Polymorphonuclear leukocytes are strongly implicated in the pathogenesis of inflammatory disease. Polymorphonuclear leukocyte recruitment at sites of inflammation, mainly sustained by the β2-integrins, is followed by the synthesis and release of inflammatory mediators, such as leukotrienes, proteolytic enzymes and reactive oxygen species. Functional and metabolic interactions between polymorphonuclear leukocytes and platelets can contribute to and exacerbate the process. The effects of the dual 5-lipoxygenase and cyclooxygenase inhibitor licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H- pyrrolizine-5-yl]-acetic acid) were studied on arachidonic acid transcellular metabolism occurring between polymorphonuclear leukocytes and platelets. The formation of leukotriene C4, a leukotriene A4-derived metabolite, by mixed polymorphonuclear leukocyte/platelet suspensions stimulated with 10 μM A23187 was inhibited by licofelone with an IC50 of 3.8±0.07 μM. The formation of 5,12-di-hydroxy-eicosatetraenoic acid (HETE) was abolished at concentrations ≥10 μM. Licofelone also inhibited the generation of reactive oxygen species by polymorphonuclear leukocytes stimulated with 1 μM n-formyl-methionyl-leucyl-phenylalanine (fMLP), 10 nM complement fraction 5a (C5a) and 1 μM platelet activating factor (PAF) with IC50s of 24.4±0.6, 11.0±1.5 and 11.7±1.2 μM; elastase release induced by the three agonists was inhibited with IC50s of 12.2±2.2, 23.5±8 and 2.6±1 μM, respectively. Homotypic polymorphonuclear leukocyte aggregation induced by fMLP, C5A and PAF was inhibited by licofelone with IC50s of 23.7±4.8, 15.6±3.4 and 15.4±4 μM, respectively. The present study extends the anti-lipoxygenase and anti-cyclooxygenase activities of licofelone to the production of arachidonic acid metabolites generated as a consequence of polymorphonuclear leukocyte-platelet transcellular metabolism and to polymorphonuclear leukocyte responses relevant to the pathogenesis of inflammation. The coexistence within the same molecule of a wide spectrum of anti-inflammatory properties is of interest.
- Adhesive interaction
- Polymorphonuclear leukocyte, human
- Transcellular metabolism
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience