Human neutrophils convert the sebum-derived polyunsaturated fatty acid Sebaleic acid to a potent granulocyte chemoattractant.
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 B(4), 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.
Cossette
Chantal
C
Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec H2X 2P2, Canada.
Patel
Pranav
P
Anumolu
Jaganmohan R
JR
Sivendran
Sashikala
S
Lee
Gue Jae
GJ
Gravel
Sylvie
S
Graham
François D
FD
Lesimple
Alain
A
Mamer
Orval A
OA
Rokach
Joshua
J
Powell
William S
WS
D002118:Calcium / Q000378:metabolism; D002630:Chemotactic Factors / Q000378:metabolism; D002633:Chemotaxis; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006098:Granulocytes / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000737:chemistry; D007249:Inflammation; D015603:Keratinocytes / Q000378:metabolism; D008041:Linoleic Acids / Q000378:metabolism*; D008956:Models, Chemical; D009249:NADP / Q000737:chemistry; D009504:Neutrophils / Q000378:metabolism*; D012629:Sebum / Q000378:metabolism*; D012867:Skin / Q000378:metabolism
D002630:Chemotactic Factors; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D008041:Linoleic Acids; C008695:octadeca-5,8-dienoic acid; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D009249:NADP; D002118:Calcium