Abstract
The cholinergic antiinflammatory pathway modulates inflammatory cytokine production through a mechanism dependent on the vagus nerve and the alpha7 subunit of the nicotinic acetylcholine receptor. GTS-21 [3-(2,4-dimethoxybenzylidene) anabaseine], a selective alpha7 agonist, inhibits inflammatory cytokine production in murine and human macrophages and in several models of inflammatory disease in vivo, but to date its antiinflammatory efficacy in human monocytes has not been characterized. We report here our findings that GTS-21 attenuates tumor necrosis factor (TNF) and interleukin 1beta levels in human whole blood activated by exposure to endotoxin. GTS-21 inhibited TNF production in endotoxin-stimulated primary human monocytes in vitro at the transcriptional level. The suppressive effect of GTS-21 was more potent than nicotine in whole blood and monocytes. Furthermore, GTS-21 attenuated TNF production in monocytes stimulated with peptidoglycan, polyinosinic-polycytidylic acid, CpG, HMGB1 (high-mobility group box 1 protein), and advanced glycation end product-modified albumin. GTS-21 decreased TNF levels in endotoxin-stimulated whole blood obtained from patients with severe sepsis. These findings establish the immunoregulatory effect of GTS-21 on human monocytes, and indicate the potential benefits of further exploration of GTS-21's therapeutic uses in human inflammatory disease.
Highlights
The cholinergic antiinflammatory pathway is a neural regulatory mechanism comprised of the vagus nerve, its principal neurotransmitter acetylcholine, and the α7 subunit of the nicotinic acetylcholine receptor [1,2,3]
We compared the inhibitory effect of GTS-21 to that of nicotine, the canonical, nonselective nicotinic acetylcholine receptor agonist
Suppression of tumor necrosis factor (TNF) production by GTS-21 was more effective than an equimolar concentration of nicotine, which did not significantly inhibit TNF levels in whole blood at the concentration tested
Summary
The cholinergic antiinflammatory pathway is a neural regulatory mechanism comprised of the vagus nerve, its principal neurotransmitter acetylcholine, and the α7 subunit of the nicotinic acetylcholine receptor [1,2,3]. Activation of the cholinergic antiinflammatory pathway by electrical stimulation of the vagus nerve attenuates proinflammatory cytokine release and improves clinical outcome in experimental models of cytokinemediated diseases, including septic shock and ischemia–reperfusion [4,5]. Activation of α7 by ligation of the receptor with cholinergic agonists effectively ameliorates disease severity in sepsis [6], pancreatitis [7], and carrageenaninduced inflammation [8]. Selective α7 cholinergic agonists, with fewer unwanted side effects, are likely to be superior therapeutic candidates for clinical development as modulators of inflammation. Because of its selectivity toward α7, an essential modulator of inflammation, GTS-21 has been tested as an anti-
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