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This Article Full Text Full Text (PDF) All Versions of this Article: 291/4/L757    most recent 00409.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Blanchet, M.-R. Articles by Cormier, Y. Search for Related Content PubMed PubMed Citation Articles by Blanchet, M.-R. Articles by Cormier, Y.

Dimethyphenylpiperazinium, a nicotinic receptor agonist, downregulates inflammation in monocytes/macrophages through PI3K and PLC chronic activation

Hopital Laval, Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Ste-Foy, Quebec, Canada

Submitted 22 September 2005 ; accepted in final form 6 May 2006

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 3, -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.

phosphatidylinositol 3-kinase; intracellular calcium; nicotinic acetylcholine receptors; phospholipase C

This article has been cited by other articles:

				M.-R. Blanchet, A. Langlois, E. Israel-Assayag, M.-J. Beaulieu, C. Ferland, M. Laviolette, and Y. Cormier Modulation of eosinophil activation in vitro by a nicotinic receptor agonist J. Leukoc. Biol., May 1, 2007; 81(5): 1245 - 1251. [Abstract] [Full Text] [PDF]