Epithelial-Mesenchymal Interactions in Fibrosis and Repair Transforming Growth Factor-beta Activation by Epithelial Cells and Fibroblasts

摘要

Abstract Transforming growth factor-beta (TGF-beta) plays a central role in driving tissue fibrosis. TGF-beta is secreted in a latent form, held latent by noncovalent association of the active cytokine with a peptide derived from cleavage of the N-terminal domain of the same gene product, and needs to be activated extracellularly to exert any of its diverse biological effects. We have shown that two of the three mammalian isoforms of TGF-beta, TGF-beta1 and TGF-beta3, depend on interactions with cell surface integrins for activation. We found that the integrin alphavbeta6 is highly induced on injured alveolar epithelial cells, potently induces TGF-beta activation, and is critical for the development of pulmonary fibrosis and acute lung injury. However, although TGF-beta drives fibrosis in virtually every anatomic site, alphavbeta6-mediated TGF-beta activation is much more restricted. For example, alphavbeta6 is not induced on injured hepatocytes and plays little or no role in cirrhosis induced by repetitive hepatocyte injury. Fibroblasts are highly contractile cells that express multiple integrins closely related to alphavbeta6, which share the promiscuous alphav subunit, so we reasoned that perhaps one or more of these alpphav integrins on fibroblasts might substitute for alphavbeta6 and activate the TGF-beta required to drive liver fibrosis. Indeed, deletion of the av subunit from activated fibroblasts protected mice from carbon tetrachloride-induced liver fibrosis. Importantly, these same mice were protected from bleomycin-induced pulmonary fibrosis and renal fibrosis caused by unilateral ureteral obstruction, despite the presence of epithelial alphavbeta6 in these mice. These results suggest that the generation and maintenance of sufficient quantities of active TGF-beta to cause tissue fibrosis in multiple organs probably depends on at least two sources-TGF-beta activation by injured epithelial cells that drives fibroblast expansion and activation and an amplification step that involves TGF-beta activation by an av integrin on activated fibroblasts. These results suggest that intervening at either of these steps could be useful for the treatment of fibrotic diseases.