Tumor Necrosis Factor and Liver Regeneration

Abstract

Liver has the remarkable ability to regenerate, but the mechanism of regeneration is still not well known. Liver resection or hepatocyte loss caused by viral or chemical injury initiates hepatocyte replication, whereas an enlarged liver mass is corrected by apoptosis. “Stem-like” cells proliferate when hepatocyte replication is blocked or delayed. Studies of the mechanisms that regulate liver growth have been done in animals subjected to partial hepatectomy (PH) or chemical injury. Liver regeneration can be divided into several phases, starting with expression of a large number of immediate early genes. Hepatocytes must be primed before they can fully respond to growth factors. Priming requires the cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6). At least four transcription factors (NF-κB, STAT3, AP-1, C/EBP) play major roles in the initiation of liver regeneration. TNF can initiate DNA replication after PH. It acts through a pathway that involves TNF receptor type 1 (TNFR-1), NF-κB, IL-6, and STAT3. We studied liver regeneration in TNFR-1, TNFR-2, and wild-type (WT) C57B1/6 mice injected with carbon tetrachloride (CC14). Lack of TNFR-1 inhibited hepatocyte DNA synthesis after CC14 injection. TNFR-1 knockout mice had little detectable NF-κB and STAT3 binding after CC14 injection. In contrast, a lack of TNFR-2 did not differ significantly in WT mice regarding NF-κB and STAT3 binding, IL-6 and TNF levels, or hepatocyte replication. We conclude that a TNFR-1 signaling pathway involving NF-κB, IL-6, and STAT3 is an important component of the hepatocyte mitogenic response induced by CC14 injury in mouse liver.