Cotinine inhibits the pro-inflammatory response initiated by multiple cell surface Toll-like receptors in monocytic THP
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SHORT REPORT
Open Access
Cotinine inhibits the pro-inflammatory response initiated by multiple cell surface Toll-like receptors in monocytic THP cells Juhi Bagaitkar1,3, Iris Zeller2, Diane E Renaud2 and David A Scott1,2*
Abstract Background: The primary, stable metabolite of nicotine [(S)-3-(1-methyl-2-pyrrolidinyl) pyridine] in humans is cotinine [(S)-1-methyl-5-(3-pyridinyl)-2-pyrrolidinone]. We have previously shown that cotinine exposure induces convergence and amplification of the GSK3β-dependent PI3 kinase and cholinergic anti-inflammatory systems. The consequence is reduced pro-inflammatory cytokine secretion by human monocytes responding to bacteria or LPS, a TLR4 agonist. Findings: Here we show that cotinine-induced inflammatory suppression may not be restricted to individual Toll-like receptors (TLRs). Indeed, in monocytic cells, cotinine suppresses the cytokine production that is normally resultant upon agonist-specific engagement of all of the major surface exposed TLRs (TLR 2/1; 2/6; 4 and 5), although the degree of suppression varies by TLR. Conclusions: These results provide further mechanistic insight into the increased susceptibility to multiple bacterial infections known to occur in smokers. They also establish THP-1 cells as a potentially suitable model with which to study the influence of tobacco components and metabolites on TLR-initiated inflammatory events. Keywords: Cholinergic anti-inflammatory pathway, Cotinine, Cytokines, GSK3β, Inflammation, THP-1 cells, Tobacco smoking, Toll-like receptors
Findings Introduction
The ability to regulate against prolonged or excessive inflammation is critical in preventing the onset of septic shock and the host-mediated damage associated with multiple chronic inflammatory diseases. On the other hand, a reduced inflammatory capacity can lead to an inability to clear pathogens and can compromise tissue remodeling [1]. In recent years the importance of the cholinergic antiinflammatory system in modulating cytokine production in response to inflammatory stimuli has become apparent. The cholinergic anti-inflammatory pathway suppresses inflammation through the activation of the α7 nicotinic
* Correspondence: [email protected] 1 Microbiology and Immunology, University of Louisville, Louisville, KY 40292, USA 2 Oral Health and Systemic Disease Research Group, University of Louisville, Louisville, KY 40292, USA Full list of author information is available at the end of the article
acetylcholine receptor (α7nAChR) on innate immune cells by neuronal and / or locally produced acetylcholine [1-4]. Nicotine, a major component of cigarette smoke, is also a potent α7nAChR agonist [5,6]. Smokers are more susceptible to multiple bacterial diseases than non-smokers [7]. The inappropriate activation of the cholinergic antiinflammatory pathway by nicotine provides mechanistic insight into this phenomenon. Nicotine is rapidly converted into multiple metabolites in humans. Of these, cotinine, a considerably more stable molecule than nicotine that frequently reaches
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