title: GTS-21 inhibits pro-inflammatory cytokine release independent of the Toll-like receptor stimulated via a transcriptional mechanism involving JAK2 activation.
abstract: The vagus nerve can limit inflammation via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). Selective pharmacological stimulation of the alpha7nAChR may have therapeutic potential for the treatment of inflammatory conditions. We determined the anti-inflammatory potential of GTS-21, an alpha7nAChR-selective partial agonist, on primary human leukocytes and compared it with nicotine, the nAChR agonist widely used for research into the anti-inflammatory effects of alpha7nAChR stimulation. Furthermore, we investigated whether the effects of both nicotinic agonists were restricted to specific Toll-like receptors (TLRs) stimulated and explored the mechanism behind the anti-inflammatory effect of GTS-21. GTS-21 and nicotine inhibited the release of pro-inflammatory cytokines in peripheral blood mononuclear cells (PBMCs), monocytes and whole blood independent of the TLR stimulated, with higher potency/efficacy for GTS-21 compared to nicotine. The anti-inflammatory cytokine IL-10 was relatively unaffected by both nicotinic agonists. The effects of GTS-21 and nicotine could not be reversed by nAChR antagonists, while the JAK2 inhibitor AG490 abolished the anti-inflammatory effects. GTS-21 downregulated monocyte cell-surface expression of TLR2, TLR4 and CD14. qPCR analysis demonstrated that the anti-inflammatory effect of GTS-21 is mediated at the transcriptional level and involves JAK2-STAT3 activation. In conclusion, GTS-21 has a profound anti-inflammatory effect in human leukocytes and that GTS-21 is more potent/efficacious than nicotine. The absence of a blocking effect of nAChR antagonists in human leukocytes might indicate different pharmacological properties of the alpha7nAChR in human leukocytes compared to other cell types. GTS-21 may be promising from a therapeutic perspective because of its suitability for human use.
authors: Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Matthijs
authors: M
authors: Kox
authors: Jeroen F
authors: JF
authors: van Velzen
authors: Jan C
authors: JC
authors: Pompe
authors: Cornelia W
authors: CW
authors: Hoedemaekers
authors: Johannes G
authors: JG
authors: van der Hoeven
authors: Peter
authors: P
authors: Pickkers
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation; D054333:Drug Partial Agonism; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000276:immunology*; D053614:Janus Kinase 2 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000096:biosynthesis / Q000502:physiology*; D014158:Transcription, Genetic; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001597:Benzylidene Compounds; C579167:Chrna7 protein, human; D016207:Cytokines; D008070:Lipopolysaccharides; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051193:Toll-Like Receptors; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; C507924:JAK2 protein, human; D053614:Janus Kinase 2