title: Concentration-dependent noncysteinyl leukotriene type 1 receptor-mediated inhibitory activity of leukotriene receptor antagonists.
abstract: The use of cysteinyl leukotriene receptor antagonists (LTRAs) for asthma therapy has been associated with a significant degree of interpatient variability in response to treatment. Some of that variability may be attributable to noncysteinyl leukotriene type 1 receptor (CysLT(1))-mediated inhibitory mechanisms that have been demonstrated for this group of drugs. We used a model of CysLT(1) signaling in human monocytes to characterize CysLT(1)-dependent and -independent anti-inflammatory activity of two chemically different, clinically relevant LTRAs (montelukast and zafirlukast). Using receptor-desensitization experiments in monocytes and CysLT(1)-transfected HEK293 cells and IL-10- and CysLT(1) small interfering RNA-induced downregulation of CysLT(1) expression, we showed that reported CysLT(1) agonists leukotriene D(4) and UDP signal through calcium mobilization, acting on separate receptors, and that both pathways were inhibited by montelukast and zafirlukast. However, 3-log greater concentrations of LTRAs were required for the inhibition of UDP-induced signaling. In monocytes, UDP, but not leukotriene D(4), induced IL-8 production that was significantly inhibited by both drugs at micromolar concentrations. At low micromolar concentrations, both LTRAs also inhibited calcium ionophore-induced leukotriene (leukotriene B(4) and leukotriene C(4)) production, indicating 5-lipoxygenase inhibitory activities. We report herein that montelukast and zafirlukast, acting in a concentration-dependent manner, can inhibit non-CysLT(1)-mediated proinflammatory reactions, suggesting activities potentially relevant for interpatient variability in response to treatment. Higher doses of currently known LTRAs or new compounds derived from this class of drugs may represent a new strategy for finding more efficient therapy for bronchial asthma.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Woszczek
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Chen
authors.forename: Sara
authors.initials: S
authors.lastname: Alsaaty
authors.forename: Sahrudaya
authors.initials: S
authors.lastname: Nagineni
authors.forename: James H
authors.initials: JH
authors.lastname: Shelhamer
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D002118:Calcium / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002464:Cell Migration Inhibition / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D003521:Cyclopropanes; D006801:Humans; D007211:Indoles; D018836:Inflammation Mediators / Q000494:pharmacology / Q000502:physiology; D007424:Intracellular Fluid / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D018448:Models, Immunological; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D048448:Phenylcarbamates; D011804:Quinolines / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000502:physiology*; D013440:Sulfides; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000494:pharmacology*; D014530:Uridine Diphosphate / Q000502:physiology
chemical_list: D000085:Acetates; D003521:Cyclopropanes; D007211:Indoles; D018836:Inflammation Mediators; D020024:Leukotriene Antagonists; D048448:Phenylcarbamates; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; D013449:Sulfonamides; D014105:Tosyl Compounds; D014530:Uridine Diphosphate; C083169:leukotriene D4 receptor; C093875:montelukast; D002118:Calcium; C062735:zafirlukast