TNF/LT? double knockout mice display abnormal inflammatory and regenerative responses to acute and chronic liver injury

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Abstract
Following acute liver injury, hepatocytes divide to facilitate regeneration. However, during chronic injury, hepatocyte proliferation is typically blocked and repair is mediated through liver progenitor (oval) cells. Signalling of the p55 tumour necrosis factor (TNF) receptor is central to these processes. Two ligands for p55 are known: TNF and lymphotoxin-alpha (LTα). However, one study suggests that another exists that mediates liver injury following viral challenge. We have therefore investigated whether ligands other than TNF and LTα are required for liver regeneration following either acute or chronic injury. Wild-type and double TNF/LTα knockout (TNF−/−LTα−/−) mice were subjected to either partial hepatectomy (PHx) or a choline-deficient ethionine-supplemented (CDE) diet. Proliferating hepatocytes, oval cells and inflammatory cells were identified and quantified in liver sections by immunohistochemistry. Liver inflammatory cells were characterised by cell surface antigen expression. Liver damage and mortality were monitored. Both hepatocyte and oval cell proliferation was reduced in TNF−/−LTα−/− mice. Lymphocyte clusters were evident in all TNF−/−LTα−/− livers and were heterogeneous, comprising B and T lymphocytes. PHx evoked liver inflammation in TNF−/−LTα−/− but not wild-type mice, whereas no difference was apparent between genotypes in CDE experiments. Thus, TNF/LTα signalling mediates liver regeneration involving both hepatocytes and progenitor cells. The hyper-inflammatory response following PHx in TNF−/−LTα−/− animals, which is absent following CDE-induced injury, demonstrates that the two forms of liver injury evoke discrete inflammatory responses and provides a model in which such differences can be examined further.