Hepatocytes express nerve growth factor during liver injury: evidence for paracrine regulation of hepatic stellate cell apoptosis

Oakley, Fiona, Trim, Nathan, Constandinou, Christothea M., Ye, Weilan, Gray, Alane M., Frantz, Gretchen, Hillan, Kenneth, Kendall, Tim, Benyon, R. Christopher, Mann, Derek A. and Iredale, John P. (2003) Hepatocytes express nerve growth factor during liver injury: evidence for paracrine regulation of hepatic stellate cell apoptosis. The American Journal of Pathology, 163 (5), 1849-1858.

Abstract

A key feature of recovery from liver fibrosis is hepatic stellate cell (HSC) apoptosis, which serves the dual function of removing the major source of neomatrix and tissue inhibitors of metalloproteinases thereby facilitating matrix degradation. The mechanisms regulating HSC apoptosis remain undefined but may include the interaction of nerve growth factor (NGF) with its receptor, p75, on HSC. In this study, by TaqMan polymerase chain reaction in situ hybridization and immunohistochemistry, we demonstrate that NGF is expressed by hepatocytes during fibrotic injury. Peak hepatocyte expression of NGF (48 hours after CCl4 injection) coincides with maximal rate of apoptosis of HSC by terminal dUTP nick-end labeling staining. Addition of recombinant NGF to HSC in tissue culture causes a dose-dependent increase in apoptosis. NGF regulates nuclear factor (NF)-?B activity, reducing p50/p65 binding detected by electromobility shift assay and reduced NF-?B CAT reporter activities from both basal unstimulated levels and after NF-?B induction by tumor necrosis factor. In each case, a relative reduction in NF-?B binding was associated with a significant increase in caspase 3 activity. These data provide evidence that NGF is expressed during fibrotic liver injury and may regulate number of activated HSCs via induction of apoptosis.

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