title: Effect of nicotine on IL-18-initiated immune response in human monocytes.
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.
authors.affiliation: Department of Pharmacology, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Hideo Kohka
authors.initials: HK
authors.lastname: Takahashi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwagaki
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Hamano
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D015232:Dinoprostone / Q000096:biosynthesis / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D020382:Interleukin-18 / Q000096:biosynthesis / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D009538:Nicotine / Q000276:immunology / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000276:immunology / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000276:immunology / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis / Q000276:immunology; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D015703:Antigens, CD; C579167:Chrna7 protein, human; D016207:Cytokines; D020382:Interleukin-18; D008565:Membrane Proteins; D018722:Nicotinic Agonists; C545644:PTGER2 protein, human; D011978:Receptors, Nicotinic; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone