A novel glutathione containing eicosanoid (FOG7) chemotactic for human granulocytes.
A biologically active glutathione adduct of the eicosanoid 5-oxo-eicosatetraenoic acid has been observed as a product formed within the murine peritoneal macrophage. This five-oxo glutathione adduct (FOG(7)) was structurally characterized using electrospray tandem mass spectrometry as a 1,4 Michael addition product 5-oxo-7-glutathionyl-8,11,14-eicosatrienoic acid. FOG(7) was found to be highly potent in stimulating eosinophil as well as neutrophil chemotaxis, also capable of initiating actin polymerization, without elevating intracellular free calcium ion concentration within either the eosinophil or polymorphonuclear leukocyte. These biological responses suggest that either FOG(7) activates a subset of receptors mediating the broader biological activity of the parent eicosanoid 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) or that a receptor not activated by 5-oxo-ETE participates in the chemotactic activity of FOG(7). The only other known biologically active glutathione adduct has been leukotriene C(4) (LTC(4)), another eicosanoid that exerts potent effects through the Cys-LT receptor. The biochemical parallel between the formation of LTC(4) and FOG(7) suggests an interesting mechanism by which biologically active eicosanoids derived from electrophilic intermediates may have unique distribution and prolonged efficacy in vivo.
Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
R C
RC
Bowers
J
J
Hevko
P M
PM
Henson
R C
RC
Murphy
D000199:Actins; D000818:Animals; D016718:Arachidonic Acid / Q000737:chemistry*; D002630:Chemotactic Factors / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte; D004804:Eosinophils / Q000187:drug effects; D005434:Flow Cytometry; D005978:Glutathione / Q000737:chemistry*; D006098:Granulocytes / Q000187:drug effects*; D006801:Humans; D017997:Leukotriene C4 / Q000031:analogs & derivatives; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008970:Molecular Weight; D009504:Neutrophils / Q000187:drug effects
D000199:Actins; D002630:Chemotactic Factors; C414562:FOG7 chemotactic; D016718:Arachidonic Acid; D017997:Leukotriene C4; D005978:Glutathione