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

Patsenker, Eleonora; Popov, Yury; Stickel, Felix; Jonczyk, Alfred; Goodman, Simon L; Schuppan, Detlef (2008). Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology, 135(2), pp. 660-70. Philadelphia, Pa.: Elsevier 10.1053/j.gastro.2008.04.009

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Clinical Pharmacology and Visceral Research [discontinued]
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology

UniBE Contributor:

Patsenker, Eleanora and Stickel, Felix

ISSN:

0016-5085

ISBN:

18538673

Publisher:

Elsevier

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:05

Last Modified:

04 May 2014 23:20

Publisher DOI:

10.1053/j.gastro.2008.04.009

PubMed ID:

18538673

Web of Science ID:

000258439900041

URI:

https://boris.unibe.ch/id/eprint/28351 (FactScience: 120251)

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