Induction by chemokines of lipid mediator synthesis in granulocyte-macrophage colony-stimulating factor-treated human neutrophils.
In recent years, there has been a growing body of evidence suggesting that IL-8 and granulocyte-macrophage CSF (GM-CSF) play an important role in inflammatory processes. We show that after GM-CSF treatment, the exposure of human neutrophils to IL-8 results in the synthesis of leukotriene (LT)B4 and platelet-activating factor. In GM-CSF-treated cells, IL-8 induced a concentration-dependent synthesis of both lipid mediators, with a threshold at 10 to 30 nM, suggesting that IL-8 could stimulate phospholipase A2 activity, an enzyme essential for both syntheses. Accordingly, IL-8 induced a substantial release of 3H-arachidonic acid in GM-CSF-treated PMN. It was also found that IL-8 activates the neutrophil 5-lipoxygenase (5-LO), the other key enzyme in LT biosynthesis. IL-8 induced 5-LO activation in a time- and concentration-dependent manner, with a threshold at 1 nM, and prior treatment of neutrophils with GM-CSF enhanced this effect of IL-8 over the 1 to 300 nM range. Neutrophil-activating peptide-2 and the melanoma growth-stimulatory activity, two peptides that are closely related to IL-8, also had the ability to activate the 5-LO and stimulate LT synthesis, albeit less potently than IL-8. Finally, pertussis toxin and the 5-LO translocation inhibitor, MK-886, both blocked the IL-8-elicited 5-LO activation. Taken together, our results raise the possibility that the combined presence of IL-8 and of GM-CSF at inflammatory foci could result in the synthesis of platelet-activating factor and LTB4 by neutrophils, thereby contributing to the amplification of the inflammatory response.
McDonald
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PP
Centre de recherche en Inflammation, immunologie et rhumatologie, Centre de recherche du CHUL Sainte-Foy, Québec, Canada.
Pouliot
M
M
Borgeat
P
P
McColl
S R
SR
D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000494:pharmacology; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000096:biosynthesis*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D010741:Phospholipases A / Q000502:physiology; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D001620:beta-Thromboglobulin
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; C061615:PPBP protein, human; D010455:Peptides; D010972:Platelet Activating Factor; D001620:beta-Thromboglobulin; D007975:Leukotriene B4; C009862:connective tissue-activating peptide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D001094:Arachidonate 5-Lipoxygenase; D010741:Phospholipases A; D054467:Phospholipases A2; D019204:GTP-Binding Proteins