Nature 405, 458-462 (25 May 2000) | doi:10.1038/35013070


Vagus nerve stimulation attenuates the systemic inflammatory response
to endotoxin


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 lethal1, 2, 3, 4. The central nervous system regulates
systemic inflammatory responses to endotoxin through humoral
mechanisms5, 6, 7, 8. Activation of afferent vagus nerve fibres by
endotoxin or cytokines stimulates hypothalamic–pituitary–adrenal anti-
inflammatory responses9, 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.


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