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ORIGINAL RESEARCH ARTICLE

11,12-Epoxyeicosatrienoic Acid Attenuates Synthesis of Prostaglandin E₂ in Rat Monocytes Stimulated with Lipopolysaccharide

Wieslaw Kozak^*,,1, David M. Aronoff^,2, Olivier Boutaud and Anna Kozak^*

^* Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912;
Institute of General and Molecular Biology, University of Nicolaus Copernicus, 87-100 Torun, Poland; and Departments of
Medicine and
Pharmacology, Vanderbilt University, Nashville, Tennessee 37232

Cytochrome P-450 monooxygenase (epoxygenase)-derived arachidonic acid (AA) metabolites, including 11,12-epoxyeicosatrienoic acid (11,12-EET), possess anti-inflammatory and antipyretic properties. Prostaglandin E₂ (PGE₂), a cyclooxygenase (COX)-derived metabolite of AA, is a well-defined mediator of fever and inflammation. We have tested the hypothesis that 11,12-EET attenuates synthesis of PGE₂ in monocytes, which are the cells that are indispensable for induction of fever and initiation of inflammation. Monocytes isolated from freshly collected rat blood were stimulated with lipopolysaccharide (LPS; 100 ng/2 x 10⁵ cells) to induce COX-2 and stimulate generation of PGE₂. SKF-525A, an inhibitor of epoxygenases, significantly augmented the lipopolysaccharide-provoked synthesis of PGE₂ in cell culture in a concentration-dependent manner. It did not affect, however, elevation of the expression of COX-2 protein in monocytes stimulated with LPS. 11,12-EET also did not affect the induction of COX-2 in monocytes incubated with lipopolysaccharide. However, 11,12-EET suppressed, in a concentration-dependent fashion, the generation of PGE₂ in incubates. Preincubation of a murine COX-2 preparation for 0–5 min with three concentrations of 11,12-EET (1, 5, and 10 µM) inhibited the oxygenation of [¹⁴C]-labeled AA by the enzyme. The inhibitory effect of 11,12-EET on COX-2 was time-and-concentration-dependent, suggesting a mechanism-based inhibition. Based on these data, we conclude that 11,12-EET suppresses generation of PGE₂ in monocytes via modulating the activity of COX-2. These data support the hypothesis that epoxygenasederived AA metabolites constitute a negative feedback on the enhanced synthesis of prostaglandins upon inflammation.

Key Words: eicosanoids • arachidonic acid • prostaglandins • cyclooxygenase-2 • epoxygenase • negative feedback • mononuclear cells • endotoxin

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