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J. Biol. Chem., Vol. 279, Issue 39, 40376-40384, September 24, 2004

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Oxidative Stress Stimulates the Synthesis of the Eosinophil Chemoattractant 5-Oxo-6,8,11,14-eicosatetraenoic Acid by Inflammatory Cells^*

Karl-Rudolf Erlemann, Joshua Rokach, and William S. Powell¶

From the Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada and the Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida 32901-6982

5-Oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) is a highly potent granulocyte chemoattractant that acts through a selective G-protein coupled receptor. It is formed by oxidation of the 5-lipoxygenase product 5-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) by 5-hydroxyeicosanoid dehydrogenase (5-HEDH). Although leukocytes and platelets display high microsomal 5-HEDH activity, unstimulated intact cells do not convert 5-HETE to appreciable amounts of 5-oxo-ETE. To attempt to resolve this dilemma we explored the possibility that 5-oxo-ETE synthesis could be enhanced by oxidative stress. We found that hydrogen peroxide and t-butyl hydroperoxide strongly stimulate 5-oxo-ETE formation by U937 monocytic cells. This was dependent on the GSH redox cycle, as it was blocked by depletion of GSH or inhibition of glutathione reductase and mimicked by oxidation of GSH to GSSG by diamide. Glucose inhibited the response to H₂O₂ through its metabolism by the pentose phosphate pathway, as its effect was reversed by the glucose-6-phosphate dehydrogenase inhibitor dehydroepiandrosterone. 5-Oxo-ETE synthesis was also strongly stimulated by hydroperoxides in blood monocytes, lymphocytes, and platelets, but not neutrophils. Unlike monocytic cells, lymphocytes and platelets were resistant to the inhibitory effects of glucose. 5-Oxo-ETE synthesis following incubation of peripheral blood mononuclear cells with arachidonic acid and calcium ionophore was also strongly enhanced by t-butyl hydroperoxide. Oxidative stress could act by depleting NADPH, resulting in the formation NADP⁺, the cofactor for 5-HEDH. This is opposed by the pentose phosphate pathway, which converts NADP⁺ back to NADPH. Oxidative stress could be an important mechanism for stimulating 5-oxo-ETE production in inflammation, promoting further infiltration of granulocytes into inflammatory sites.

Received for publication, February 5, 2004 , and in revised form, June 28, 2004.

^* This work was supported by Canadian Institutes of Health Research Grant MOP-6254 (to W. S. P.), the Heart and Stroke Foundation of Quebec (to W. S. P.), the J. T. Costello Memorial Research Fund, National Institutes of Health Grants DK44730 and HL69835 (to J. R.), and National Science Foundation Grant CHE-90-13145 for an AMX-360 NMR instrument (to J. R.). 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: Meakins-Christie Laboratories, McGill University, 3626 St. Urbain St., Montreal, Quebec H2X 2P2, Canada. Tel.: 514-398-3864 (ext. 094071); Fax: 514-398-7483; E-mail: William.Powell{at}McGill.ca.

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