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.
Wada
Wataru
W
Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
Kuwano
Hiroyuki
H
Hasegawa
Yoshihisa
Y
Kojima
Itaru
I
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