Differential expression of transforming growth factor-β and its receptors in hepatocytes and nonparenchymal cells of rat liver after CCl 4 administration

Abstract

Background/Aims: Transforming growth factor-β (TGF-β) 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-β receptor expression contributes to the liver diseases. Methods: The mRNA expression of TGF-β1, TGF-β type I receptor (TGFβRI), TGF-β II receptor (TGFβRII) and TGF-β type III receptor (TGFβRIII) in rat livers injured by CCl 4 administration was studied by Northern blotting. The mRNA expression patterns were confirmed by in situ hybridization. Result: The peak of TGF-β1 mRNA expression was observed 48 h after acute intoxication with CCl 4 in nonparenchymal cells. However, the levels of TGFβRI and TGFβRII 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. TGFβRII mRNA expression was depressed more and for longer than that or TGFβRI mRNA. Analysis in separated hepatocytes and nonparenchymal cells from the injured livers indicated that the mRNA changes occurred in hepatocytes. Nonparenchymal cells expressed TGFβRI and TGFβRII mRNAs at constant levels during liver regeneration. TGFβRIII 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-β1 is increased in CCl 4-treated livers, it may induce liver fibrogenesis via nonparenchymal cells; (ii) mitoinhibitory effect of TGF-β1 on hepatocytes is transiently relieved by down-regulation of TGF-β receptors for 72 h post-damage; and (iii) the resistance to TGF-β growth inhibition between24 to 48 h may be predominantly due to down-regulation of the expression of TGFβRII.