Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression.
OBJECTIVE
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.
Patsenker
Eleonora
E
Institute of Clinical Pharmacology, University of Bern, Bern, Switzerland.
Popov
Yury
Y
Stickel
Felix
F
Jonczyk
Alfred
A
Goodman
Simon L
SL
Schuppan
Detlef
D
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001652:Bile Ducts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002779:Cholestasis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000951:Antigens, Neoplasm; D003094:Collagen; D005353:Fibronectins; D018836:Inflammation Mediators; D016023:Integrins; D011725:Pyridines; D016212:Transforming Growth Factor beta; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C529593:EMD 527040; C073878:integrin alphavbeta6