BioMed Research International / 2014 / Article / Tab 3

Review Article

Vagus Nerve through 7 nAChR Modulates Lung Infection and Inflammation: Models, Cells, and Signals

Table 3

Modulatory effects of activation of nAChR on signaling pathways.

PathwaysSpeciesModelsInterventionsMajor resultsOutcomeReferences

Cell culture:  
epithelial cells; macrophages; or monocytes
TLRs agonists;  
nAChR agonists: nicotine; or GTS-21 pretreatment
(i) In human monocytes, GTS-21 attenuated TLR2, TLR3, TLR4, TLR9, and RAGE-mediated TNF production.  
(ii) GTS-21 decreased TNF levels in endotoxin-stimulated whole blood obtained from patients with severe sepsis.  
(iii) GTS-21 downregulated monocyte cell-surface expression of TLR2, TLR4, and CD14.  
(iv) An anti-inflammatory effect of nicotine on splenocytes isolated from control Wistar Kyoto rats (inhibition of interleukin-6 release) is reversed to a proinflammatory increase of interleukin-6 release from splenocytes of young, prehypertensive, and spontaneously hypertensive rats (SHRs).  
(v) The serum levels of both IL-6 and IL-1β in response to TLR7/8 activation with Clo97 (intraperitoneally) were markedly suppressed by the subcutaneous infusion of nicotine in WKY rats and conversely significantly enhanced in SHRs.
Downregulation of MyD88 and TLR signaling[66, 94, 123]

NF-κBMouse Sepsis; cell culture of macrophages;  
RAW cells
(i) In bronchial epithelial cells, nicotine decreased MyD88 protein, NF-κB p65 protein, NF-κB activity, and p-I-κBα expression induced by CE or LPS.  
(ii) GTS-21 inhibits NF-κB activation in endotoxin-stimulated RAW cells in a dose-dependent manner.  
(iii) Nicotine inhibits p65 NF-κB nuclear translocation in the BAL proinflammatory cells in acid-induced ALI mouse model.  
(iv) Inhibition of STAT3 phosphorylation mimicked the nAChR signaling, inhibiting NF-κB and cytokine production in macrophages.  
(v) Choline dose dependently suppressed NF-κB activation in response to endotoxin.
Suppress activation of NF-κB[5, 97, 124, 125]

Jak-Stat3 Mouse;  
endothelial cells;  
cell culture;  
depletion; or blockade of nAChR
(i) STAT3 was phosphorylated by the tyrosine kinase Jak2 that was recruited to the nAChR.  
(ii) The anti-inflammatory effect of nicotine required the ability of phosphorylated STAT3 to bind and transactivate its DNA response elements.  
(iii) In a mouse model of intestinal manipulation, stimulation of the vagus nerve ameliorated surgery-induced inflammation and postoperative ileus by activating STAT3 in intestinal macrophages.  
(iv) GTS-21 inhibits proinflammatory cytokine release independent of the Toll-like receptor stimulated via a transcriptional mechanism involving JAK2 activation. The inhibitor α-BTX could reverse these effects.  
(v) Both α7 nAChR activation and inhibition of JAK2 blunt STAT3 phosphorylation.  
(vi) Inhibition of STAT3 protein expression enhanced cytokine production and abrogated α7 nAChR signaling.  
(vii) nAChR controls TNF production in macrophages through a mechanism that requires STAT3 protein expression but not its tyrosine phosphorylation.
(viii) In vivo, inhibition of STAT3 tyrosine phosphorylation by stattic prevented systemic inflammation and improved survival in experimental sepsis.  
(ix) Cholinergic agonists suppress IL-6-mediated endothelial cell activation through the JAK2/STAT3 pathway.  
(x) Nicotine and GTS-21 treatment decreased levels of SOCS3 in activated endothelial cells.  
(xi) MicroRNA-124 mediates the cholinergic anti-inflammatory action through Stat3 and inhibits the production of proinflammatory cytokines.
Activation of α7 nAChR is protective through Jak2-STAT3 signaling pathway in macrophages and endothelial cells[14, 94, 95, 97, 126]

Cell culture: neurons; macrophages; monocytes;  
CLP sepsis
or DMPP; MLA;  
PI3K inhibitors treatment
(i) Nicotine improved sepsis-induced mortality, attenuated organ failure, and suppressed inflammatory cytokines, which were abolished by MLA.  
(ii) In macrophages, nicotine enhanced PI3K/AKT1 activation and reduced PU.1 activity and TLR4 expression. MLA and PI3K inhibitors blocked this effect of nicotine.  
(iii) In brain cortex primary cells, the nAChR was physically associated with the PI3K p85 subunit and Fyn. Activation of nAChR phosphorylates AKT1.  
(iv) Nicotine stimulation of nAChR transduces signals to PI3K and AKT1 via JAK2 in a cascade.  
(v) Coimmunoprecipitation of PI3K and nAChR , −4, and −7 subunits. Treatment of monocytes for 24 h with 10, 20, and 40 μM DMPP dose dependently inhibited TNF release.
Neuroprotective effect and anti-inflammation[127130]

PC12 cells, rat pheochromocytoma cells;
SH-SY5Y neuroblastoma cells
Nicotine, choline, GTS-21, SSR-180711A, and PNU-282987(i) nAChR agonist-triggered Ca2+ transient in PC12 cells induces activation of CaMKII, leading to sequential phosphorylation of p38 MAPK, MEK1/2, ERK1/2, and CREB.  
(ii) TLR and DR signaling, such as PI3K/AKT signaling, p38 signaling, and ERK signaling, were also significantly modulated by nicotine.
Cognition[131, 132]

ERK1/2RatsPC12 cellsPNU-282987,  
(i) Robust induction of ERK phosphorylation followed exposure of PC12 cells to the selective agonist PNU-282987 in the presence of the alpha 7 nAChR modulator PNU-120596.  
(ii) ERK phosphorylation was transient and was attenuated by the selective antagonist MLA.  
(iii) Consistent with allosteric modulation of alpha 7 nAChRs, PNU-120596 enhanced both the agonist potency and efficacy in activating ERK.

DMPP: dimethylphenylpiperazinium; CE: cigarettes extract; JAK2: Janus kinase 2; PI3K: phosphatidylinositol 3-kinase; WKY: Wistar Kyoto; SHRs: spontaneously hypertensive rats; DR: death receptor; MLA: methyllycaconitine.