Growth Factor beta; C403414:integrin alphavbeta8; D007633:Keratins