TY - JOUR
T1 - Role of acidic sphingomyelinase in Fas/CD95-mediated cell death
AU - Lin, Tesu
AU - Genestier, Laurent
AU - Pinkoski, Michael J.
AU - Castro, Arturo
AU - Nicholas, Shelby
AU - Mogil, Rona
AU - Paris, Francois
AU - Fuks, Zvi
AU - Schuchman, Edward H.
AU - Kolesnick, Richard N.
AU - Green, Douglas R.
PY - 2000/3/24
Y1 - 2000/3/24
N2 - 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 μg/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 (≥4 μg/25 g mouse). These data indicate a role for aSMase in Fas-mediated cell death in some but not all tissues.
AB - 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 μg/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 (≥4 μg/25 g mouse). These data indicate a role for aSMase in Fas-mediated cell death in some but not all tissues.
UR - http://www.scopus.com/inward/record.url?scp=0034708831&partnerID=8YFLogxK
U2 - 10.1074/jbc.275.12.8657
DO - 10.1074/jbc.275.12.8657
M3 - Article
C2 - 10722706
AN - SCOPUS:0034708831
SN - 0021-9258
VL - 275
SP - 8657
EP - 8663
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 12
ER -