The Coordination of Prostaglandin E2 Production by Sphingosine-1-phosphate and Ceramide-1-phosphate
- Benjamin J. Pettus,
- Kazuyuki Kitatani,
- Charles E. Chalfant,
- Tarek A. Taha,
- Toshihiko Kawamori,
- Jacek Bielawski,
- Lina M. Obeid and
- Yusuf A. Hannun
- Departments of Biochemistry & Molecular Biology (B.J.P., K.K., T.A.T., J.B., L.M.O., Y.A.H.) and Pathology and Laboratory Medicine (T.K.) Medical University of South Carolina, Charleston, South Carolina; the Department of Biochemistry, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (C.E.C.); and the Ralph Johnson H. Veteran Affairs Medical Center, Charleston, South Carolina (L.M.O.)
- Address correspondence to:
Dr. Yusuf A. Hannun, Department of Biochemistry and Molecular Biology, Room 501, Basic Science Building, Medical University of South Carolina, 173 Ashley Avenue, P.O. Box 250509, Charleston, SC 29425. E-mail: hannun{at}musc.edu
Abstract
The ability of pro-inflammatory cytokines such as interleukin-1β (IL-1β) to induce the major inflammatory mediator prostaglandin (PG) E2 depends on the activation of two rate-limiting enzymes, phospholipase A2 (PLA2) and cyclooxygenase 2 (COX-2). PLA2 acts to generate arachidonic acid, which serves as the precursor substrate for COX-2 in the metabolic pathway leading to PGE2 production. However, less is known about the mechanisms that coordinate the regulation of these two enzymes. We have provided prior evidence that sphingosine kinase 1 and its bioactive lipid product sphingosine-1-phosphate (S1P) mediate the effects of cytokines on COX-2 induction, whereas ceramide kinase and its distinct product, ceramide-1-phosphate (C1P), are required for the activation and translocation of cPLA2 (FASEB J17:1411-1421. 2003; J Biol Chem278:38206-38213, 2003; J Biol Chem279:11320-11326, 2004). Herein, we show that these two pathways are independent but coordinated, resulting in synergistic induction of PGE2. Moreover, the combination of both S1P and C1P recapitulates the temporal and spatial activation of cPLA2 and with COX-2 seen IL-1β. Taken together, the results provide, for the first time, a mechanism that assures the coordinate expression and activation in time and space of COX-2 and cPLA2, assuring maximal production of PGE2.
Footnotes
-
This work was supported in part by National Institutes of Health grants CA87584 (to Y.A.H.), GM62887 (to L.M.O.), and HL072925 (to C.E.C.), National Institute of General Medical Sciences Medical Scientist Training Program grant GM08716 and Hollings Cancer Center Wachovia Scholarship (to B.J.P.), the Hollings Cancer Center Department of Defense grant GC3532-03-42153CM and Center of Biomedical Research Excellence grant P20-RR017677 (to T.K.), and the Department of Veterans Affairs merit review grant (to C.E.C).
-
B.J.P. and K.K. contributed equally to this work.
-
ABBREVIATIONS: IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; PLA2, phospholipase A2; cPLA2, cytosolic phospholipase A2; COX-2, cyclooxygenase 2; S1P, sphingosine-1-phosphate; SK1, sphingosine kinase 1; CK1, ceramide kinase 1; PBS, phosphate-buffered saline; RNAi, RNA interference; AA, arachidonic acid; siRNA, small-interfering RNA; SCR, scrambled RNAi.
-
- Received October 26, 2004.
- Accepted May 4, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
