Type I procollagen production and cell proliferation is mediated by transforming growth factor-beta in a model of hepatic fibrosis.
Fibrosis is a significant component of advanced chronic inflammatory liver diseases and is caused by the accumulation of extracellular matrix, including type I procollagen. The mechanism by which fibrosis develops in liver tissue remains unknown. We tested the effects of transforming growth factor beta 1 (TGF-beta), a cytokine that alters cell differentiation and proliferation, and bleomycin, a cytotoxic glycopeptide antibiotic, on cultured isolated rat hepatocytes. TGF-beta (1 ng/ml) inhibited radiolabeled thymidine incorporation 39% at 24 h and 69% at 48 h. Inhibition of hepatocyte proliferation was dose dependent. Bleomycin (1 microgram/ml) significantly inhibited radiolabeled thymidine incorporation at 48 h (44%). Neutralizing antibody to thymidine incorporation at 48 h (44%). Neutralizing antibody to TGF-beta (TGF-beta-Ab) attenuated the inhibition of proliferation by TGF-beta and bleomycin in a concentration-dependent manner. The addition of either TGF-beta or bleomycin increased immunostaining of type I procollagen in hepatocytes. The addition of TGF-beta-Ab alone increased cell proliferation, suggesting that neutralization of endogenous TGF-beta may attenuate the inhibition of hepatocyte proliferation. These data suggest that the hepatocyte contains type I procollagen and, under some conditions, produces TGF-beta. We propose that procollagen production in rat hepatocytes is induced by TGF-beta and may be related to endogenous production of this cytokine in response to cell injury. The cytotoxic effect of bleomycin is mediated by TGF-beta and inhibition of TGF-beta and bleomycin with TGF-beta-Ab attenuates the additive effects of those compounds on isolated rat hepatocytes. These data provide a model of collagen expression in isolated rat hepatocytes.
Eghbali-Fatourechi
G
G
Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Sieck
G C
GC
Prakash
Y S
YS
Maercklein
P
P
Gores
G J
GJ
Fitzpatrick
L A
LA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011347:Procollagen / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*
D000906:Antibodies; D011347:Procollagen; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D004815:Epidermal Growth Factor; D004247:DNA