Human granulocyte-macrophage colony-stimulating factor and other cytokines prime human neutrophils for enhanced arachidonic acid release and leukotriene B4 synthesis.
Human recombinant granulocyte-macrophage CSF (GM-CSF) "primes" neutrophils for enhanced biologic responses to a number of secondary stimuli. Here, we examined the properties of neutrophil priming by GM-CSF and other growth factors such as human rTNF and granulocyte CSF. Although GM-CSF has a negligible direct effect on [3H]arachidonic acid release, it enhances or "primes" neutrophils for three- to fivefold increased release of [3H]arachidonic acid, induced by 1.0 microM A23187 and the chemotactants FMLP, platelet-activating factor, and leukotriene B4 (LTB4) (all 0.1 microM). The priming effects of GM-CSF were concentration- and time-dependent (maximum 100 pM, 1 h at 23 degrees C), and consistent with the determined dissociation constant of the human GM-CSF receptor. Indomethacin (10(-8) M), cycloheximide (100 micrograms/ml), and pertussis toxin (200 ng/ml, 2 h at 37 degrees C) had no effect on GM-CSF-, A23187, or platelet-activating factor-induced [3H]arachidonic acid release. The lipoxygenase inhibitor, nordihydroguaiaretic acid, however, totally abolished A23187-induced [3H]arachidonic acid release from both diluent- and GM-CSF-treated neutrophils. Consistent with this observation, we found that GM-CSF-pretreated neutrophils synthesize increased levels of LTB4 after stimulation with A23187 and chemotactic factors. GM-CSF enhances neutrophil arachidonic acid release and LTB4 synthesis, and thereby may amplify the inflammatory response to chemotactic factors and other physiologically relevant stimuli.
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood*; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D002630:Chemotactic Factors / Q000494:pharmacology; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D016209:Interleukin-8; D007975:Leukotriene B4 / Q000096:biosynthesis*; D009637:Masoprocol / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D037342:Pertussis Toxin; D011863:Radioimmunoassay; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D001095:Arachidonic Acids; D002630:Chemotactic Factors; D003115:Colony-Stimulating Factors; D006133:Growth Substances; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D010566:Virulence Factors, Bordetella; D016179:Granulocyte Colony-Stimulating Factor; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin; D009637:Masoprocol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003513:Cycloheximide; D037342:Pertussis Toxin; D007213:Indomethacin