Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression

Gastroenterology. 2008 Aug;135(2):660-70. doi: 10.1053/j.gastro.2008.04.009. Epub 2008 Apr 16.

Abstract

Background & aims: Integrin alphavbeta6 is highly expressed on certain activated epithelia, where it mediates attachment to fibronectin and serves as coreceptor for the activation of latent transforming growth factor (TGF)-beta1. Because its role in liver fibrosis is unknown, we studied alphavbeta6 function in vitro and explored the antifibrotic potential of the specific alphavbeta6 antagonist EMD527040.

Methods: Experimental liver fibrosis was studied in rats after bile duct ligation (BDL) and in Mdr2(abcb4)(-/-) mice. Different doses of EMD527040 were given to rats from week 2 to 6 after BDL and to Mdr2(-/-) mice from week 4 to 8. Liver collagen was quantified, and expression of alphavbeta6 and fibrosis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. alphavbeta6-expressing cells, bile duct proliferation, and apoptosis were assessed histologically. The effect of EMD527040 on cholangiocyte adhesion, proliferation, apoptosis, and TGF-beta1 activation was studied in vitro.

Results: alphavbeta6 was highly expressed on proliferating bile duct epithelia in fibrosis, with 100-fold increased transcript levels in advanced fibrosis. EMD527040 attenuated bile ductular proliferation and peribiliary collagen deposition by 40%-50%, induced down-regulation of fibrogenic and up-regulation of fibrolytic genes, and improved liver architecture and function. In vitro alphavbeta6 inhibition reduced activated cholangiocyte proliferation, their adhesion to fibronectin, and endogenous activation of TGF-beta1 by 50% but did not affect bile duct apoptosis.

Conclusions: Integrin alphavbeta6 is strongly up-regulated in proliferating bile duct epithelia and drives fibrogenesis via adhesion to fibronectin and auto/paracrine TGF-beta1 activation. Pharmacologic inhibition of alphavbeta6 potently inhibits the progression of primary and secondary biliary fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism
  • Apoptosis / drug effects
  • Bile Ducts / drug effects*
  • Bile Ducts / metabolism
  • Bile Ducts / pathology
  • Bile Ducts / surgery
  • Cell Adhesion / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cholestasis / complications
  • Cholestasis / drug therapy*
  • Cholestasis / metabolism
  • Cholestasis / pathology
  • Collagen / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Fibronectins / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammation Mediators / blood
  • Integrins / antagonists & inhibitors*
  • Integrins / genetics
  • Integrins / metabolism
  • Ligation
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / prevention & control*
  • Mice
  • Mice, Knockout
  • Pyridines / pharmacology*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Up-Regulation

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Antigens, Neoplasm
  • EMD 527040
  • Fibronectins
  • Inflammation Mediators
  • Integrins
  • P-glycoprotein 2
  • Pyridines
  • Transforming Growth Factor beta
  • integrin alphavbeta6
  • Collagen