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J. Biol. Chem., Vol. 283, Issue 17, 11234-11243, April 25, 2008

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Human Neutrophils Convert the Sebum-derived Polyunsaturated Fatty Acid Sebaleic Acid to a Potent Granulocyte Chemoattractant^*

Chantal Cossette, Pranav Patel, Jaganmohan R. Anumolu, Sashikala Sivendran, Gue Jae Lee, Sylvie Gravel, François D. Graham, Alain Lesimple^¶, Orval A. Mamer^¶, Joshua Rokach¹, and William S. Powell²

From the Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada, the ^¶Mass Spectrometry Unit, McGill University, Montreal, Quebec H3A 1A4, Canada, and Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida 32901-6982

Sebaleic acid (5,8-octadecadienoic acid) is the major polyunsaturated fatty acid in human sebum and skin surface lipids. The objective of the present study was to investigate the metabolism of this fatty acid by human neutrophils and to determine whether its metabolites are biologically active. Neutrophils converted sebaleic acid to four major products, which were identified by their chromatographic properties, UV absorbance, and mass spectra as 5-hydroxy-(6E,8Z)-octadecadienoic acid (5-HODE), 5-oxo-(6E,8Z)-octadecadienoic acid (5-oxo-ODE), 5S,18-dihydroxy-(6E,8Z)-octadecadienoic acid, and 5-oxo-18-hydroxy-(6E,8Z)-octadecadienoic acid. The identities of these metabolites were confirmed by comparison of their properties with those of authentic chemically synthesized standards. Both neutrophils and human keratinocytes converted 5-HODE to 5-oxo-ODE. This reaction was stimulated in neutrophils by phorbol myristate acetate and in keratinocytes by oxidative stress (t-butyl-hydroperoxide). Both treatments dramatically elevated intracellular levels of NADP⁺, the cofactor required by 5-hydroxyeicosanoid dehydrogenase. In keratinocytes, this was accompanied by a rapid increase in intracellular GSSG levels, consistent with the involvement of glutathione peroxidase. 5-Oxo-ODE stimulated calcium mobilization in human neutrophils and induced desensitization to 5-oxo-6,8,11,14-eicosatetraenoic acid but not leukotriene B₄, indicating that this effect was mediated by the OXE receptor. 5-Oxo-ODE and its 8-trans isomer were equipotent with 5-oxo-6,8,11,14-eicosatetraenoic acid in stimulating actin polymerization and chemotaxis in human neutrophils, whereas 5-HODE, 5-oxo-18-hydroxy-(6E,8Z)-octadecadienoic acid, and 5S,18-dihydroxy-(6E,8Z)-octadecadienoic acid were much less active. We conclude that neutrophil 5-lipoxygenase converts sebaleic acid to 5-HODE, which can be further metabolized to 5-oxo-ODE by 5-hydroxyeicosanoid dehydrogenase in neutrophils and keratinocytes. Because of its chemoattractant properties, sebum-derived 5-oxo-ODE could be involved in neutrophil infiltration in inflammatory skin diseases.

Received for publication, November 20, 2007 , and in revised form, February 13, 2008.

^* This work was supported by Canadian Institutes of Health Research Grant MOP-6254 (to W. S. P.), the J. T. Costello Memorial Research Fund, and National Institutes of Health Grant HL81873 (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.

¹ Supported by National Science Foundation Grants CHE-90-13145 (for the AMX-360 NMR instrument) and CHE-03-42251 (for the Bruker 400 MHz NMR instrument).

² To whom correspondence should be addressed: Meakins-Christie Laboratories, Dept. of Medicine, 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, K.-R. Erlemann, G. E. Grant, J. Rokach, and W. S. Powell Substrate Selectivity of 5-Hydroxyeicosanoid Dehydrogenase and Its Inhibition by 5-Hydroxy-{Delta}6-Long-Chain Fatty Acids J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 335 - 341. [Abstract] [Full Text] [PDF]