Role of leukotrienes in the regulation of human granulocyte behaviour: dissociation between agonist-induced activation and retardation of apoptosis

1 Since most inflammatory mediators that stimulate granulocyte responsiveness also delay apoptosis, it is often assumed that activation and longevity are causally related. Using isolated human peripheral blood neutrophils and eosinophils, we examined this association by exploiting the proinflammatory lipid mediators, the leukotrienes (LTs), and investigated granulocyte function and apoptosis. 2 LTB4 induced elevation of intracellular free Ca2+ concentration ([Ca2+](i)), cell polarisation and retardation of neutrophil apoptosis, although the antiapoptotic effect occurred only at concentrations greater than or equal to300 nM. LTB4-induced activation was attenuated by CP-105,696, a BLT1-specific antagonist suggesting classical LTB4 receptor BLT1 involvement. 3 Despite demonstrating the presence of the neutrophil intracellular LTB4 receptor peroxisome-proliferator activator receptor-alpha (PPARalpha) in neutrophils, the selective PPARalpha agonist WY-14,643 did not mimic LTB4-induced prosurvival effects. 4 LTB4-induced survival, however, also appeared to be mediated by BLT1 since CP-105,696 inhibited the LTB4-mediated antiapoptotic effect. Furthermore, based on studies with CP-105,696 and 5-lipoxygenase inhibitors, lipopolysaccharide (LPS)-, granulocyte - macrophage colony-stimulating factor (GM-CSF)-, dexamethasone- and dibutyryl-cAMP(db-cAMP)-induced delay of neutrophil apoptosis did not involve autocrine production of LTB4. 5 Although LTB4 and LTD4 induced human eosinophil [Ca2+](i) elevation and polarization, these LTs did not influence eosinophil apoptosis. Furthermore, LTB4- and LTD4-induced eosinophil activation was attenuated by CP-105,696 and the Cys-LT1 receptor antagonist montelukast, respectively, highlighting specific receptor dependency. 6 Thus, mediator-triggered granulocyte activation and antiapoptotic pathways are distinct events that can be differentially regulated.