Abstract
Nicotine is thought to inhibit the production of proinflammatory cytokines from macrophages through an anti-inflammatory pathway that is dependent on nicotinic acetylcholine receptor alpha7 subunit (alpha7-nAChR). IL-18, an important proinflammatory cytokine, is reported to induce the expression of adhesion molecules on monocytes, thus enhancing cell-to-cell interactions with T-cells and contributing to IL-18-initiated cytokine production. Accordingly, inhibition of IL-18 suppresses systemic inflammatory responses. In the present study, we found that nicotine inhibited the IL-18-enhanced expression of ICAM-1, B7.2, and CD40 on monocytes, and the production of IL-12, IFN-gamma, and TNF-alpha by PBMC. A nonselective and a selective alpha7-nAChR antagonist, mecamylamine, and alpha-bungarotoxin abolished the effects of nicotine, suggesting that this depends on alpha7-nAChR stimulation. It is reported that nicotine induces prostaglandinE2 (PGE(2)) production in PBMC through the up-regulation of cyclooxygenase (COX)-2 expression. PGE(2) is known to activate the EP2/EP4-receptor, leading to an increase in cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity. Consistent with this, we found that COX-2 and PKA inhibitors prevented the effects of nicotine on adhesion molecule expression and cytokine production, indicating that the mechanism of action of nicotine may be via endogenous PGE(2) production.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD / biosynthesis
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Antigens, CD / immunology
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Cells, Cultured
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Cyclic AMP / immunology
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / biosynthesis
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Cyclic AMP-Dependent Protein Kinases / immunology
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Cyclooxygenase 2 / biosynthesis
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Cyclooxygenase 2 / immunology
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Cytokines / biosynthesis
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Cytokines / immunology
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Dinoprostone / biosynthesis
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Dinoprostone / immunology
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / immunology
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Humans
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Interleukin-18 / biosynthesis
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Interleukin-18 / immunology*
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Macrophage Activation / drug effects
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Macrophage Activation / immunology
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Membrane Proteins / biosynthesis
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Membrane Proteins / immunology
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Monocytes / immunology*
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Monocytes / metabolism
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Nicotine / immunology
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Nicotine / pharmacology*
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Nicotinic Agonists / immunology
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Nicotinic Agonists / pharmacology*
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Receptors, Nicotinic / immunology
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Receptors, Nicotinic / metabolism
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Receptors, Prostaglandin E / biosynthesis
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Receptors, Prostaglandin E / immunology
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Receptors, Prostaglandin E, EP2 Subtype
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Signal Transduction / drug effects*
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Signal Transduction / immunology
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alpha7 Nicotinic Acetylcholine Receptor
Substances
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Antigens, CD
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Chrna7 protein, human
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Cytokines
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Interleukin-18
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Membrane Proteins
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Nicotinic Agonists
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PTGER2 protein, human
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Receptors, Nicotinic
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Receptors, Prostaglandin E
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Receptors, Prostaglandin E, EP2 Subtype
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alpha7 Nicotinic Acetylcholine Receptor
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Nicotine
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Cyclic AMP
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Cyclooxygenase 2
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PTGS2 protein, human
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Cyclic AMP-Dependent Protein Kinases
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Dinoprostone