Cotreatment with interferon-α and γ reduces liver fibrosis in a rat model

Background/Aims: Interferon-α is used widely to treat viral hepatitis. Interferon-γ modulates a system attacking infected cells and also has an anti-fibrotic effect. A treatment with interferon-α and -γ has undergone trials in eliminating hepatitis C virus. We investigated effects of cotreatment in a liver fibrosis model to explore anti-fibrotic effects. Methods: Rats were assigned to groups including normal controls (NC), CCl₄ controls, rat interferon-α treatment, rat interferon-γ treatment, and cotreatment. All groups except normal controls received CCl₄ orally for 8 weeks. At the beginning of the third week of exposure, 6 weeks of treatment were initiated according to interferon group. Digitally analyzed immunohistochemistry, biochemical assays, and Northern analysis were performed. Results: Pixels (×10⁵) per field containing immunoreactive type III collagen (fibrotic density) in CCl₄ controls, interferon-α, interferon-γ, and cotreatment groups respectively were 8.1±1.8, 5.0±0.7, 4.9±0.8 and 3.0±0.9. Liver hydroxyproline content correlated with fibrotic density, and was significantly low in the cotreatment group. Plasma hyaluronate and transaminase were significantly low in cotreatment and interferon-α groups. Northern blotting showed lowest mRNA expression for type I collagen, desmin, transforming growth factor (TGF)-β1, and matrix metalloproteinase-2 mRNA in the cotreatment group; tissue inhibitor of metalloproteinase-1 and -2 mRNAs were significantly low in the interferon-γ group. Conclusions: Cotreatment can suppress collagen and transforming growth factor-β1 and has an overall anti-fibrotic effect without exacerbating inflammation.