Granulocyte/macrophage colony-stimulating factor affects myo-inositol metabolism in a novel manner. Implications for its priming action on human neutrophils.
Little is known about the signal transduction processes involved in the priming action of granulocyte/macrophage colony-stimulating factor (GM-CSF) on neutrophils. This study has used myo-[3H]inositol-labelled human neutrophils to determine whether preincubation with GM-CSF influences myo-inositol (Ins) metabolism in control cells, or in cells stimulated with the bacterial chemoattractant N-formyl-methionyl-leucyl-phenylalanine (fMetLeuPhe). GM-CSF pretreatment did not influence the total cellular 3H radioactivity content, demonstrating that the cytokine had no effect on Ins uptake. However, neutrophils pretreated with GM-CSF showed a dramatic 25-40% fall in the free [3H]Ins content of the cell, which was almost quantitatively recovered in a 2-4-fold increase in radioactivity within PtdIns. The remainder of the 3H radioactivity was found proportionately distributed throughout all other [3H]Ins-containing metabolites. Interestingly, in comparison with controls, the GM-CSF-stimulated increases in [3H]polyphosphoinositide (including 3-phosphorylated lipids) and [3H]Ins polyphosphate contents were consistently higher than that observed with PtdIns. This observation suggests that GM-CSF influences the hormone-sensitive pool of PtdIns, possibly through the activation of a PtdIns synthase which is rate-limiting to subsequent metabolic pathways. This is the first report of an action of GM-CSF on Ins metabolism, and highlights the conversion of Ins to PtdIns as a key regulatory metabolic step.
MacPhee
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SmithKline Beecham Pharmaceuticals, Welwyn, Herts, U.K.
D002478:Cells, Cultured; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D006801:Humans; D007294:Inositol / Q000378:metabolism*; D007295:Inositol Phosphates / Q000302:isolation & purification / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects
D007295:Inositol Phosphates; D007294:Inositol; D009240:N-Formylmethionine Leucyl-Phenylalanine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor