Abstract
The cholinergic anti-inflammatory pathway plays an important role in controlling inflammation. This study investigated the effects of varenicline, an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, on inflammatory cytokine levels, cell proliferation, and migration rates in a lipopolysaccharide (LPS)-induced inflammation model in RAW 264.7 murine macrophage cell lines. The cells were treated with increasing concentrations of varenicline, followed by LPS incubation for 24 h. Prior to receptor-mediated events, anti-inflammatory effects of varenicline on different cytokines and chemokines were investigated using a cytokine array. Nicotinic AChR–mediated effects of varenicline were investigated by using a non-selective nAChR antagonist mecamylamine hydrochloride and a selective α7nAChR antagonist methyllycaconitine citrate. TNFα, IL-1β, and IL-6 levels were determined by the ELISA test in cell media 24 h after LPS administration and compared with those of dexamethasone. The rates of cellular proliferation and migration were monitored for 24 h after drug treatment using a real-time cell analysis system. Varenicline decreased LPS-induced cytokines and chemokines including TNFα, IL-6, and IL-1β via α7nAChRs to a similar level that observed with dexamethasone. Varenicline treatment decreased LPS-induced cell proliferation, without any nAChR involvement. On the other hand, the LPS-induced cell migration rate decreased with varenicline via α7nAChR. Our data suggest that varenicline inhibits LPS-induced inflammatory response by activating α7nAChRs within the cholinergic anti-inflammatory pathway, reducing the cytokine levels and cell migration.
Highlights
Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, induces “pathogen-associated molecular pattern (PAMP) recognition receptors”
This study investigated the effects of varenicline on α7 nicotinic acetylcholine receptor (α7nAChR)–mediated activation of cholinergic anti-inflammatory pathway (CAP), cell proliferation, and migration induced by LPS
This study shows that varenicline significantly inhibits LPSinduced pro-inflammatory cytokine levels via α7nAChR along with concomitant cell proliferation and migration, suggesting its potential value in the prevention of inflammation by activating the cholinergic anti-inflammatory pathway
Summary
Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, induces “pathogen-associated molecular pattern (PAMP) recognition receptors” Clinical studies showed that agents acting on the cholinergic anti-inflammatory pathway improved sequential organ failure and mortality rates in patients with sepsis (Zimmermann et al, 2017; Pinder et al, 2019a; Pinder et al, 2019b). Studies showed that α7nAChR agonists, such as nicotine, acetylcholine, choline, or GTS-21 modulate LPS-induced proinflammatory cytokines, promote and improve survival in different experimental models (Borovikova et al, 2000; Pavlov et al, 2007; Fujii et al, 2017; Zimmermann et al, 2017; Snider et al, 2018). Α7nAChR-activating agents appear to have therapeutic efficacy in inflammatory processes (Borovikova et al, 2000; Bernik et al, 2002; De Jonge and Ulloa, 2007; Zimmermann et al, 2017; Pinder et al, 2019a; Pinder et al, 2019b)
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