Long lasting macrophage cytokine suppression by alpha 7 nAChR requires JAK/STAT (138.23)

Abstract The central nervous system regulates innate immunity reflexively, as action potentials transmitted in the vagus nerve suppress cytokine release during endotoxemia. The mechanism of cytokine release by this neural circuit requires signaling through the alpha 7 nicotinic acetylcholine receptor (a7 nAChR), but the duration of this protection is incompletely understood. Electrical vagus nerve stimulation (VNS) in mice significantly inhibited serum TNF levels during endotoxemia, even when endotoxin was given 2, 24 or 48 h after VNS. This inhibition of TNF was abolished in a7 nAChR deficient mice, confirming the mechanism that requires this receptor. One-hour exposure of human macrophages to acetylcholine in vitro reduced endotoxin-induced increases in IKKbeta, IkappaBalpha activity and TNF release for up to 24 h after removal of acetylcholine. Levels of Supressor of Cytokine Signaling 1-3, A20, BCL3, IkappaBNS and IkappaBzeta were not altered in human macrophages 15 min to 8 h after exposure to acetylcholine, but exposure of macrophages to the selective JAK/STAT inhibitor AG490 abolished the cytokine suppressing effect of acetylcholine. Together with previous work indicating that JAK/STAT forms a signaling complex with a7 nAChR, these results suggest that JAK/STAT activation is required for long lasting suppression of macrophage cytokine release after transient exposure to acetylcholine.