(LATENT) TRANSFORMING-GROWTH-FACTOR-BETA IN LIVER PARENCHYMAL-CELLS, ITS INJURY-DEPENDENT RELEASE, AND PARACRINE EFFECTS ON RAT HEPATIC STELLATE CELLS

Cultured parenchymal liver cells (PC) were recently recognized to cont ain (latent) transforming growth factor beta (TGF-beta) while the expr ession of TGF-beta mRNA remains controversial, This study was designed to analyze PC in different microenvironments (liver in situ, highly p urified, isolated, and cultured PC) regarding the qualitative and quan titative content of mature and latent TGF-beta protein (immunostaining s, enzyme-linked immunosorbent assay [ELISA], and enzyme-labeled fluor escence [ELF] technique), The results were compared with its gene expr ession (reverse-transcription polymerase chain reaction [PT PCR]), In all microenvironments, PC contained latent TGF-beta, which was partial ly activated after cell isolation and culture, The amount of total TGF -beta (mature plus latent) of latency-associated peptide (LAP) and of latent TGF-beta binding protein (LTBP) were shown to decrease during c ulture. In contrast, TGF-beta(2) and TGF-beta(3) mRNA and LTBP-1 and - 3 mRNA expression were first detectable after culture. Permeabilizatio n of cell membranes in whole liver and of isolated PC with streptolysi n O or carbon tetrachloride, respectively, released TGF-beta, a part o f which was integrated in the large latent complex as estimated by ana lytical gel filtration chromatography, The TGF-beta released by damage d PC induces paracrine effects on hepatic stellate cell cultures, It s timulates hyaluronan synthesis and antagonizes the effect of mitogenic factor(s) of PC on [H-3]thymidine incorporation, The results strongly suggest that the main part of hepatocellular TGF-beta is not generate d by de novo synthesis but from uptake into the liver in vivo, The imm unodetection of preexisting mature TGF-beta after isolation of the cel ls is probably caused by intracellular activation of latent TGF-beta. The injury-dependent discharge of TGF-beta from PC might be an importa nt mechanism for initiation and perpetuation of various forms of chron ic human liver diseases.