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 LTB(4) induced elevation of intracellular free Ca(2+) concentration ([Ca(2+)](i)), cell polarisation and retardation of neutrophil apoptosis, although the antiapoptotic effect occurred only at concentrations > or =300 nM. LTB(4)-induced activation was attenuated by CP-105,696, a BLT1-specific antagonist suggesting classical LTB(4) receptor BLT1 involvement. 3 Despite demonstrating the presence of the neutrophil intracellular LTB(4) receptor peroxisome-proliferator activator receptor-alpha (PPARalpha) in neutrophils, the selective PPARalpha agonist WY-14,643 did not mimic LTB(4)-induced prosurvival effects. 4 LTB(4)-induced survival, however, also appeared to be mediated by BLT1 since CP-105,696 inhibited the LTB(4)-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 LTB(4). 5 Although LTB(4) and LTD(4) induced human eosinophil [Ca(2+)](i) elevation and polarization, these LTs did not influence eosinophil apoptosis. Furthermore, LTB(4)- and LTD(4)-induced eosinophil activation was attenuated by CP-105,696 and the Cys-LT(1) 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.
Murray
Joanna
J
Rayne Laboratory, Respiratory Medicine Unit, Centre for Inflammation Research, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG.
Ward
Carol
C
O'Flaherty
Joseph T
JT
Dransfield
Ian
I
Haslett
Christopher
C
Chilvers
Edwin R
ER
Rossi
Adriano G
AG
D000085:Acetates / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001578:Benzopyrans / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002264:Carboxylic Acids / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003521:Cyclopropanes; D004804:Eosinophils / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology / Q000502:physiology*; D017998:Leukotriene D4 / Q000494:pharmacology / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology; D013440:Sulfides
D000085:Acetates; D000276:Adjuvants, Immunologic; D001578:Benzopyrans; D002264:Carboxylic Acids; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D011804:Quinolines; D013440:Sulfides; D007975:Leukotriene B4; D017998:Leukotriene D4; C093875:montelukast; D002118:Calcium; C089698:CP 105696