Stimulation of alpha 7 cholinergic receptors inhibits lipopolysaccharide-induced neutrophil recruitment by a tumor necrosis factor alpha-independent mechanism.

Abstract

The cholinergic nervous system controls inflammation by inhibiting the release of proinflammatory cytokines such as tumor necrosis factor (TNF) alpha from lipopolysaccharide (LPS)-stimulated macrophages. The key endogenous mediator of this so-called cholinergic anti-inflammatory pathway is acetylcholine, the principal neurotransmitter of the vagus nerve, which specifically interacts with alpha7 cholinergic receptors expressed by macrophages and other cell types to inhibit TNF-alpha production. We here investigated the capacity of the selective alpha7 cholinergic receptor agonist 3-(2,4-dimethoxybenzylidene) anabaseine (GTS-21) to inhibit LPS-induced inflammatory responses in mice in vivo. To this end, mice received an intraperitoneal injection of LPS (from Escherichia coli, 200 microg) preceded by GTS-21 (4 mg/kg) or vehicle. GTS-21 strongly inhibited LPS-induced TNF-alpha release into the peritoneal cavity and the circulation. In addition, GTS-21 attenuated the influx of neutrophils into peritoneal fluid upon administration of LPS. This inhibitory effect on neutrophil recruitment by GTS-21 was independent of its effect on TNF-alpha release, considering that etanercept, a potent TNF-alpha-blocking protein containing the extracellular domain of the p75 TNF-alpha receptor, did not influence LPS-induced neutrophil influx either in the presence or in the absence of GTS-21 treatment. GTS-21 did not reduce the local secretion of macrophage inflammatory protein 2 and keratinocyte-derived cytokine, suggesting that altered concentrations of these neutrophil-attracting chemokines did not contribute to GTS-21-induced inhibition of neutrophil migration. These data identify a novel anti-inflammatory effect of chemical alpha7 cholinergic receptor stimulation that is independent from its capacity to inhibit TNF-alpha production.

• Authors: Ida A J Giebelen, David J van Westerloo, Gregory J LaRosa, Alex F de Vos, Tom van der Poll
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 27 Issue 4 Pg. 443-7 (Apr 2007) ISSN: 1073-2322 [Print] United States
• PMID: 17414429 (Publication Type: Journal Article)

Chemical References

• Benzylidene Compounds
• Chrna7 protein, mouse
• Cytokines
• Lipopolysaccharides
• Nicotinic Agonists
• Pyridines
• Receptors, Nicotinic
• Tumor Necrosis Factor-alpha
• alpha7 Nicotinic Acetylcholine Receptor
• 3-(2,4-dimethoxybenzylidene)anabaseine

Topics

• Animals
• Benzylidene Compounds (pharmacology)
• Cell Migration Inhibition
• Cytokines (metabolism)
• Female
• Lipopolysaccharides (antagonists & inhibitors, pharmacology)
• Mice
• Mice, Inbred C57BL
• Neutrophil Infiltration (immunology)
• Nicotinic Agonists (pharmacology)
• Pyridines (pharmacology)
• Receptors, Nicotinic (metabolism, physiology)
• Tumor Necrosis Factor-alpha (physiology)
• alpha7 Nicotinic Acetylcholine Receptor