The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE.
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.
Rosas-Ballina
Mauricio
M
Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Goldstein
Richard S
RS
Gallowitsch-Puerta
Margot
M
Yang
Lihong
L
Valdés-Ferrer
Sergio Iván
SI
Patel
Nirav B
NB
Chavan
Sangeeta
S
Al-Abed
Yousef
Y
Yang
Huan
H
Tracey
Kevin J
KJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000097:blood; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000819:agonists* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D018805:Sepsis / Q000097:blood / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001597:Benzylidene Compounds; D018679:Cholinergic Agonists; C579167:Chrna7 protein, human; D016207:Cytokines; D004731:Endotoxins; D053583:Interleukin-1beta; D011725:Pyridines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011978:Receptors, Nicotinic; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; C044101:endotoxin, Escherichia coli; D009538:Nicotine; C088936:3-(2,4-dimethoxybenzylidene)anabaseine