The dependence of transforming growth factor-beta-induced collagen production on autocrine factor activin A in hepatic stellate cells.
The present study was conducted to examine the role of activin A in the activation of cultured rat hepatic stellate cells (HSC). HSC expressed mRNA for the beta(A)-subunit of activin and the type I and II activin receptors. TGF-beta increased the mRNA expression of the beta(A)-subunit of activin as well as the release of the beta(A) dimer, activin A. Exogenous activin A activated HSC and increased the expression of alpha-smooth muscle actin and collagen. Exogenous follistatin, an antagonist of activin A, blocked not only the effect of activin A but also the effect of TGF-beta on the expression of type I collagen. Similarly, follistatin inhibited TGF-beta-induced secretion of collagen from HSC. Additionally, the effect of TGF-beta was markedly reduced in HSC overexpressing the dominant-negative type II activin receptor. In contrast, the effect of activin A on the collagen production was not affected in HSC overexpressing the dominant-negative type II TGF-beta receptor. In conclusion, an autocrine factor activin A mediates part of the action of TGF-beta on the production of collagen in HSC. The results also suggest that follistatin may be useful for the treatment of hepatic fibrosis.
Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
Wataru
W
Wada
Hiroyuki
H
Kuwano
Yoshihisa
Y
Hasegawa
Itaru
I
Kojima
D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D028341:Activins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D038681:Follistatin / Q000494:pharmacology; D005799:Genes, Dominant; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D028322:Inhibin-beta Subunits / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D011506:Proteins; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
D038681:Follistatin; D011506:Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins; D003094:Collagen; D028322:Inhibin-beta Subunits; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A