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J. Biol. Chem., Vol. 281, Issue 34, 24695-24703, August 25, 2006

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Acid Ceramidase but Not Acid Sphingomyelinase Is Required for Tumor Necrosis Factor--induced PGE₂ Production^*

Youssef H. Zeidan, Benjamin J. Pettus, Saeed Elojeimy, Tarek Taha, Lina M. Obeid^¶||, Toshihiko Kawamori^**, James S. Norris, and Yusuf A. Hannun¹

From the Departments of Biochemistry and Molecular Biology, Microbiology and Immunology, ^**Pathology and Laboratory Medicine, and ^||Medicine, Medical University of South Carolina, Charleston, South Carolina 29425 and the ^¶Department of Veterans Affairs Medical Center, Charleston, South Carolina 29401

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 TNF/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 TNF-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 TNF and subsequent PGE₂ biosynthesis. Taken together, these results define a novel role for AC in the TNF/PGE₂ pathway. In addition, the results of this study warrant careful reconsideration of desipramine as a specific inhibitor for ASMase.

Received for publication, May 17, 2006

^* This work was supported in part by National Institutes of Health Grants CA87584 (to Y. A. H.), GM62887 (to L. M. O.), Hollings Cancer Center Dept. of Defense Grant GC3532-03-42153CM, Center of Biomedical Research Excellence Grant P20-RR017677 (to T. K.), and a MERIT Award by the Office of Research and Development, Dept. of Veterans Affairs, Ralph H. Johnson Veterans Affairs Medical Center (Charleston, SC) (to L. M. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology Medical University of South Carolina, 175 Ashley Ave., P.O. Box 250509, Charleston, SC 29425. Tel.: 843-792-9318; Fax: 843-792-4322; E-mail: hannun{at}musc.edu.

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