Granulocyte and granulocyte-macrophage colony-stimulating factors exert differential effects on neutrophil...

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.