Adenylyl cyclase 6 mediates inhibition of TNF in the inflammatory reflex

Laura Tarnawski, Colin Reardon, April S. Caravaca, Mauricio Rosas-Ballina, Michael W. Tusche, Anna R. Drake, La Queta K. Hudson, William M. Hanes, Jian Hua Li, William R. Parrish, Kaie Ojamaa, Yousef Al-Abed, Michael Faltys, Valentin A. Pavlov, Ulf Andersson, Sangeeta S. Chavan, Yaakov A. Levine, Tak W. Mak, Kevin J. Tracey, Peder S. Olofsson

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase+ T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macrophages. Here, we observed that electrical vagus nerve stimulation with a duration of 0.1–60 s significantly reduced systemic TNF release in experimental endotoxemia. This suppression of TNF was sustained for more than 24 h, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for 1 h in vitro attenuated TNF production for up to 24 h in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger a change in macrophage behavior that requires AC and phosphorylation of the cAMP response element binding protein (CREB). These observations further our mechanistic understanding of neural regulation of inflammation and may have implications for development of bioelectronic medicine treatment of inflammatory diseases.

Original languageEnglish (US)
Article number2648
JournalFrontiers in Immunology
Issue numberNOV
StatePublished - Nov 27 2018


  • Acetylcholine
  • Adenylyl cyclase 6
  • Choline acetyltransferase
  • Inflammatory reflex
  • Sustained TNF inhibition
  • Vagus nerve stimulation/VNS
  • Α7nAChR

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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