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.

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.

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 α and tumor necrosis factor–related apoptosis-inducing ligand.

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.