CD95 ligand is a proliferative and antiapoptotic signal in quiescent hepatic stellate cells.
OBJECTIVE
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.
Reinehr
Roland
R
Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich Heine University, Düsseldorf, Germany.
Sommerfeld
Annika
A
Häussinger
Dieter
D
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics*; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D010766:Phosphorylation; D012313:RNA / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D053222:Fas Ligand Protein; D017382:Reactive Oxygen Species; D012313:RNA; D066246:ErbB Receptors