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J. Biol. Chem., Vol. 280, Issue 17, 16579-16585, April 29, 2005

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Redirection of Eicosanoid Metabolism in mPGES-1-deficient Macrophages^*

Catherine E. Trebino, James D. Eskra, Timothy S. Wachtmann, Jose R. Perez, Thomas J. Carty, and Laurent P. Audoly

From the Inflammation, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340

Microsomal prostaglandin E synthase (mPGES)-1 is one of several prostaglandin E synthases involved in prostaglandin H₂ (PGH2) metabolism. In the present report, we characterize the contribution of mPGES-1 to cellular PGH2 metabolism in murine macrophages by studying the synthesis of eicosanoids and expression of eicosanoid metabolism enzymes in wild type and mPGES-1-deficient macrophages. Thioglycollate-elicited macrophages isolated from mPGES-1–/– animals and genetically matched wild type controls were stimulated with diverse pro-inflammatory stimuli. Prostaglandins were released in the following order of decreasing abundance from wild type macrophages stimulated with lipopolysaccharide: prostaglandin E₂ (PGE2) > thromboxane B₂ (TxB2) > 6-keto prostaglandin F₁ (PGF1), prostaglandin F₂ (PGF2), and prostaglandin D₂ (PGD2). In contrast, we detected in mPGES-1–/– macrophages a >95% reduction in PGE2 production resulting in the following altered prostaglandin profile: TxB2 > 6-keto PGF1 and PGF2 > PGE2, despite the comparable release of total prostaglandins. No significant change in expression pattern of key prostaglandin-synthesizing enzymes was detected between the genotypes. We then further profiled genotype-related differences in the eicosanoid profile using macrophages pre-stimulated with lipopolysaccharide followed by a 10-min incubation with 10 µM [³H]arachidonic acid. Eicosanoid products were subsequently identified by reverse phase high pressure liquid chromatography. The dramatic reduction in [³H]PGE2 formation from mPGES-1–/– macrophages compared with controls resulted in TxB2 and 6-keto PGF1 becoming the two most abundant prostaglandins in these samples. Our results also suggest a 5-fold increase in 12-[³H]hydroxyheptadecatrienoic acid release in mPGES-1–/– samples. Our data support the hypothesis that mPGES-1 induction in response to an inflammatory stimulus is essential for PGE2 synthesis. The redirection of prostaglandin production in mPGES-1–/– cells provides novel insights into how a cell processes the unstable endoperoxide PGH2 during the inactivation of a major metabolic outlet.

Received for publication, October 25, 2004 , and in revised form, February 17, 2005.

^* 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.

To whom correspondence should be addressed. Present address: Dept. of Pharmacology, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Quebec H9H 3L1, Canada. Tel.: 514-428-2864; Fax: 514-428-3921; E-mail: laurent_audoly{at}merck.com.

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