Dimethyphenylpiperazinium, a nicotinic receptor agonist, downregulates inflammation in monocytes/macrophages through PI3K and PLC chronic activation.
Activation of nicotinic acetylcholine receptors (nAChRs) on inflammatory cells induces anti-inflammatory effects. The intracellular mechanisms that regulate this effect are still poorly understood. In neuronal cells, nAChRs are associated with phosphatidylinositol 3-kinase (PI3K). This enzyme, which can activate phospholipase C (PLC), is also present in monocytes. The aim of this study was to assess the role of these proteins in the signaling pathways involved in the anti-inflammatory effect of dimethylphenylpiperazinium (DMPP), a synthetic nAChR agonist, on monocytes and macrophages. The results indicate that PI3K is associated with alpha3, -4, and -5 nAChR subunits in monocytes. The PI3K inhibitors wortmannin and LY294002 abrogated the inhibitory effect of DMPP on LPS-induced TNF release by monocytes. Treatment with DMPP for 24 and 48 h provoked a mild PLC phosphorylation, which was blocked by the nAChR antagonist mecamylamine and reversed by PI3K inhibitors. Treatment of monocytes and alveolar macrophages with DMPP reduced the inositol 1,4,5-trisphosphate (IP3)-dependent intracellular calcium mobilization induced by platelet-activating factor (PAF), an effect that was reversed by mecamylamine in alveolar macrophages. DMPP did not have any effect on PAF receptor expression. DMPP also inhibited the thapsigargin-provoked calcium release, indicating that the endoplasmic reticulum calcium stores might be depleted by treatment with the nAChR agonist. Taken together, these results suggest that PI3K and PLC activation is involved in the anti-inflammatory effect of DMPP. PLC limited, but constant activation could induce, the depletion of intracellular calcium stores, leading to the anti-inflammatory effect of DMPP.
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.
Israël-Assayag
Evelyne
E
Daleau
Pascal
P
Beaulieu
Marie-Josée
MJ
Cormier
Yvon
Y
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D010738:Type C Phospholipases / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D002121:Calcium Channel Blockers; D008070:Lipopolysaccharides; D018722:Nicotinic Agonists; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D004246:Dimethylphenylpiperazinium Iodide; D015544:Inositol 1,4,5-Trisphosphate; D019869:Phosphatidylinositol 3-Kinases; D010738:Type C Phospholipases; D002118:Calcium