Hepatic stem cells (oval cells) proliferate within the liver after exposure to a variety of hepatic carcinogens and can generate both hepatocytes and bile duct cells. Oval cell proliferation is commonly seen in the preneoplastic stages of liver carcinogenesis, often accompanied by an inflammatory response. Tumor necrosis factor (TNF), an inflammatory cytokine, is also important in liver regeneration and hepatocellular growth. The experiments reported here explore the relationship among the TNF inflammatory pathway, liver stem cell activation, and tumorigenesis. We demonstrate that TNF is upregulated during oval cell proliferation induced by a choline-deficient, ethionine-supplemented diet and that it is expressed by oval cells. In TNF receptor type 1 knockout mice, oval cell proliferation is substantially impaired and tumorigenesis is reduced. Oval cell proliferation is impaired to a lesser extent in interleukin 6 knockout mice and is unchanged in TNF receptor type 2 knockout mice. These findings demonstrate that TNF signaling participates in the proliferation of oval cells during the preneoplastic phase of liver carcinogenesis and that loss of signaling through the TNF receptor type 1 reduces the incidence of tumor formation. The TNF inflammatory pathway may be a target for therapeutic intervention during the early stages of liver carcinogenesis.

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-␤ (LT␤) and interferon gamma ( T he liver has the capacity to regenerate after acute injury by hepatocyte cell division. However, in circumstances where hepatocyte proliferation is attenuated or blocked, the liver is repopulated after induction, proliferation, and differentiation of the stem cell compartment, which includes oval cells. 1 These alternative methods of liver regeneration can be modeled in mice by partial hepatectomy (PHx) and by feeding them a choline-deficient, ethionine-supplemented (CDE) diet. Surgical resection of a portion of liver mimics acute injury, stimulating a replication response from residual healthy parenchymal cells, which undergo cell division to replace the lost liver mass. 1 The CDE diet damages the liver parenchyma and prevents hepatocyte division, leading to activation and rapid induction of large numbers of oval cells in mice. 2 The replication response after PHx involves a rapid and highly coordinated series of biochemical events resulting in hepatocytes undergoing a relatively synchronized progression through the cell cycle. Immediately after the insult, immediate early genes are activated by transcription factors such as nuclear factor kappa B, activating protein 1 (AP1), and STAT-3. The immediate early phase lasts approximately 4 hours in rodents and precedes the delayed early gene response, which renders the hepatocytes responsive to growth factors that drive the