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

Abstract

. Dimethyphenylpiperazinium, a nicotinic receptor agonist, downregulates inflammation in monocytes/macrophages through PI3K and PLC chronic activation. Am J Physiol Lung Cell Mol Physiol 291: L757-L763, 2006. First published June 16, 2006 doi:10.1152/ajplung.00409.2005.-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 NICOTINIC RECEPTOR AGONISTS show anti-inflammatory properties in vivo. Studies have demonstrated that administration of nicotine has anti-inflammatory effects in a mouse model of hypersensitivity pneumonitis, reduces the incidence of type 1 (autoimmune) diabetes and ulcerative colitis (1,21,24), and improves survival in experimental sepsis (27). Moreover, dimethylphenylpiperazinium (DMPP), a synthetic nicotinic acetylcholine receptor (nAChR) agonist, reduces airway inflammation as well as the increase in airway resistance in a mouse model of asthma (2). Finally, both nAChR agonists nicotine and DMPP have protective effects on early phase hepatic ischemia-reperfusion injury (6, 27).These effects are further supported by in vitro studies showing that nicotine reduces the production of IL-1 by macrophages (22), TNF expression and IFN-␥ and IL-10 mRNA production by alveolar macrophages (AM) (1). Nicotine also has inhibitory effects on the express...

Phospholipase C Activity Affinity Purifies with the Torpedo Nicotinic Acetylcholine Receptor

“…Also, the presence of DAG in a reconstituted membrane influences the ability of the nAChR to undergo agonist-induced conformational transitions. Our results support the novel hypothesis that nicotinic acetylcholine receptors influence cellular events by mechanisms that do not involve the flux of ions into the cell (13)(14)(15)(16)(17). The nAChR may be able to alter the lipid composition of its surrounding microenvironment in a manner that enhances its own function.…”

Identification and Characterization of Poly(I:C)-induced Molecular Responses Attenuated by Nicotine in Mouse Macrophages

“…Previous investigations of the anti-inflammatory effect of nicotine were limited to study of signaling molecules/ transcription factors, such as NF-kB, IkB, Jak2, and STAT3 (de Jonge et al, 2005;Blanchet et al, 2006;Yoshikawa et al, 2006;Cheng et al, 2007). Protein phosphorylation plays an important role in signal transduction from pathogen to inflammatory products.…”

“…Activation of a7-nAChR increases the intracellular calcium concentration in both neurons and some nonneuron cells (Vijayaraghavan et al, 1992;Bertrand et al, 1993;Sopori et al, 1998;Shoop et al, 2001;Blanchet et al, 2006). However, the a7-nAChR expressed on the surface of RAW264.7 cells or peritoneal macrophages, apparently activated by nicotine and sensitive to inhibition by a-BTX, is not able to raise [Ca 21 ] i , because nicotine-treated cells yield [Ca 21 ] i signal that is almost the same as in the negative-control cells.…”

“…Binding of nAChR agonists such as nicotine, acetylcholine, GTS-21, and DMPP to a7-or a7-like nAChR attenuates or suppresses inflammation (Borovikova et al, 2000;Wang et al, 2003;Blanchet et al, 2006;RazaniBoroujerdi et al, 2007;Mikulski et al, 2010;Kox et al, 2011). Hence, cholinergic signaling via nAChR in immune cells is the subject of attempts to develop treatments for inflammatory diseases/disorders and gives rise to the concept of a "cholinergic anti-inflammatory pathway" (Pavlov et al, 2003).…”

Sperm Epidermal Growth Factor Receptor (EGFR) Mediates α7 Acetylcholine Receptor (AChR) Activation to Promote Fertilization

“…It is known that in other cell types ␣7nAChR is capable of activating signal transduction pathways that do not involve the channel activity of the receptor (71,72). Among the signal transducers, it can activate the PLC␥/PI3K and ERK1/2 two pathways known to be involved in sperm AR (57,73,74).…”