Differential lymphotoxin-β and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury†

The liver regenerates after acute injury via hepatocyte cell division; during chronic injury, when hepatocyte replication is impaired or blocked, liver progenitor oval cells mediate liver regeneration. If both regeneration options are blocked in animal models, then liver failure and death ensues. The mechanisms underlying oval cell induction, proliferation, and subsequent liver regeneration remain poorly characterized. In particular, cell-signaling pathways that distinguish the alternative pathways are unknown. This study shows that in a mouse model, hepatic expression of lymphotoxin-β (LTβ) and interferon gamma (IFNγ) transcripts is increased in response to the choline-deficient, ethionine-supplemented (CDE) diet, which induces oval cell–mediated liver regeneration. Oval cells express LTβ and IFNγ transcripts, contributing to the increased expression in the liver of mice fed the CDE diet. An attenuated oval cell response to such a diet was observed in LTβ receptor-, LTβ-, and IFNγ-gene targeted mice. Loss of LTβ and LTβ receptor signaling reduced the number of oval cells expressing A6 and muscle pyruvate kinase. The lack of IFNγ signaling reduced muscle pyruvate kinase+, but not A6+, oval cells. In contrast, partial hepatectomy suppressed LTβ and IFNγ transcripts. We also show that IFNγ induces STAT-3 phosphorylation in an oval cell line. In conclusion, LTβ, LTβ receptor, and IFNγ are involved in oval cell–mediated, but not hepatocyte-mediated, liver regeneration, and the absence of these pathways impairs the oval cell–dependent regenerative response. (HEPATOLOGY 2005;41:327–335.)