Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

Vertebrates achieve internal homeostasis during infection or injury by bala ncing the activities of proinflammatory and anti-inflammatory pathways. End otoxin (lipopolysaccharide), produced by all gram-negative bacteria, activa tes macrophages to release cytokines that are potentially lethal(1-4). The central nervous system regulates systemic inflammatory responses to endotox in through humoral mechanisms(5-8). Activation of afferent vagus nerve fibr es by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti -inflammatory responses(9-11). However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. He re, we describe a previously unrecognized, parasympathetic anti-inflammator y pathway by which the brain modulates systemic inflammatory responses to e ndotoxin. Acetylcholine, the principle vagal neurotransmitter, significantl y attenuated the release of cytokines (tumour necrosis factor (TNF), interl eukin (IL)-1 beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct e lectrical stimulation of the peripheral vagus nerve in vivo during lethal e ndotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.