Modulation of transforming growth factor beta function in hepatocytes and hepatic stellate cells in rat liver injury.

Abstract

Transforming growth factor beta (TGF-beta) regulates hepatocyte proliferation and biosynthesis of the extracellular matrix. This study investigated alternations in sensitivity to TGF-beta1 and binding properties for ligand in hepatocytes and hepatic stellate cells (HSC) after CCl(4) administration. Plasma TGF-beta1 levels in rats after CCl(4) administration were determined using ELISA. Effects of TGF-beta1 were examined by DNA synthesis in hepatocytes and by measurement of fibronectin production in HSC after CCl(4) administration. Binding of (125)I TGF-beta1 was tested in these cells. Plasma TGF-beta1 levels were increased as early as 24 hours and were maximal by 48 hours. The antiproliferative response to TGF-beta1 decreased in hepatocytes at 48 hours and normalised at 72 hours. Fibronectin production of both normal and injured HSC was affected by TGF-beta1 treatment. Cross linked ligand/receptor complexes were detected in normal hepatocytes and HSC. However, these levels decreased specifically in hepatocytes at 48 hours and normalised by 72 hours. Downregulation of TGF-beta receptor occurred in hepatocytes after chemical insult and TGF-beta1 could not transduce its antiproliferative signal. Recovery of TGF-beta receptor expression causes the signal to transduce to the nucleus at 72 hours. In HSC, whenever TGF-beta1 is increased, TGF-beta1 can transduce its signal for fibronectin production via its receptor because signalling receptors are expressed constantly.