Effect of tumour necrosis factor-α on proliferation, activation and protein synthesis of rat hepatic stellate cells

Background/Aims: Hepatic stellate cells represent the principal matrix-synthesising cells of damaged liver and are targets of a number of cytokines currently under investigation. The study analyses the effects of tumour necrosis factor-α and interferon-γ on proliferation, “activation” and protein synthesis of hepatic stellate cells. Methods: Primary cultures of hepatic stellate cells were exposed to tumour necrosis factor-α and interferon-γ. Cell proliferation, was studied by 3H-thymidine and bromo-deoxy-uridine incorporation. Protein synthesis was analysed using immunoprecipitation, Western- and Northern blotting techniques. Results: Proliferation of hepatic stellate cells was reduced by tumor necrosis factor-α and interferon-γ, while “activation” of hepatic stellate cells as assessed by expression of smooth muscle α-actin and of TGF-β/activin type I receptor was induced by tumour necrosis factor-α but downregulated by interferon-γ. Tumour necrosis factor-α increased the synthesis of distinct extracellular matrix proteins, particularly of fibronectin and tenascin, but decreased collagen type III expression. In contrast, interferon-γ reduced the synthesis of all connective tissue proteins tested. Among the protease inhibitors, interferon-γ induced C1-esterase inhibitor synthesis, while tumour necrosis factor-α stimulated plasminogen activator inhibitor type 1 production. Conclusions: Tumour necrosis factor-α and interferon-γ decrease proliferation of hepatic stellate cells, while “activation” of hepatic stellate cells and synthesis of proteins involved in matrix metabolism are regulated in a differential, cytokine-specific manner, suggesting that both cytokines play an important role in liver repair.