Interferon tau–induced hepatocyte apoptosis in sheep
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Clinical applications of Type I interferon (IFN) are limited by adverse side effects mediated largely by unknown mechanisms. This study examined the mechanisms of acute hepatic injury in lambs treated with systemic administration of IFN-tau, a Type I IFN. Liver tissues were collected at 24, 48, or 96 hours after treatment with either IFN-tau or saline. Histopathology revealed acute hepatopathy including cellular swelling, cytoplasmic aggregates, and apoptosis in all IFN-tau-treated lambs, which were accompanied by elevation of aspartate transaminase (AST) (P <.01). The number of apoptotic hepatocytes in IFN-tau-treated lambs was higher than for control lambs (P <.001). Immunohistochemistry for proliferating cell nuclear antigen (PCNA) revealed that IFN-tau induced hepatocyte growth arrest at the G0/G1 phase of the cell cycle and that the majority of hepatocytes in S or G2 phase were eliminated by apoptosis. We investigated expression of bax-alpha and bcl-2, acting as pro- and antiapoptotic molecules, in IFN-tau-induced apoptosis. Northern blot analysis revealed increased expression of bax-alpha messenger RNA (mRNA) in IFN-tau-treated lambs (P <.01) compared with control lambs, consistent with the expression pattern for bax-alpha protein. However, there was no detectable difference in expression of bcl-2 proteins between control and IFN-tau-treated lambs. The levels of bax-alpha associated with the mitochondria also increased during IFN-tau treatment. Bax-alpha immunostaining showed scattered immunoreactive hepatocytes with morphological hallmarks of apoptosis. These results suggest that IFN-tau induces growth arrest as well as apoptosis by regulating bax-alpha expression. These pathological effects of IFN-tau on sheep liver indicate potential mechanisms of Type 1 IFN-induced hepatotoxicity in animals and humans.