The Selective α7 Agonist GTS-21 Attenuates Cytokine Production in Human Whole Blood and Human Monocytes Activated by Ligands for TLR2, TLR3, TLR4, TLR9, and RAGE

被引:0
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作者
Mauricio Rosas-Ballina
Richard S. Goldstein
Margot Gallowitsch-Puerta
Lihong Yang
Sergio Iván Valdés-Ferrer
Nirav B. Patel
Sangeeta Chavan
Yousef Al-Abed
Huan Yang
Kevin J. Tracey
机构
[1] The Feinstein Institute for Medical Research,Laboratory of Biomedical Science
来源
Molecular Medicine | 2009年 / 15卷
关键词
Human Monocytes; Anabaseine; Monocyte Stimulation; Cholinergic Anti-inflammatory Pathway; Polyinosinic-polycytidylic Acid;
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摘要
The cholinergic antiinflammatory pathway modulates Inflammatory cytokine production through a mechanism dependent on the vagus nerve and the α7 subunit of the nicotinic acetylcholine receptor. GTS-21 [3-(2,4-dimethoxybenzylidene) anabaseine], a selective α7 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 1β 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.
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页码:195 / 202
页数:7
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