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J. Biol. Chem., Vol. 279, Issue 27, 28159-28164, July 2, 2004

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5-Oxo-6,8,11,14-eicosatetraenoic Acid Stimulates the Release of the Eosinophil Survival Factor Granulocyte/Macrophage Colony-stimulating Factor from Monocytes^*

Panagiota B. Stamatiou¶, Chi-Chung Chan, Guillaume Monneret||, Diane Ethier, Joshua Rokach**, and William S. Powell

From the Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada, the Departments of Pharmacology and Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec H9R 4P8, Canada, and the ^**Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida 32901-6988

Allergic diseases such as asthma are characterized by tissue eosinophilia induced by the combined effects of chemoattractants and cytokines. Lipid mediators are a major class of endogenous chemoattractants, among which 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is the most potent for human eosinophils. In this study, we investigated the effects of 5-oxo-ETE on eosinophil survival by flow cytometry. We found that this compound could promote eosinophil survival in the presence of small numbers of contaminating monocytes, but not in their absence. The conditioned medium from monocytes treated for 24 h with 5-oxo-ETE also strongly promoted eosinophil survival, whereas the medium from vehicle-treated monocytes had no effect. An antibody against the granulocyte/macrophage colony-stimulating factor (GM-CSF) completely blocked the response of eosinophils to the conditioned medium from 5-oxo-ETE-treated monocytes, whereas an antibody against interleukin-5 had no effect. Furthermore, 5-oxo-ETE stimulated the release of GM-CSF from cultured monocytes in amounts compatible with eosinophil survival activity, with a maximal effect being observed after 24 h. This effect was concentration-dependent and could be observed at concentrations in the picomolar range. 5-Oxo-ETE and leukotriene B₄ had similar effects on GM-CSF release at low concentrations, but 5-oxo-ETE induced a much stronger response at concentrations of 10 nM or higher. This is the first report that 5-oxo-ETE can induce the release of any cytokine, suggesting that it could be an important mediator in allergic and other inflammatory diseases due both to its chemoattractant properties and to its potent effects on the synthesis of the survival factor GM-CSF.

Received for publication, February 11, 2004 , and in revised form, May 3, 2004.

^* This work was supported in part by Canadian Institutes of Health Research Grant MOP-6254 and the Heart and Stroke Foundation of Quebec (to W. S. P.) and by National Institutes of Health Grants DK44730 and HL69835 (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.

^¶ Supported by a studentship awarded jointly by the Fonds Québécors de recherche sur la nature et les technologies and the Merck Frosst Centre for Therapeutic Research.

^|| Present address: Flow Cytometry Unit, Immunology Lab., Lyon-Sud University Hospital, 69495 Pierre-Bénite, France.

Recipient of National Science Foundation Grant CHE-90-13145 for an AMX-360 NMR instrument.

To whom correspondence should be addressed: Meakins-Christie Labs., 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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				P. Patel, C. Cossette, J. R. Anumolu, S. Gravel, A. Lesimple, O. A. Mamer, J. Rokach, and W. S. Powell Structural Requirements for Activation of the 5-Oxo-6E,8Z, 11Z,14Z-eicosatetraenoic Acid (5-Oxo-ETE) Receptor: Identification of a Mead Acid Metabolite with Potent Agonist Activity J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 698 - 707. [Abstract] [Full Text] [PDF]