Differential activation of leukotriene biosynthesis by granulocyte-macrophage colony-stimulating factor and interleukin-5 in an eosinophilic substrain of HL-60 cells.
Cytokines can stimulate eosinophils to produce cysteinyl leukotrienes (LTs) in the lung that provoke tissue destruction associated with asthma. Priming of an eosinophilic substrain of HL-60 cells (HL-60#7) with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) before ionophore challenge was found to produce an apparent 45% increase in total LT production in a dose-dependent manner (ED50 = 150 pmol/L) that could be accounted for by a decrease in the time required for maximal formation of LTs. GM-CSF had no effect on the kinetic parameters of LTC4 synthase and therefore probably acts upstream of this catalytic event. Incubation with interleukin-5 (IL-5), however, had no effect on LT biosynthesis. This differential priming ability was not a consequence of different receptor populations or differences in the affinity or stability of the ligand-receptor complexes of GM-CSF and IL-5. GM-CSF and IL-5 each displayed similar populations of high-affinity binding sites and neither GM-CSF nor IL-5 were able to cross-compete for the other's receptor binding sites. Analysis of phosphotyrosine patterns suggest that IL-5 is incapable of transducing a signal in eosinophilic HL-60#7 cells even though IL-5 and GM-CSF receptors mediate signal transduction via a common beta-chain component that is also necessary for high-affinity binding. Overall, this unique system may permit the dissection of distinct events responsible for specific intracellular signals transduced separately by GM-CSF or IL-5.
Scoggan
K A
KA
Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Montreal, Quebec, Canada.
Ford-Hutchinson
A W
AW
Nicholson
D W
DW
D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002454:Cell Differentiation / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D018922:HL-60 Cells / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015848:Interleukin-5 / Q000494:pharmacology*; D015289:Leukotrienes / Q000096:biosynthesis*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000187:drug effects; D018123:Receptors, Interleukin / Q000187:drug effects; D053649:Receptors, Interleukin-5; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction
D002087:Butyrates; D015848:Interleukin-5; D015289:Leukotrienes; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D011994:Recombinant Proteins; D020148:Butyric Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases