Role of acidic sphingomyelinase in Fas/CD95-mediated cell death

Engagement of the Fas receptor has been reported to induce ceramide generat ion via activation of acidic sphingomyelinase (aSMase). However, the role o f aSMase in Fas-mediated cell, death is controversial. Using genetically en gineered mice deficient in the aSMase gene (aSMase(-/-)), we found that thy mocytes, concanavalin A-activated T cells, and lipopolysaccharide-activated B cells derived from both aSMase(-/-) and aSMase(+/+) mice were equally se nsitive to Fas-mediated cell death, triggered by either anti-Fas antibody o r Fas ligand in vitro. Similarly, activation-induced apoptosis of T lymphoc ytes was unaffected by the status of aSMase, and aSMase(-/-) mice failed to show immunological symptoms seen in animals with defects in Fas function, In vivo, intravenous injection of 3 mu g/25 g mouse body weight of anti-Fas Jo2 antibody into asMase(-/-) mice failed to affect hepatocyte apoptosis o r mortality, whereas massive hepatocyte apoptosis and animal death occurred in wild type littermates, Animals heterozygous for aSMase deficiency were also significantly protected. Susceptibility of aSMase(-/-) mice to anti-Fa s antibody was demonstrated with higher antibody doses (greater than or equ al to 4 mu g/25 g mouse). These data indicate a role for aSMase in Fas-medi ated cell death in some but not all tissues.