Acetylcholine as Cytokine

Science's STKE  02 Aug 2005:
Vol. 2005, Issue 295, pp. tw280
DOI: 10.1126/stke.2952005tw280

Inflammatory responses in the gut are a major concern for abdominal surgery patients, because enteric inflammation can lead to postoperative ileus, or paralysis of the bowel (see Metz and Tracey). de Jonge et al. provide mechanistic insight into how the vagus nerve suppresses enteric inflammation by activating nicotinic acetylcholine receptors (the α7 homopentameric form; α7 nAChRs) on peritoneal macrophages. Initial studies with isolated peritoneal mouse macrophages showed that nicotine suppressed release of inflammatory cytokines (TNF, MIP-2, and IL-6), stimulated phosphorylation of signal transducer and activator of transcription 3 (STAT3), and increased the abundance (through stimulation of gene expression) of suppressor of cytokine signaling 3 (SOCS3). Using dominant-negative STAT3, de Jonge et al. showed that STAT3 was essential for the decrease in TNF production, and using short-interfering RNA (siRNA), they showed that SOCS3 was involved, but not absolutely required, for the decreased TNF production. Pharmacological analysis identified the receptor as α7, and nicotine stimulated the interaction between the α7 nAChR and Jak2, a kinase that phosphorylates STAT3. Vagal stimulation in a mouse model of postoperative ileus improved gastric motility after intestinal manipulation and decreased granulocyte infiltration. Vagal stimulation did not suppress inflammation if the intestinal segments were exposed to the nAChR antagonist hexamethonium. Inflammatory cytokines were reduced in the peritoneal cavity after vagal stimulation, and expression of Socs3 was increased in the muscularis (smooth muscle) tissue. Furthermore, in mice that received vagal stimulation, phosphorylated STAT3-positive macrophages were present in the intestinal tissue. Stat3–/– mice were defective in vagal suppression of inflammatory infiltrates in manipulated intestinal tissue, supporting the critical role of STAT3 in this cholinergic response. Thus, cholinergic input to the gastrointestinal tissue mediates an antiinflammatory response through activation of Jak-STAT signaling by α7 nAChR.

C. N. Metz, K. J. Tracey, It takes nerve to dampen inflammation. Nat. Immunol. 6, 756-757 (2005). [PubMed]

W. J. de Jonge, E. P. van der Zanden, F. O. The, M. F. Bijlsma, D. J. van Westerloo, R. J. Bennink, H.-R. Berthoud, S. Uematsu, S. Akira, R. M. van den Wijngaard, G. E. Boechzstaens, Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat. Immunol. 6, 844-851 (2005). [PubMed]