Different physiology of interferon-α/-γ in models of liver regeneration in the rat

Liver regeneration may take place after liver injury through replication of hepatocytes or hepatic progenitor cells called oval cells. Interferons (IFN) are natural cytokines with pleiotrophic effects including antiviral and antiproliferative actions. No data are yet available on the physiology and cellular source of natural IFNs during liver regeneration. To address this issue, we have analyzed the levels and biologic activities of IFN-alpha/IFN-gamma in two models of partial hepatectomy. After 2/3rd partial hepatectomy (PH), hepatic levels of IFN-alpha and IFN-gamma declined transiently in contrast to a transient increase of the IFN-gamma serum level. After administration of 2-acetylaminofluorene and partial hepatectomy (AAF/PH model), however, both IFN-alpha and IFN-gamma expression were up-regulated in regenerating livers. Again, the IFN-gamma serum level was transiently increased. Whereas hepatic IFN-gamma was up-regulated early (day 1-5), but not significantly, in the AAF/PH model, IFN-alpha was significantly up-regulated at later time points in parallel to the peak of oval cell proliferation (days 7-9). Biological activity of IFN-alpha was shown by activation of IFN-alpha-specific signal transduction and induction of IFN-alpha specific-gene expression. We found a significant infiltration of the liver with inflammatory monocyte-like mononuclear phagocytes (MNP) concomitant to the frequency of oval cells. We localized IFN-alpha production only in MNPs, but not in oval cells. These events were not observed in normal liver regeneration after standard PH. We conclude that IFN-gamma functions as an acute-phase cytokine in both models of liver regeneration and may constitute a systemic component of liver regeneration. IFN-alpha was increased only in the AAF/PH model, and was associated with proliferation of oval cells. However, oval cells seem not to be the source of IFN-alpha. Instead, inflammatory MNP infiltrating AAF/PH-treated livers produce IFN-alpha. These inflammatory MNPs may be involved in the regulation of the oval cell compartment through local expression of cytokines, including IFN-alpha.