CELL-SPECIFIC EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA IN RAT-LIVER - EVIDENCE FOR AUTOCRINE REGULATION OF HEPATOCYTE PROLIFERATION

Expression of the group of cytokines known as transforming growth fact or-beta (TGF-beta 1, -beta 2 and -beta 3) is increased during liver re generation induced by a 70% partial hepatectomy, The origin of these c hanges was examined in purified isolates of hepatocytes, sinusoidal en dothelial cells, Kupffer cells (liver macrophages), and lipocytes (Ito or stellate cells) from normal and regenerating liver, In normal live r, TGF-beta 1 and -beta 2 levels were relatively high in sinusoidal en dothelial cells and Kupffer cells, After partial hepatectomy, an early peak of TGF-beta 2 and -beta 3 was present in all four cell types, fo llowed by a sustained increase in mRNA for TGF-beta 1, -beta 2, and -b eta 3 primarily in the hepatocyte population, The specificity of these changes was established by examining a mechanistically different inju ry model, fibrosis induced by ligation of the biliary duct. In this mo del, TGF beta mRNA was increased only in lipocytes and the increase wa s progressive over a 7-d period of observation, Secretion of TGF beta protein was examined in cell isolates placed in short-term primary cul ture and generally reflected the corresponding mRNA level. The TGF bet a released by hepatocytes was entirely in the latent form, whereas the individual nonparenchymal cell isolates released 50-90% active TGF be ta. Hepatocyte-conditioned culture medium, after treatment to activate latent TGF beta, inhibited hepatocellular DNA synthesis as did the au thentic factor, The data indicate that after injury TGF beta increases selectively in the cells that are the target of the factor, i.e., in hepatocytes after partial hepatectomy and in lipocytes in inflammation and fibrosis, We conclude that the effects of TGF beta in liver regen eration and fibrogenesis are predominantly, if not exclusively, autocr ine.