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(American Journal of Pathology. 2003;163:1849-1858.)
© 2003 American Society for Investigative Pathology

Hepatocytes Express Nerve Growth Factor during Liver Injury

Evidence for Paracrine Regulation of Hepatic Stellate Cell Apoptosis

Fiona Oakley^*, Nathan Trim^*, Christothea M. Constandinou^*, Weilan Ye, Alane M. Gray, Gretchen Frantz, Kenneth Hillan, Tim Kendall^*, R. Christopher Benyon^*, Derek A. Mann^* and John P. Iredale^*

From the Liver Research Group,^*IIR Division, School of Medicine, Southampton General Hospital, Southampton, United Kingdom; and the Departments of Molecular Biologyand Pathology,Genentech Incorporated, South San Francisco, California

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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