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GTS-21 has cell-specific anti-inflammatory effects independent of α7 nicotinic acetylcholine receptors
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GTS-21 has cell-specific anti-inflammatory effects independent of α7 nicotinic acetylcholine receptors
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Journal Article
GTS-21 has cell-specific anti-inflammatory effects independent of α7 nicotinic acetylcholine receptors
2019
Overview
α7 Nicotinic acetylcholine receptors (nAChRs) reportedly reduce inflammation by blocking effects of the important pro-inflammatory transcription factor, nuclear factor kappa-light chain-enhancer of B cells (NFκB). The α7 nAChR partial agonist GTS-21 reduces secretion of pro-inflammatory cytokines including interleukin-6 (IL6) and tumor-necrosis factor (TNF) in models of endotoxemia and sepsis, and its anti-inflammatory effects are widely ascribed to α7 nAChR activation. However, mechanistic details of α7 nAChR involvement in GTS-21 effects on inflammatory pathways remain unclear. Here, we investigate how GTS-21 acts in two cell systems including the non-immune rat pituitary cell line GH4C1 expressing an NFκB-driven reporter gene and cytokine secretion by ex vivo cultures of primary mouse macrophages activated by lipopolysaccharide (LPS). GTS-21 does not change TNF-stimulated NFκB signaling in GH4C1 cells expressing rat α7 nAChRs, suggesting that GTS-21 requires additional unidentified factors besides α7 nAChR expression to allow anti-inflammatory effects in these cells. In contrast, GTS-21 dose-dependently suppresses LPS-induced IL6 and TNF secretion in primary mouse macrophages endogenously expressing α7 nAChRs. GTS-21 also blocks TNF-induced phosphorylation of NFκB inhibitor alpha (IκBα), an important intermediary in NFκB signaling. However, α7 antagonists methyllycaconitine and α-bungarotoxin only partially reverse GTS-21 blockade of IL6 and TNF secretion. Further, GTS-21 significantly inhibited LPS-induced IL6 and TNF secretion in macrophages isolated from knockout mice lacking α7 nAChRs. These data indicate that even though a discrete component of the anti-inflammatory effects of GTS-21 requires expression of α7 nAChRs in macrophages, GTS-21 also has anti-inflammatory effects independent of these receptors depending on the cellular context.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
Acetylcholine receptors (nicotinic)
/ alpha7 Nicotinic Acetylcholine Receptor - biosynthesis
/ Animals
/ Anti-Inflammatory Agents - pharmacology
/ Benzylidene Compounds - pharmacology
/ Cloning
/ Gene Expression Regulation - drug effects
/ Kinases
/ Ligands
/ Lipopolysaccharides - toxicity
/ Macrophages, Peritoneal - metabolism
/ Macrophages, Peritoneal - pathology
/ Medicine and Health Sciences
/ Mice
/ Nicotine
/ Rats
/ Research and Analysis Methods
/ Rodents
/ Sepsis
