BACKGROUND: The Toll-like receptor (TLR) plays an important role in the induction of the hyperinflammatory response and tissue injury in sepsis. The cholinergic antiinflammatory pathway serves as a link between the parasympathetic and innate immune systems. We examined the antiinflammatory effect of nicotine, a potent α7 nicotinic acetylcholine receptor (α7nAChR) agonist, with regard to TLR expression and signaling during sepsis. METHODS: Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP). The subjects received intraperitoneal nicotine (400 μg/kg) immediately after CLP for the biochemical study and 0, 24, 48, and 72 hours after CLP for the survival test. Intraperitoneal methyllycaconitine (MLA; 5 mg/kg), an α7nAChR antagonist, was administered 5 minutes prior to nicotine treatment. We evaluated the effects of nicotine using α7nAChR and phosphoinositide 3-kinase (PI3K) inhibitors in lipopolysaccharide-stimulated RAW264.7 cells. RESULTS: Nicotine improved sepsis-induced mortality, attenuated organ failure, and suppressed inflammatory cytokines, which were abolished by MLA. Nicotine enhanced PI3K/Akt activation and reduced PU.1 activity and TLR4 expression. MLA and PI3K inhibitors blocked this effect of nicotine. CONCLUSIONS: Our findings suggest that stimulation of the cholinergic antiinflammatory pathway by nicotine protects against septic injury and that this may be associated with inhibition of TLR4 expression via α7nAChR/PI3K signaling.
BACKGROUND: The Toll-like receptor (TLR) plays an important role in the induction of the hyperinflammatory response and tissue injury in sepsis. The cholinergic antiinflammatory pathway serves as a link between the parasympathetic and innate immune systems. We examined the antiinflammatory effect of nicotine, a potent α7 nicotinic acetylcholine receptor (α7nAChR) agonist, with regard to TLR expression and signaling during sepsis. METHODS: Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP). The subjects received intraperitoneal nicotine (400 μg/kg) immediately after CLP for the biochemical study and 0, 24, 48, and 72 hours after CLP for the survival test. Intraperitoneal methyllycaconitine (MLA; 5 mg/kg), an α7nAChR antagonist, was administered 5 minutes prior to nicotine treatment. We evaluated the effects of nicotine using α7nAChR and phosphoinositide 3-kinase (PI3K) inhibitors in lipopolysaccharide-stimulated RAW264.7 cells. RESULTS:Nicotine improved sepsis-induced mortality, attenuated organ failure, and suppressed inflammatory cytokines, which were abolished by MLA. Nicotine enhanced PI3K/Akt activation and reduced PU.1 activity and TLR4 expression. MLA and PI3K inhibitors blocked this effect of nicotine. CONCLUSIONS: Our findings suggest that stimulation of the cholinergic antiinflammatory pathway by nicotine protects against septic injury and that this may be associated with inhibition of TLR4 expression via α7nAChR/PI3K signaling.
Authors: Carmelo Carmona-Rivera; Monica M Purmalek; Erica Moore; Meryl Waldman; Peter J Walter; H Martin Garraffo; Karran A Phillips; Kenzie L Preston; Jonathan Graf; Mariana J Kaplan; Peter C Grayson Journal: JCI Insight Date: 2017-02-09
Authors: Meredith S Shiels; Hormuzd A Katki; Neal D Freedman; Mark P Purdue; Nicolas Wentzensen; Britton Trabert; Cari M Kitahara; Michael Furr; Yan Li; Troy J Kemp; James J Goedert; Cindy M Chang; Eric A Engels; Neil E Caporaso; Ligia A Pinto; Allan Hildesheim; Anil K Chaturvedi Journal: J Natl Cancer Inst Date: 2014-10-01 Impact factor: 13.506
Authors: María C Maldifassi; Carolina Martín-Sánchez; Gema Atienza; José L Cedillo; Francisco Arnalich; Anna Bordas; Francisco Zafra; Cecilio Giménez; María Extremera; Jaime Renart; Carmen Montiel Journal: J Biol Chem Date: 2018-07-13 Impact factor: 5.157