11,12-Epoxyeicosatrienoic Acid Attenuates Synthesis of Prostaglandin E2in Rat Monocytes Stimulated with Lipopolysaccharide

Experimental Biology and Medicine - Tập 228 Số 7 - Trang 786-794 - 2003
Wiesław Kozak1,2,3,4,5, David M. Aronoff1,3,4,5, Olivier Boutaud1,3,4,5, Anna Kozak1,3,4,5
1Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912;
2Departments of
3Institute of General and Molecular Biology, University of Nicolaus Copernicus, 87-100 Torun, Poland; and Departments of
4Medicine, and
5Pharmacology, Vanderbilt University, Nashville, Tennessee 37232

Tóm tắt

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 PGE2in 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 × 105cells) to induce COX-2 and stimulate generation of PGE2. SKF-525A, an inhibitor of epoxygenases, significantly augmented the lipopolysaccharide-provoked synthesis of PGE2in 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 PGE2in 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 PGE2in 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.

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Experimental Biology and Medicine

Tập 228 Số 7

786-794

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