Modulation of eosinophil activation in vitro by a nicotinic receptor agonist.
Nicotinic receptor agonists decreased the infiltration of eosinophils into the lung and airways in a mouse model of asthma. To better understand the mechanisms implicated in this anti-inflammatory phenomenon, the expression of nicotinic acetylcholine receptors (nAChRs) and the effect of dimethylphenylpiperazinium (DMPP), a nonselective nAChR agonist, on human blood eosinophils were studied. The expression of alpha-3, -4, and -7 nAChR subunits on human blood eosinophils was measured by cell ELISA and immunocytochemistry. mRNA expression for all three subunits was evaluated by quantitative RT-PCR. The effect of DMPP on leukotriene C4 (LTC4) and matrix metalloproteinase-9 (MMP-9) production, eosinophil migration, and intracellular calcium mobilization was measured. The results show that the alpha-3, -4, and -7 nAChR subunits and mRNAs are expressed by blood eosinophils. In vitro treatment of these cells with various concentrations of DMPP reduced platelet-activating factor (PAF)-induced LTC4 production significantly. DMPP (160 microM) decreased eotaxin, and 5-oxo-6,8,11,14-eicosatetranoic acid induced eosinophil migration through Matrigel by 40.9% and 55.5%, respectively. This effect was reversed by the nAChR antagonist mecamylamine. In addition, DMPP reduced MMP-9 release and the inositol 1,4,5-triphosphate-dependent intracellular calcium increase provoked by PAF. Taken together, these results indicate that functional nAChRs are expressed on eosinophils and that nAChR agonists down-regulate eosinophil function in vitro. These anti-inflammatory effects could be of interest in the treatment of allergic asthma.
Blanchet
Marie-Renée
MR
Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, 2725 Chemin Ste-Foy, Ste-Foy, Québec, Canada, G1V 4G5.
Langlois
Anick
A
Israël-Assayag
Evelyne
E
Beaulieu
Marie-Josée
MJ
Ferland
Claudine
C
Laviolette
Michel
M
Cormier
Yvon
Y
D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology*; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D017997:Leukotriene C4 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D021122:Protein Subunits / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013329:Structure-Activity Relationship
D001095:Arachidonic Acids; C515456:CCL11 protein, human; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D018722:Nicotinic Agonists; D010972:Platelet Activating Factor; D021122:Protein Subunits; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; D017997:Leukotriene C4; D004246:Dimethylphenylpiperazinium Iodide; D020780:Matrix Metalloproteinase 9; D002118:Calcium