Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-κB phosphorylation and nuclear factor-κB transcriptional activity through nicotinic acetylcholine receptor α7

Abstract

Summary Macrophages/monocytes and the proinflammatory mediators, such as tumour necrosis factor (TNF)‐α, prostaglandin E2 (PGE2), macrophage inflammatory protein (MIP)‐1α and MIP‐1α, play a critical role in the progression of immunological disorders including rheumatoid arthritis, Behçet’s disease and Crohn’s disease. In addition, the nicotinic acetylcholine receptor‐α7 (α7nAChR) subunit is an essential regulator of inflammation. In this study, we evaluated the expression of the α7nAChR subunit on human peripheral monocytes and the effect of nicotine on the production of these proinflammatory mediators by activated monocytes. Fluorescein isothiocyanate (FITC)‐labelled α‐bungarotoxin demonstrated the cell surface expression of the α7nAchR subunit. Pretreatment with low‐dose nicotine caused inhibition of TNF‐α, PGE2, MIP‐1α and MIP‐1α production, and mRNA expression of TNF‐α, MIP‐1α and MIP‐1α and COX‐2 in lipopolysaccharide (LPS)‐activated monocytes. These suppressive effects of nicotine were caused at the transcriptional level and were mediated through α7nAChR. Nicotine suppressed the phosphorylation of I‐κB, and then inhibited the transcriptional activity of nuclear factor‐κB. These immunosuppressive effects of nicotine may contribute to the regulation of some immune diseases.

Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia

“…3). Indeed, the existence of a brain cholinergic anti-inflammatory pathway mediated by ␣7-nAChR is now well substantiated: macrophages, microvascular endothelial cells, and microglia express ␣7-nAChR on their surface, and the activation of these receptors resulted in immunosuppressive effects (350,370,451).…”

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“…22 Moreover, in other studies, nicotine was observed to significantly decrease the secretion of inflammatory mediators in human monocyte-macrophages by inhibiting activation of nuclear factor (NF)-κB. 32,33 It has been suggested that nicotine could be an important regulator of monocytemacrophages, through its role in the cholinergic antiinflammatory pathway, [34][35][36] mediated, in part, by inhibiting NF-κB and activating the transcription factor STAT3, a negative regulator of inflammation, via interaction with acetylcholine receptor α-7. 37 Contrary to the evidence showing antiinflammatory properties of smoking in monocytemacrophages, most 38,39 but not all studies 40 have reported a negative correlation between cigarette smoking and adiponectinemia, a well-known antiinflammatory adipokine that increases PPARG and insulin sensitivity.…”

The α7 nicotinic acetylcholine receptor on fibroblast‐like synoviocytes and in synovial tissue from rheumatoid arthritis patients: A possible role for a key neurotransmitter in synovial inflammation

“…The ␣7nAChR is expressed by various immune cells, including monocytes (15), macrophages (5,16), T and B lymphocytes (17,18), and dendritic cells (19). In addition to this classic ␣7nAChR, the human genome contains an alternative ␣7 transcript designated dup␣7 or "cholinergic receptor family with sequence similarity to 7A" (CHRFAM7A) (20).…”