The dependence of transforming growth factor-beta-induced collagen production on autocrine factor activin A in hepatic stellate cells

Endocrinology. 2004 Jun;145(6):2753-9. doi: 10.1210/en.2003-1663. Epub 2004 Mar 4.

Abstract

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.

MeSH terms

  • Activin Receptors, Type I / metabolism
  • Activin Receptors, Type II / genetics
  • Activin Receptors, Type II / metabolism
  • Activins / metabolism
  • Activins / pharmacology
  • Activins / physiology*
  • Animals
  • Cells, Cultured
  • Collagen / biosynthesis*
  • Follistatin / pharmacology
  • Genes, Dominant
  • Hepatocytes / metabolism*
  • Humans
  • Inhibin-beta Subunits / metabolism
  • Inhibin-beta Subunits / pharmacology
  • Inhibin-beta Subunits / physiology*
  • Proteins*
  • Rats
  • Recombinant Proteins / pharmacology
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / physiology*

Substances

  • Follistatin
  • Proteins
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • activin A
  • Activins
  • Collagen
  • Inhibin-beta Subunits
  • ACVR1 protein, human
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • activin receptor type II-A