Bagaitkar Juhi, Zeller Iris, Renaud Diane E, Scott David A
Microbiology and Immunology, University of Louisville, Louisville, KY, 40292, USA.
Tob Induc Dis. 2012 Nov 23;10(1):18. doi: 10.1186/1617-9625-10-18.
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.
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.
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.
尼古丁[（S）-3-（1-甲基-2-吡咯烷基）吡啶]在人体内的主要稳定代谢产物是可替宁[（S）-1-甲基-5-（3-吡啶基）-2-吡咯烷酮]。我们之前已经表明，可替宁暴露会诱导GSK3β依赖性PI3激酶和胆碱能抗炎系统的趋同和放大。其结果是，对细菌或脂多糖（一种TLR4激动剂）作出反应的人类单核细胞分泌的促炎细胞因子减少。
在这里我们表明，可替宁诱导的炎症抑制可能不限于单个Toll样受体（TLR）。事实上，在单核细胞中，可替宁抑制了所有主要表面暴露的TLR（TLR 2/1；2/6；4和5）激动剂特异性结合后通常产生的细胞因子产生，尽管抑制程度因TLR而异。
这些结果为吸烟者中已知的对多种细菌感染易感性增加提供了进一步的机制性见解。它们还将THP-1细胞确立为一种潜在合适的模型，用于研究烟草成分和代谢产物对TLR引发的炎症事件的影响。
