Acid ceramidase but not acid sphingomyelinase is required for tumor necrosis factor-α-induced PGE2 production

Youssef H. Zeidan, Benjamin J. Pettus, Saeed Elojeimy, Tarek Taha, Lina M. Obeid, Toshihiko Kawamori, James S. Norris, Yusuf A. Hannun

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53 Scopus citations

Abstract

Sphingolipids are well established effectors of signal transduction downstream of the tumor necrosis factor (TNF) receptor. In a previous study, we showed that the sphingosine kinase/sphingosine 1-phosphate (S1P) pathway couples TNF receptor to induction of the cyclooxygenase 2 gene and prostaglandin synthesis (Pettus, B. J., Bielawski, J., Porcelli, A. M., Reames, D. L., Johnson, K. R., Morrow, J., Chalfant, C. E., Obeid, L. M., and Hannun, Y. A. (2003) FASEB J. 17, 1411-1421). In this study, the requirement for acid sphingomyelinase and sphingomyelin metabolites in the TNFα/prostaglandin E2 (PGE2) pathway was investigated. The amphiphilic compound desipramine, a frequently employed inhibitor of acid sphingomyelinase (ASMase), blocked PGE2 production. However, the action of desipramine was independent of its action on ASMase, since neither genetic loss of ASMase (Niemann-Pick fibroblasts) nor knockdown of ASMase using RNA interference affected TNFα-induced PGE2 synthesis. Further investigations revealed that desipramine down-regulated acid ceramidase (AC), but not sphingosine kinase, at the protein level. This resulted in a time-dependent drop in sphingosine and S1P levels. Moreover, exogenous administration of either sphingosine or S1P rescued PGE2 biosynthesis after desipramine treatment. Interestingly, knockdown of endogenous AC by RNA interference attenuated cyclooxygenase 2 induction by TNFα and subsequent PGE 2 biosynthesis. Taken together, these results define a novel role for AC in the TNFα/PGE2 pathway. In addition, the results of this study warrant careful reconsideration of desipramine as a specific inhibitor for ASMase.

Original languageEnglish (US)
Pages (from-to)24695-24703
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number34
DOIs
StatePublished - Aug 25 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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