title: Stimulation of alpha7 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.
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Hamano
authors.forename: Hideo Kohka
authors.initials: HK
authors.lastname: Takahashi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwagaki
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; D018950:Lipopolysaccharide Receptors; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine