Enhancement by GM-CSF of agonist-induced 5-lipoxygenase activation in human neutrophils involves protein synthesis and gene transcription.
We investigated the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the 5-lipoxygenase (5-LO) component of the leukotriene (LT) biosynthetic pathway of human neutrophils, in order to better understand the mechanism whereby the cytokine primes for LT synthesis. We found that GM-CSF increased 5-LO activation elicited by platelet-activating factor (PAF), N-formyl-methionyl-leucyl-phenylalanine (fMLP), C5a, LTB4, IL-8 and calcium ionophore A23187, as determined by using an exogenous substrate. A close correlation was observed between the priming kinetics of GM-CSF on 5-LO activation and on LT synthesis; moreover, the effects of the cytokine on both 5-LO activation and LT synthesis were inhibited when the cells had been exposed to either the protein synthesis inhibitor, cycloheximide (CX), or the transcription inhibitor, actinomycin D (AD), prior to incubation with GM-CSF. These results raise the possibility that the priming by GM-CSF of LT synthesis may involve an effect of the cytokine on 5-LO protein synthesis and gene expression.
McDonald
P P
PP
Centre de recherche en Inflammation, immunologie et rhumatologie, Centre hospitalier de l'Université Laval, Ste-Foy, Québec, Canada.
Pouliot
M
M
Borgeat
P
P
D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D015289:Leukotrienes / Q000096:biosynthesis; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D015289:Leukotrienes; D003609:Dactinomycin; D000001:Calcimycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003513:Cycloheximide; D001094:Arachidonate 5-Lipoxygenase