Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 34, Pages 24695-24703Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M604713200
Keywords
-
Categories
Funding
- NCI NIH HHS [CA87584] Funding Source: Medline
- NCRR NIH HHS [P20-RR017677] Funding Source: Medline
- NIGMS NIH HHS [GM62887] Funding Source: Medline
Ask authors/readers for more resources
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 alpha/prostaglandin E-2 (PGE(2)) 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 alpha-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 PGE(2) biosynthesis after desipramine treatment. Interestingly, knockdown of endogenous AC by RNA interference attenuated cyclooxygenase 2 induction by TNF alpha and subsequent PGE(2) biosynthesis. Taken together, these results define a novel role for AC in the TNF alpha/ PGE(2) pathway. In addition, the results of this study warrant careful reconsideration of desipramine as a specific inhibitor for ASMase.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available