Stimulation of Α7 Nicotinic Acetylcholine Receptor Inhibits Cd14 and the Toll-Like Receptor 4 Expression in Human Monocytes

Abstract

The lipopolysaccharide (LPS)-receptor complex, CD14/toll-like receptor 4, is known to play a role in the immune responses during sepsis. Excessive inflammation and tumor necrosis factor (TNF)-alpha synthesis have been reported to cause morbidity and mortality in endotoxemia and sepsis. Cell-to-cell interaction through the engagement between intercellular adhesion molecule 1, B7.1, and CD40 on monocytes and their ligands on T cells has been suggested to play a role in the inflammatory response such as TNF-alpha and interleukin 10 production. Nicotine, with the stimulation of the nicotinic acetylcholine receptor alpha7 subunit (alpha7-nAChR), has now become the focus of attention because of its anti-inflammatory effects. However, little is known about the mechanism of the inhibitory effects induced by nicotine on the LPS-induced immune responses. In the present study, we found that nicotine suppressed the expression of CD14, toll-like receptor 4, intercellular adhesion molecule 1, B7.1, and CD40 on monocytes and the production of TNF-alpha, but not interleukin 10, in human peripheral blood mononuclear cells in the presence of LPS. The actions of nicotine were reversed by a nonselective and a selective alpha7-nAChR antagonist, mecamylamine and alpha-bungarotoxin, respectively. Therefore, nicotine might inhibit the LPS receptor complex expression via alpha7-nAChR, thus leading to a decrease in the adhesion molecule expression and TNF-alpha production. Moreover, we demonstrated that a nuclear factor-kappaB and a p38 mitogen-activated protein kinase inhibitor mimicked the actions of nicotine in the presence of LPS. These results suggested that the nuclear factor-kappaB and p38 mitogen-activated protein kinase might be involved in the actions of nicotine.

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

“…These actions are blocked by a nonselective and a selective a7-nAChR antagonist, mecamylamine and a-bungarotoxin, respectively. Moreover, a NF-kB and a p38 MAPK inhibitor mimicked the actions of nicotine in the presence of LPS (Hamano et al, 2006). Both GTS-21, an a7-nAChR partial agonist, and nicotine inhibit the release of proinflammatory cytokines by PBMCs, monocytes, and whole blood independent of the TLR stimulated.…”

“…Treatment with cholinergic agonist(s) activates the JAK2-STAT3 pathway and suppresses NF-kB activity (de Jonge et al, 2005;Yoshikawa et al, 2006). Nicotine also suppresses expression of TLR4 antigens on monocytes and production of tumor necrosis factor (TNF)-a peptides by human peripheral blood mononuclear cells (PBMCs) in the presence of LPS (Hamano et al, 2006). These actions are blocked by a nonselective and a selective a7-nAChR antagonist, mecamylamine and a-bungarotoxin, respectively.…”

“…Toll-like receptor (TLR) pathways, especially TLR4, the receptor for Gram-negative bacterial lipopolysaccharide (LPS) (Wittebole et al, 2010), a7-nAChR, and multiple signaling pathways (Sugano et al, 1998;Wang et al, 2004;de Jonge et al, 2005;Arredondo et al, 2006;Hamano et al, 2006;Park et al, 2008;Cui and Li, 2010) are involved in the anti-inflammatory effect of nicotine. Stimulation of TLRs activates transcription factor nuclear factor-kB (NF-kB) and stress-activated protein kinases (Slack et al, 2000;Beutler, 2004) involved in the expression of mRNAs of inflammatory cytokines.…”

Crohn’s disease as an immunodeficiency

“…This receptor is expressed on macrophages (as well as other immune cells), where its predominant effect is anti-inflammatory [80]. The effect of nicotine acting through this receptor to suppress lipopolysaccharide-induced cytokine secretion in particular [81] indicates a mechanism by which smoking may exacerbate macrophage hyporesponsiveness [12] and contribute further to bacterial persistence in CD.…”

Increased vagal tone accounts for the observed immune paralysis in patients with traumatic brain injury

“…In this context, it is noteworthy that ex vivo treatment of human monocytes with nicotine (stimulation of the cholinergic anti-inflammatory pathway) resulted in downregulation of TLR4 expression in human monocytes. 54 This observation may also explain the attenuated production of proinflammatory cytokines in blood of trauma patients that was stimulated ex vivo with LPS, the primary ligand for TLR4. 15 In this prospect, increased vagal activity may represent a negative feedback mechanism counteracting the massive systemic proinflammatory response.…”