1. The Picower Institute for Medical Research, Manhasset, New York 11030, USA
2. Department of Psychology, University of Colorado, Boulder, Colorado 80309, USA
3. Department of Emergency Medicine and Department of Surgery, North Shore University Hospital, Manhasset, New York 11030, USA
4. Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA

Correspondence to: Kevin J. Tracey⁴ Correspondence and requests for materials should be addressed to L.V.B. (e-mail: Email: lborovikova@mindspring.com) or K.J.T. (e-mail: Email:  kjtracey@sprynet.com).

Abstract

Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal^{1, 2, 3, 4}. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms^{5, 6, 7, 8}. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic–pituitary–adrenal anti-inflammatory responses^{9, 10, 11}. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.