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

被引:112
作者
Lin, T
Genestier, L
Pinkoski, MJ
Castro, A
Nicholas, S
Mogil, R
Paris, F
Fuks, Z
Schuchman, EH
Kolesnick, RN
Green, DR [1 ]
机构
[1] La Jolla Inst Allergy & Immunol, Div Cellular Immunol, San Diego, CA 92121 USA
[2] Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA
[3] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA
[4] Mem Sloan Kettering Canc Ctr, Lab Signal Transduct, New York, NY 10021 USA
关键词
D O I
10.1074/jbc.275.12.8657
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Engagement of the Fas receptor has been reported to induce ceramide generation via activation of acidic sphingomyelinase (aSMase). However, the role of aSMase in Fas-mediated cell, death is controversial. Using genetically engineered mice deficient in the aSMase gene (aSMase(-/-)), we found that thymocytes, concanavalin A-activated T cells, and lipopolysaccharide-activated B cells derived from both aSMase(-/-) and aSMase(+/+) mice were equally sensitive to Fas-mediated cell death, triggered by either anti-Fas antibody or Fas ligand in vitro. Similarly, activation-induced apoptosis of T lymphocytes 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 or 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-Fas antibody was demonstrated with higher antibody doses (greater than or equal to 4 mu g/25 g mouse). These data indicate a role for aSMase in Fas-mediated cell death in some but not all tissues.
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页码:8657 / 8663
页数:7
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