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J. Biol. Chem., Vol. 275, Issue 35, 27316-27323, September 1, 2000
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From the Department of Physiology, University of Tuebingen,
Gmelinstrasse 5 and § Department of Neurology,
University of Tuebingen, Hoppe-Seyler-Strasse 3, 72076 Tuebingen,
Germany and the ¶ Laboratory of Signal Transduction and
Acid sphingomyelinase (ASM) is reported to
have an essential function in stress-induced apoptosis although the
physiological function of ASM in receptor-triggered apoptosis is
unknown. Here, we delineate a pivotal role for ASM in CD95-triggered
apoptosis of peripheral lymphocytes or hepatocytes in vivo.
We employed intravenous injection of anti-CD4 antibodies or
phytohemagglutinin that was previously shown to result in apoptosis
of peripheral blood lymphocytes or hepatocytes via the endogenous
CD95/CD95 ligand system. Our results demonstrate a high susceptibility
in normal mice whereas ASM knock-out mice fail to immunodeplete T cells
or develop autoimmune-like hepatitis. Likewise, ASM-deficient mice or
hepatocytes and splenocytes ex vivo manifest resistance to
anti-CD95 treatment. These results provide in vivo evidence for an important physiological function of ASM in CD95-induced apoptosis.
CD95-mediated Apoptosis in Vivo Involves Acid
Sphingomyelinase*
,
,
Department of Radiation Oncology, Memorial
Sloan-Kettering Cancer Center, New York, New York 10021
*
The study was supported in part by Deutsche
Forschungsgemeinschaft Grant GU 335/2-3, grants from the Association
International Cancer Research, the Interdisciplinary Center for
Clinical Research (to E. G.) and the Mildred Scheel Stiftung
Grant 1502/5-2 (to M. W. and E. G.), and by National Institutes
of Health Grants CA52462 (to Z. F.) and CA42385 (to R. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
49-7071-2972196; Fax: 49-7071-293073; E-mail:
erich.gulbins@uni- tuebingen.de.
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