Effect of natural interferon α on proliferation and apoptosis of hepatic stellate cells

Inhibition of the proliferation of hepatic stellate cells (HSC) is clinically important for the control of liver fibrosis and cirrhosis. Interferons are now frequently used for chronic viral hepatitis because of their anti-viral activity. However, patients treated with interferons exhibit a regression of liver fibrosis even if viral eradication is not achieved, indicating that interferon itself has anti-fibrotic activity. Herein, we show the anti-proliferation and pro-apoptotic activity of natural interferon alpha against HSC. We found that interferon alpha inhibited serum-stimulated [H-3]thymidine incorporation of HSC in a dose-dependent manner, with a significant reduction at more than 100 U/ml. Interferon alpha also attenuated PDGF-BB-stimulated DNA synthesis of HSC. Although the molecular mechanism behind these phenomena has not been defined, we found that interferon alpha triggers the apoptosis of HSC treated with low-dose tumor necrosis factor alpha, as determined by the Alamar blue assay, morphology, and DNA ladder formation. Furthermore, interferon alpha decreased inhibitor of caspase-activated DNase (ICAD) levels, which may augment tumor necrosis factor alpha-induced cell death signals. Thus, interferon alpha regulates the number of myofibroblastic hepatic stellate cells and may clinically contribute to the regression of human liver fibrosis.