Granulocyte and granulocyte-macrophage colony-stimulating factors exert differential effects on neutrophil platelet-activating factor generation and release.
The haemopoietic recombinant human cytokines granulocyte and granulocyte-macrophage colony-stimulating factor (rhG-CSF and rhGM-CSF) are used to facilitate recovery of bone marrow function following cytotoxic chemotherapy. Recent clinical experience indicates that rhG-CSF is better tolerated than rhGM-CSF. Thus, we have compared the priming effects of rhG-CSF and rhGM-CSF on superoxide anion (O2-) generation and platelet-activating factor (PAF) synthesis by neutrophils. During a 60-min incubation of neutrophils with rhGM-CSF (1 nM) or recombinant human tumour necrosis factor-alpha (rhTNF-alpha; 0.3 nM), cell-associated PAF levels increased, and upon stimulation with FMLP (100 nM) there was a striking amplification of PAF formation (8-13-fold) and release (24-36-fold). In contrast, in rhG-CSF (1 nM)-primed cells, there was no increase in cell-associated PAF levels and neither PAF synthesis nor PAF release was amplified following stimulation with FMLP. On the other hand, each of rhG-CSF, rhGM-CSF or rhTNF-alpha increased subsequent FMLP (100 nM)-induced O2- generation (by 89%, 166% and 115%, respectively). These results suggest the existence of distinct intracellular signalling pathways for cytokine priming. Furthermore, some of the more severe adverse reactions to the administration of rhGM-CSF may be a result of the biosynthesis and/or release of the potent inflammatory mediator, PAF.
Stewart
A G
AG
Microsurgery Research Centre, St Vincent's Hospital, Victoria, Australia.
Cotterill
T
T
Harris
T
T
D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010972:Platelet Activating Factor / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D016897:Respiratory Burst / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D010972:Platelet Activating Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D016179:Granulocyte Colony-Stimulating Factor; D016718:Arachidonic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002118:Calcium