Fas (CD95, APO‐1) antigen expression and function in murine liver endothelial cells: implications for the regulation of apoptosis in liver endothelial cells

ABSTRACTThe Fas (CD95, APO‐1) receptor is a membrane‐associated polypeptide that can mediate apoptosis in various cell types. Although Fas receptor is expressed in endothelial cells (EC), little is known about its function in these cells. The expression of Fas by liver endothelial cells (LEC) suggests that upon stimulation, apoptosis may occur in these cells. We show that Fas is highly and constitutively expressed in cloned murine liver endothelial cells (LEC‐1). In contrast, FasL expression was not detected at the protein and mRNA level in these cells. Our results show that Fas ligation in LEC‐1 induces apoptotic cell death, indicating that Fas receptor is functional in these cells. The doses of Fas agonist required to induce LEC‐1 apoptosis were higher than those used previously in other cells, including hepatocytes, suggesting that LEC‐1 are highly resistant to the Fas apoptotic pathway. TNF treatment of LEC‐1 induced up‐regulation of Fas receptor on these cells. In contrast, TNF did not induce the expression of FasL on LEC‐1. An increased susceptibility to Fas‐mediated apoptosis was observed in TNF‐treated LEC‐1. Enhanced susceptibility to Fas‐mediated apoptosis was also observed in LEC‐1 pretreated with actinomycin D, suggesting that transcription of message coding for protective proteins is necessary to protect these cells against Fas‐mediated apoptosis. Up‐regulation of VCAM‐1 and ICAM‐1 was observed in LEC‐1 treated with a dose of Fas agonist that does not induce apoptosis. To our knowledge, this is the first report that Fas mediates apoptosis in LEC, suggesting that apoptosis of these cells may participate in the liver damage observed in animals after receiving anti‐Fas mAb or soluble FasL. Our findings also suggest that the Fas/FasL system may transduce activating signals independently of cell death in LEC‐1.—Cardier, J. E., Schulte, T., Kammer, H., Kwak, J., Cardier, M. Fas (CD95, APO‐1) antigen expression and function in murine liver endothelial cells: implications for the regulation of apoptosis in liver endothelial cells. FASEB J. 13, 1950–1960 (1999)