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J. Biol. Chem., Vol. 279, Issue 33, 34256-34268, August 13, 2004

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Cyclooxygenase-1-dependent Prostaglandin Synthesis Modulates Tumor Necrosis Factor- Secretion in Lipopolysaccharide-challenged Murine Resident Peritoneal Macrophages^*

From the ^aDepartments of Biochemistry and Chemistry, the ^bVanderbilt Institute for Chemical Biology, the ^cCenter for Pharmacology and Drug Toxicology, the ^dCenter in Molecular Toxicology, the ^fDepartment of Pediatrics and Cell and Developmental Biology and Pharmacology, the ^gDivision of Reproductive and Developmental Biology, and the ⁱDepartment of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146

Comprehensive studies of prostaglandin (PG) synthesis in murine resident peritoneal macrophages (RPM) responding to bacterial lipopolysaccharide (LPS) revealed that the primary PGs produced by RPM were prostacyclin and PGE₂. Detectable increases in net PG formation occurred within the first hour, and maximal PG formation had occurred by 6–10 h after LPS addition. Free arachidonic acid levels rose and peaked at 1–2 h after LPS addition and then returned to baseline. Cyclooxygenase-2 (COX-2) and microsomal PGE synthase levels markedly increased upon exposure of RPM to LPS, with the most rapid increases in protein expression occurring 2–6 h after addition of the stimulus. RPM constitutively expressed high levels of COX-1. Studies using isoform-selective inhibitors and RPM from mice bearing targeted deletions of ptgs-1 and ptgs-2 demonstrated that COX-1 contributes significantly to PG synthesis in RPM, especially during the initial 1–2 h after LPS addition. Selective inhibition of either COX isoform resulted in increased secretion of tumor necrosis factor- (TNF-); however, this effect was much greater with the COX-1 than with the COX-2 inhibitor. These results demonstrate autocrine regulation of TNF- secretion by endogenous PGs synthesized primarily by COX-1 in RPM and suggest that COX-1 may play a significant role in the regulation of the early response to endotoxemia.

Received for publication, March 8, 2004 , and in revised form, June 3, 2004.

^* This work was supported in part by National Institutes of Health Grants GM15431 (to L. J. M.), HD12304, HD33994, and DA06668 (to S. K. D.), and GM15431, CA77839, DK48831, and RR00095 (to J. D. M.). 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.

^h A Lalor Foundation Postdoctoral Fellow.

^j Recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.

^e To whom correspondence should be addressed: Dept. of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146. Tel.: 615-343-7327; Fax: 615-343-7534; E-mail: c.rouzer{at}vanderbilt.edu.

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