Stimulation of the α7 nicotinic acetylcholine receptor protects against sepsis by inhibiting toll-like receptor via phosphoinositide 3-kinase activation

Tae Hoon Kim, So Jin Kim, Sun Mee Lee

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1668-1677
Number of pages10
JournalJournal of Infectious Diseases
Volume209
Issue number10
DOIs
StatePublished - 15 May 2014
Externally publishedYes

Keywords

  • nicotine
  • PI3K
  • PU.1.
  • sepsis
  • TLR
  • α7nAChR

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