Enhancement of human eosinophil cytotoxicity and leukotriene synthesis by biosynthetic (recombinant) granulocyte-macrophage colony-stimulating factor.
Culture medium conditioned by activated human T lymphocytes enhances the in vitro cytotoxicity of purified human eosinophils toward Schistosoma mansoni larvae, suggesting the existence of a mechanism for T lymphocyte regulation of eosinophil function. Here we show that purified biosynthetic (recombinant) human T lymphocyte granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced markedly two eosinophil functions: cytotoxicity toward schistosomula by a mean of 676%, and calcium ionophore A23187-induced generation of leukotriene C4 (LTC4) by a mean of 135%. Augmentation of each eosinophil function by GM-CSF was time- and dose-dependent, with a dose-response relationship at concentrations between 1 and 20 pM. Tumor necrosis factor (TNF) enhanced eosinophil cytotoxicity with slower kinetics, a different dose-dependence relationship, and to a lower maximum, as compared with GM-CSF. There was no detectable effect of TNF on calcium ionophore A23187-induced generation of LTC4. The effect of GM-CSF on arachidonic acid metabolism to LTC4 reached a plateau with 60 min of incubation before stimulation with ionophore, and was characterized by an initial augmentation of the intracellular level of LTC4 and a subsequent increment in extracellular LTC4. Thus, GM-CSF can serve as a mediator for T lymphocyte regulation of functions of mature eosinophils. It is also the first defined macromolecule known to enhance metabolism of membrane-derived arachidonic acid via the 5-lipoxygenase pathway.
D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D011994:Recombinant Proteins / Q000494:pharmacology; D013189:SRS-A / Q000378:metabolism*; D012550:Schistosoma mansoni / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha
D003115:Colony-Stimulating Factors; D006023:Glycoproteins; D011994:Recombinant Proteins; D013189:SRS-A; D014409:Tumor Necrosis Factor-alpha; D000001:Calcimycin