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J. Biol. Chem., Vol. 280, Issue 29, 26690-26700, July 22, 2005

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Glycerylprostaglandin Synthesis by Resident Peritoneal Macrophages in Response to a Zymosan Stimulus^*

Carol A. Rouzer and Lawrence J. Marnett

From the Departments of Biochemistry and Chemistry, the Vanderbilt Institute of Chemical Biology, the Center in Molecular Toxicology, and the Center for Pharmacology and Drug Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146

Cyclooxygenase (COX)-2 oxygenates arachidonic acid (AA) and 2-arachidonylglycerol (2-AG) to endoperoxides, which are subsequently transformed to prostaglandins (PGs) and glycerylprostaglandins (PG-Gs). PG-G formation has not been demonstrated in intact cells treated with a physiological agonist. Resident peritoneal macrophages, which express COX-1, were pretreated with lipopolysaccharide to induce COX-2. Addition of zymosan caused release of 2-AG and production of the glyceryl esters of PGE₂ and PGI₂ over 60 min. The total quantity of PG-Gs (16 ± 6 pmol/10⁷ cells) was much lower than that of the corresponding PGs produced from AA (21,000 ± 7,000 pmol/10⁷ cells). The differences in PG-G and PG production were partially explained by differences in the amounts of 2-AG and AA released in response to zymosan. The selective COX-2 inhibitor, SC236, reduced PG-G and PG production by 49 and 17%, respectively, indicating a significant role for COX-1 in PG-G and especially PG synthesis. Time course studies indicated that COX-2-dependent oxygenation rapidly declined 20 min after zymosan addition. When exogenous 2-AG was added to macrophages, a substantial portion was hydrolyzed to AA and converted to PGs; 1 µM 2-AG yielded 820 ± 200 pmol of PGs/10⁷ cells and 78 ± 41 pmol of PG-Gs/10⁷ cells. SC236 reduced PG-G and PG production from exogenous 2-AG by 88 and 76%, respectively, indicating a more significant role for COX-2 in the utilization of exogenous substrate. In conclusion, lipopolysaccharide-pretreated macrophages produce PG-Gs from endogenous 2-AG during zymosan phagocytosis, but PG-G formation is limited by substrate hydrolysis and inactivation of COX-2.

Received for publication, January 27, 2005 , and in revised form, May 23, 2005.

^* This work was supported by National Institutes of Health Grant GM15431. 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: Dept. of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146. Tel.: 615-343-7329; Fax: 615-343-7534; E-mail: larry.marnett{at}vanderbilt.edu.

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