Inhibition of Integrin αvβ6 on Cholangiocytes Blocks Transforming Growth Factor-β Activation and Retards Biliary Fibrosis Progression

Abstract

Background and aims-Integrin αvβ6 is highly expressed on certain activated epithelia, where it mediates attachment to fibronectin and serves as coreceptor for the activation of latent TGFβ1. Since its role in liver fibrosis is unknown, we studied αvβ6 function in vitro and explored the antifibrotic potential of the specific αvβ6 antagonist EMD527040.

Targeting liver fibrosis: Strategies for development and validation of antifibrotic therapies

“…TGF␤2, connective tissue growth factor (CTGF), and platelet-derived growth factor (PDGF)-BB that drive the activation of HSC, [13][14][15][16] de novo express profibrogenic integrin ␣v␤6 17 , produce ECM components such as basement membrane proteins, 18 and induce early programs of ductal plate formation by releasing Hedgehog ligands that stimulate HSC. 19 Activated HSC, in turn, produce growth and survival factors for adjacent cholangiocytes, creating a positive fibrogenic feedback loop (Fig.…”

“…Activated cholangiocytes play an important role in fibrogenesis. 16,17,26 Their inhibition prevents excessive release or activation of profibrogenic growth factors, such as TGF␤1, TGF␤2, or CTGF. Cell lines of activated cholangiocytes have become available for testing of inhibitors.…”

“…Cell lines of activated cholangiocytes have become available for testing of inhibitors. 17,27,28 Cultures of hepatocytes, Kupffer cells, or various lymphocyte subpopulations are currently of limited utility, because these cells can display both fibrogenic or fibrolytic activities, depending on context and state of activation. 3,29 Precision-cut Tissue Culture Slices.…”

“…48 An intriguing novel target is the integrin ␣v␤6, a cell surface receptor that is expressed on activated epithelia during embryogenesis, wound healing, and tumorigenesis. 49 ␣v␤6 anchors these epithelia to a provisional ECM of tenascin and fibronectin 17 and through tethering latent TGF␤1 promotes its proteolytic activation. 50 In the liver, ␣v␤6 is exclusively expressed on activated cholangiocytes that are potent promoters of liver fibrogenesis.…”

“…50 In the liver, ␣v␤6 is exclusively expressed on activated cholangiocytes that are potent promoters of liver fibrogenesis. 17,26,51 Its successful targeting by a blocking antibody 51 or a small molecule inhibitor specifically blocked proliferation of profibrogenic cholangiocytes and concomitant TGF␤1 activation at the site of fibrogenesis. 17,26 Promising targeted approaches are summarized in Table 3.…”