Role of transforming growth factor beta type II receptor in hepatic fibrosis: studies of human chronic hepatitis C and experimental fibrosis in rats.
Transforming growth factor beta (TGF-beta) is an antiproliferative and profibrogenic cytokine that signals through a receptor consisting of type I and type II (TbetaRII) components. We have examined changes in the expression of TbetaRII during liver injury, correlating this with the antiproliferative and profibrogenic effects of TGF-beta1. The experimental material consisted of biopsy samples of liver from patients with chronic hepatitis C and rats in which liver injury was induced by ligation of the common bile duct. Stellate cells were isolated from normal or injured rat liver and studied as fresh isolates. In the biopsy samples from patients, mRNAs for TGF-beta1 and TbetaRII were measured using competitive reverse polymerase chain reaction (PCR). TGF-beta1 mRNA was significantly increased in chronic hepatitis C relative to healthy controls (P =.03), while TbetaRII mRNA was significantly decreased (P =.001). In the rat model, 5 days after bile duct ligation during increased TGF-beta expression, mRNA for TbetaRII in stellate cells was 40% of that in stellate cells from control livers. This coincided with increased expression of collagen I mRNA and proliferation of stellate cells. The reciprocal relationship between expression of TGF-beta and the type II receptor suggest ligand-mediated receptor down-regulation. The decreased level of TbetaRII appears to be permissive for proliferation while supporting ongoing fibrogenesis. We conclude that modulation of this receptor may be critical to the progression of wound repair in liver.
Roulot
D
D
Liver Center Laboratory, San Francisco General Hospital, San Francisco, CA, USA. dominique.roulot@avc.ap-hop-paris.fr
Sevcsik
A M
AM
Coste
T
T
Strosberg
A D
AD
Marullo
S
S
D000328:Adult; D000368:Aged; D000818:Animals; D001652:Bile Ducts / Q000502:physiology; D001706:Biopsy; D002478:Cells, Cultured; D004727:Endothelium / Q000166:cytology / Q000276:immunology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D012016:Reference Values; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics
D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II