Integrin αvβ8-Mediated Activation of Transforming Growth Factor-β Inhibits Human Airway Epithelial Proliferation in Intact Bronchial Tissue

Abstract

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.

Integrin-Mediated Transforming Growth Factor-β Activation Regulates Homeostasis of the Pulmonary Epithelial-Mesenchymal Trophic Unit

“…Thus, we found that the integrin ␣ v ␤ 8 is expressed at high levels in fragments of intact bronchial tissues and that it mediates activation of TGF-␤, ultimately inhibiting epithelial cell growth. 20 These findings suggest a possible role for TGF-␤ during the reactivation of the EMTU in the injured adult airway. However, the EMTU has only been rigorously experimentally defined in nonhuman lung systems, which have significant differences in anatomy and cell-type distribution from human lungs.…”

MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-β8

“…The 3 0 -untranslated region (3 0 UTR) of integrinb8 harbors a typical target sequence for miR-93 ( Figure 6a). It has been reported that integrin-b8 can function as a negative regulator of cell proliferation when activated by tumor growth factor-b (Cambier et al, 2000;Fjellbirkeland et al, 2003). We analyzed integrin-b8 expression in tumor sections and cells expressing miR-93.…”

“…Our results suggest that expression of integrin-b8 can facilitate cell death. It has been reported that integrin-b8 is a negative regulator of cell proliferation (Fjellbirkeland et al, 2003;Cambier et al, 2005). The reduced levels of integrin-b8 on the tumor cell surface may favor endothelial cell activities and angiogenesis.…”

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

“…(d) Airway fibroblasts respond to IL-1β by increasing β8 expression and αvβ8-mediated TGF-β activation. Increased TGF-β activation by airway fibroblasts causes (e) autocrine effects on the fibrogenic fibroblast phenotype by increasing Col I and αSMA and (f) paracrine effects on adjacent airway epithelium, which inhibits epithelial proliferation (10,44,66) and contributes to the increased expression of β6 by adjacent airway epithelial cells, forming a self-amplifying loop of TGF-β activation.…”