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CD95 ligand is a proliferative and antiapoptotic signal in quiescent hepatic stellate cells.
Gastroenterology. 2008 May; 134(5):1494-506.G

Abstract

BACKGROUND & AIMS

Despite expression of CD95 (Fas) receptor, hepatic stellate cells (HSCs) are fairly resistant toward CD95 ligand (CD95L)-induced cell death. The underlying mechanisms and the function of the CD95 system in quiescent HSCs, however, are unknown.

METHODS

The effects of CD95L on quiescent, 1- to 2-day cultured rat HSCs were studied with regard to CD95 activation, signal transduction, proliferation, and apoptosis.

RESULTS

In quiescent HSCs, CD95L led to a rapid phosphorylation of the epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (Erk), and c-Src, but not of c-Jun-N-terminal kinase and p47(phox), an activating subunit of reduced nicotinamide adenine dinucleotide phosphate oxidase. CD95L-induced EGFR and Erk phosphorylation were abolished after proteinase inhibition by GM6001 and in the presence of neutralizing epidermal growth factor antibodies, suggestive of a ligand-dependent EGFR phosphorylation in response to CD95L. In quiescent HSCs, CD95L did not induce apoptotic cell death but stimulated HSC proliferation and triggered a rapid inactivating CD95 tyrosine nitration that was not detected in activated HSCs (10-14 days of culture). EGFR phosphorylation, HSC proliferation, and CD95 tyrosine nitration were also triggered by tumor necrosis factor alpha and tumor necrosis factor-related apoptosis-inducing ligand.

CONCLUSIONS

In quiescent HSCs, CD95L and other death receptor ligands are mitogens through a ligand-dependent EGFR phosphorylation. Simultaneously, an antiapoptotic signaling is triggered by CD95L-induced CD95 tyrosine nitration. This unusual response to death receptor ligands may help quiescent HSCs to participate in liver regeneration following liver injury.

Authors+Show Affiliations

Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Düsseldorf, Germany.No affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18471522

Citation

Reinehr, Roland, et al. "CD95 Ligand Is a Proliferative and Antiapoptotic Signal in Quiescent Hepatic Stellate Cells." Gastroenterology, vol. 134, no. 5, 2008, pp. 1494-506.
Reinehr R, Sommerfeld A, Häussinger D. CD95 ligand is a proliferative and antiapoptotic signal in quiescent hepatic stellate cells. Gastroenterology. 2008;134(5):1494-506.
Reinehr, R., Sommerfeld, A., & Häussinger, D. (2008). CD95 ligand is a proliferative and antiapoptotic signal in quiescent hepatic stellate cells. Gastroenterology, 134(5), 1494-506. https://doi.org/10.1053/j.gastro.2008.02.021
Reinehr R, Sommerfeld A, Häussinger D. CD95 Ligand Is a Proliferative and Antiapoptotic Signal in Quiescent Hepatic Stellate Cells. Gastroenterology. 2008;134(5):1494-506. PubMed PMID: 18471522.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CD95 ligand is a proliferative and antiapoptotic signal in quiescent hepatic stellate cells. AU - Reinehr,Roland, AU - Sommerfeld,Annika, AU - Häussinger,Dieter, Y1 - 2008/02/14/ PY - 2007/10/02/received PY - 2008/01/31/accepted PY - 2008/5/13/pubmed PY - 2008/6/5/medline PY - 2008/5/13/entrez SP - 1494 EP - 506 JF - Gastroenterology JO - Gastroenterology VL - 134 IS - 5 N2 - BACKGROUND & AIMS: Despite expression of CD95 (Fas) receptor, hepatic stellate cells (HSCs) are fairly resistant toward CD95 ligand (CD95L)-induced cell death. The underlying mechanisms and the function of the CD95 system in quiescent HSCs, however, are unknown. METHODS: The effects of CD95L on quiescent, 1- to 2-day cultured rat HSCs were studied with regard to CD95 activation, signal transduction, proliferation, and apoptosis. RESULTS: In quiescent HSCs, CD95L led to a rapid phosphorylation of the epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (Erk), and c-Src, but not of c-Jun-N-terminal kinase and p47(phox), an activating subunit of reduced nicotinamide adenine dinucleotide phosphate oxidase. CD95L-induced EGFR and Erk phosphorylation were abolished after proteinase inhibition by GM6001 and in the presence of neutralizing epidermal growth factor antibodies, suggestive of a ligand-dependent EGFR phosphorylation in response to CD95L. In quiescent HSCs, CD95L did not induce apoptotic cell death but stimulated HSC proliferation and triggered a rapid inactivating CD95 tyrosine nitration that was not detected in activated HSCs (10-14 days of culture). EGFR phosphorylation, HSC proliferation, and CD95 tyrosine nitration were also triggered by tumor necrosis factor alpha and tumor necrosis factor-related apoptosis-inducing ligand. CONCLUSIONS: In quiescent HSCs, CD95L and other death receptor ligands are mitogens through a ligand-dependent EGFR phosphorylation. Simultaneously, an antiapoptotic signaling is triggered by CD95L-induced CD95 tyrosine nitration. This unusual response to death receptor ligands may help quiescent HSCs to participate in liver regeneration following liver injury. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/18471522/CD95_ligand_is_a_proliferative_and_antiapoptotic_signal_in_quiescent_hepatic_stellate_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(08)00254-0 DB - PRIME DP - Unbound Medicine ER -