Differential expression of transforming growth factor-β and its receptors in hepatocytes and nonparenchymal cells of rat liver after CCl4 administration

Background/Aims: Transforming growth factor-beta (TGF-beta) is a family of multifunctional proteins that regulate hepatocyte proliferation, and biosynthesis of the extracellular matrix. In this study we examined whether modulation of TGF-beta receptor expression contributes to the liver diseases. Methods: The mRNA expression of TGF-beta 1, TGF-beta type I receptor (TGF beta RI), TGF-beta type II receptor (TGF beta RII) and TGF-beta type III receptor (TGF beta RIII) in rat livers injured by CCl4 administration was studied by Northern blotting, The mRNA expression patterns mere confirmed by in situ hybridization. Result: The peak of TGF-beta 1 mRNA expression was observed 48 h after acute intoxication with CCl4 in nonparenchymal cells, However, the levels of TGF beta RI and TGF beta RII mRNA expression decreased from 24 h to 48 h and from 12 h to 48 h, respectively, and returned to the normal level by 72 h. TGF beta RII mRNA expression was depressed more and for longer than that of TGF beta RI mRNA. Analysis in separated hepatocytes and nonparenchymal cells from the injured livers indicated that the mRNA changes occurred in hepatocytes, Nonparenchymal cells expressed TGF beta RI and TGF beta RII mRNAs at constant levels during liver regeneration, TGF beta RIII mRNA, ,which also decreased after 12 h, was not apparent in hepatocytes but only in nonparenchymal cells. Conclusions: These observations suggest that: (i) whenever TGF-beta 1 is increased in CCl4-treated livers, it may induce liver fibrogenesis via nonparenchymal cells; (ii) the mitoinhibitory effect of TGF-beta 1 on hepatocytes is transiently relieved by down-regulation of TGF-beta receptors for 72 h post-damage; and (iii) the resistance to TGF-beta growth inhibition between 24 to 48 h may be predominantly due to down-regulation of the expression of TGF beta RII.