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

Hepatocytes express nerve growth factor during liver injury: evidence for paracrine regulation of hepatic stellate cell apoptosis
Hepatocytes express nerve growth factor during liver injury: evidence for paracrine regulation of hepatic stellate cell apoptosis
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.
0002-9440
1849-1858
Oakley, Fiona
f5f32319-966d-46b1-b774-bd7548022ff3
Trim, Nathan
afa06514-3691-4aa3-89b3-c5c3853102ba
Constandinou, Christothea M.
b62268b3-4e77-42f2-9ba9-d989ffb10501
Ye, Weilan
22fe4c6f-191d-4d9b-a1b7-bc622e898de4
Gray, Alane M.
a66f4013-c15f-4c75-bdca-5fbe4567f0e9
Frantz, Gretchen
e051de03-f213-4a96-8ceb-7682ee4140a3
Hillan, Kenneth
7fcee37c-fac7-431e-8231-17d52baa8e6e
Kendall, Tim
46abfa7a-8d31-48e9-8824-6096bf7f4213
Benyon, R. Christopher
6efa9278-56e6-47ec-9854-78afd98dd4c9
Mann, Derek A.
7a0eb3d7-c2ca-432f-82a0-f4b0df08755d
Iredale, John P.
607673ce-77b2-4418-b317-2aa778110ee2
Oakley, Fiona
f5f32319-966d-46b1-b774-bd7548022ff3
Trim, Nathan
afa06514-3691-4aa3-89b3-c5c3853102ba
Constandinou, Christothea M.
b62268b3-4e77-42f2-9ba9-d989ffb10501
Ye, Weilan
22fe4c6f-191d-4d9b-a1b7-bc622e898de4
Gray, Alane M.
a66f4013-c15f-4c75-bdca-5fbe4567f0e9
Frantz, Gretchen
e051de03-f213-4a96-8ceb-7682ee4140a3
Hillan, Kenneth
7fcee37c-fac7-431e-8231-17d52baa8e6e
Kendall, Tim
46abfa7a-8d31-48e9-8824-6096bf7f4213
Benyon, R. Christopher
6efa9278-56e6-47ec-9854-78afd98dd4c9
Mann, Derek A.
7a0eb3d7-c2ca-432f-82a0-f4b0df08755d
Iredale, John P.
607673ce-77b2-4418-b317-2aa778110ee2

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.

Record type: Article

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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Published date: 2003

Identifiers

Local EPrints ID: 27296
URI: http://eprints.soton.ac.uk/id/eprint/27296
ISSN: 0002-9440
PURE UUID: fa2ffa27-137b-4728-aba3-cd31bc689206

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Date deposited: 26 Apr 2006
Last modified: 08 Jan 2022 09:55

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Contributors

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

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