Abstract
Nicotine stimulation of α7 nicotinic acetylcholine receptor (α7 nAChR) powerfully inhibits pro-inflammatory cytokine production in lipopolysaccharide (LPS)-stimulated macrophages and in experimental models of endotoxemia. A signaling pathway downstream from the α7 nAChRs, which involves the collaboration of JAK2/STAT3 and NF-κB to interfere with signaling by Toll-like receptors (TLRs), has been implicated in this anti-inflammatory effect of nicotine. Here, we identifiy an alternative mechanism involving interleukin-1 receptor-associated kinase M (IRAK-M), a negative regulator of innate TLR-mediated immune responses. Our data show that nicotine up-regulates IRAK-M expression at the mRNA and protein level in human macrophages, and that this effect is secondary to α7 nAChR activation. By using selective inhibitors of different signaling molecules downstream from the receptor, we provide evidence that activation of STAT3, via either JAK2 and/or PI3K, through a single (JAK2/PI3K/STAT3) or two convergent cascades (JAK2/STAT3 and PI3K/STAT3), is necessary for nicotine-induced IRAK-M expression. Moreover, down-regulation of this expression by small interfering RNAs specific to the IRAK-M gene significantly reverses the anti-inflammatory effect of nicotine on LPS-induced TNF-α production. Interestingly, macrophages pre-exposed to nicotine exhibit higher IRAK-M levels and reduced TNF-α response to an additional LPS challenge, a behavior reminiscent of the ‘endotoxin tolerant’ phenotype identified in monocytes either pre-exposed to LPS or from immunocompromised septic patients. Since nicotine is a major component of tobacco smoke and increased IRAK-M expression has been considered one of the molecular determinants for the induction of the tolerant phenotype, our findings showing IRAK-M overexpression could partially explain the known influence of smoking on the onset and progression of inflammatory and infectious diseases.
Highlights
Cigarette smoking stronggly influences the onset and clinical course of various pathologies through a complex set of actions affecting the body’s defense mechanisms that range from proinflammatory to immune-suppressive [1,2,3,4]
To analyze whether the up-regulation of interleukin-1 receptor-associated kinase M (IRAK-M) elicited by nicotine was the result of increased gene transcription, we performed Quantitative Real-Time PCR (qPCR) experiments to determine the time-course of IRAK-M mRNA levels in MØ stimulated with nicotine for different periods (Figure 1B)
Our results show that nicotine up-regulates IRAK-M mRNA expression, with levels peaking at 6 h and declining to baseline levels at 24 h of incubation with the drug
Summary
Cigarette smoking stronggly influences the onset and clinical course of various pathologies through a complex set of actions affecting the body’s defense mechanisms that range from proinflammatory to immune-suppressive [1,2,3,4]. Its anti-inflammatory action, like that of the endogenous neurotransmitter ACh, is due to its binding to and activation of a7 nicotinic acetylcholine receptors (a7 nAChRs) on resident macrophages under the control of the ‘cholinergic antiinflammatory pathway’ (CAP) [5,6,9,10]. This anti-inflammatory pathway, first identified by the Tracey group, constitutes the efferent arm of a vagal nerve circuit directly linked to the immune system. The physiological activation of CAP is critical to ensure the appropriate magnitude of the inflammatory response to an infection or injury since it culminates in T cell release of ACh and the interaction of the neurotransmitter with a7 nAChRs on resident macrophages in the spleen, thereby inhibiting proinflammatory cytokine production by these macrophages [11,12]
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