Overexpression of Acid Ceramidase Protects from Tumor Necrosis Factor-Induced Cell Death

doi:10.1084/jem.192.5.601

Published online 5 September 2000.

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© The Rockefeller University Press, 0022-1007/2000/9/601/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 5, September 5, 2000 601-612

Original Article

Overexpression of Acid Ceramidase Protects from Tumor Necrosis Factor–Induced Cell Death

Astrid Strelow^a, Katussevani Bernardo^a, Sabine Adam-Klages^a, Thomas Linke^b, Konrad Sandhoff^b, Martin Krönke^a, and Dieter Adam^a

^a Institut für Immunologie, Christian-Albrechts-Universität Kiel, 24105 Kiel, Germany
^b Kekulé-Institut für Organische Chemie und Biochemie, 53121 Bonn, Germany
Institut für Immunologie der Christian-Albrechts-Universität Kiel, Michaelisstr. 5, 24105 Kiel, Germany.49-431-597-333549-431-597-3375

dadam{at}email.uni-kiel.de

Tumor necrosis factor (TNF) signals cell death and simultaneouslyinduces generation of ceramide. To evaluate the contributionof ceramide to TNF-dependent cell death, we generated clonesof the TNF-sensitive cell line L929 that constitutively overexpresshuman acid ceramidase (AC). Ceramidase, in concert with sphingosinekinase, metabolizes ceramide to sphingosine-1-phosphate (SPP),an inducer of proliferation. In response to TNF, parental L929cells display a significant increase in intracellular ceramidecorrelated with an "atypical apoptosis" characterized by membraneblebbing, DNA fragmentation and degradation of poly(ADP-ribose)polymerase despite a lack of caspase activity. These featuresare strongly reduced or absent in AC-overexpressing cells. Pharmacologicalsuppression of AC with N-oleoylethanolamine restored the accumulationof intracellular ceramide as well as the sensitivity of thetransfectants to TNF, implying that an enhanced metabolizationof intracellular ceramide by AC shifts the balance between intracellularceramide and SPP levels towards cell survival. Correspondingly,inhibition of ceramide production by acid sphingomyelinase alsoincreased survival of TNF-treated L929 cells.

Key Words: ceramidase • L929 cell • tumor necrosis factor • cell death • ceramide

Abbreviations used in this paper: 7-AAD, 7-amino-actinomycinD; AC, acid ceramidase; A-SMase, acid sphingomyelinase; C₁₆-ceramide,N-palmitoylsphingosine; DAPI, 4',6-diamidino-2-phenylindole;NOE, N-oleoylethanolamine; N-SMase, neutral sphingomyelinase;PARP, poly (ADP-ribose) polymerase; SPP, sphingosine-1-phosphate;zDEVD-afc, benzyloxycarbonyl-Asp-Glu-Val-Asp-aminotrifluoromethylcoumarin;zIETD-afc, benzyloxycarbonyl-Ile-Glu-Thr-Asp-aminotrifluoromethylcoumarin;zVAD-fmk, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone.

K. Bernardo and M. Krönke's current address is Institutfür Medizinische Mikrobiologie und Hygiene, UniversitätKöln, Goldenfelsstr. 19-21, 50935 Köln, Germany.

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