Effects of Interleukin-6 on the Growth of Normal and Transformed Rat Liver Cells in Culture

Recombinant human interleukin-6 produced a dose-dependent inhibition of DNA synthesis in both growing and mitogen-stimulated cultures of normal rat liver epithelial cells and also in primary rat hepatocytes. A significant inhibition of DNA synthesis (P<0.001) was obtained with 1 ng/ml (10 Units/ml) interleukin-6 in normal rat liver epithelial cells. The ID50 for inhibition of DNA synthesis in primary rat hepatocytes was 1 ng/ml. In contrast to the effects of transforming growth factor beta (Type I), where an almost complete inhibition of DNA synthesis could be achieved with either cell type, the maximal inhibition observed with interleukin-6 for both of these cell types was about 45%. Thus distinct mechanisms are involved in the inhibition of liver cell growth by these growth modulators. Transformed liver-derived cell lines were relatively resistant to the growth inhibitory effects of both interleukin-6 and TGF-beta 1 compared with the normal cells. However, human Hep G2 cells, which were completely resistant to the growth inhibitory effects of TGF-beta 1, were moderately inhibited by interleukin-6, indicating that the mechanisms responsible for the acquired resistance to growth inhibition is different for these growth inhibitors. The ability of interleukin-6 to function as a growth inhibitor in vitro was confirmed using normal rat liver epithelial cells. Interleukin-6 at a concentration of 10 ng/ml produced a significant decrease (P<0.05) in the proliferation of these cells. These data demonstrate that interleukin-6 may have the capability of functioning as a growth regulatory polypeptide for liver cells in vivo. The differential responsiveness of normal and transformed cells to its inhibitory activity suggest that its synthesis during the course of hepatocarcinogenesis could participate in the altered growth regulation of preneoplastic and neoplastic cells.