Neuropeptide regulation of proinflammatory cytokine responses

Severe traumatic injuries and infections are frequently accompanied by life-threatening shock and are associated with increases in the proinflammatory cytokines, particularly tumor ne- crosis factor a (TNF-a). The body's first percep- tion of injury is the nociceptive or pain response. This response is induced at the site of injury and is transmitted systemically by sensory neuropeptides, the tachykinins, released from sensory afferent c-fiber neurons. We studied the role of tachykinins in regulating the production of proinflammatory cytokines induced by the administration of bacte- rial lipopolysaccharide. Destruction of terminal sensory nerve endings before lipopolysaccharide administration abrogates tachykinin synthesis and down-regulates TNF-a transcription and secretion. In contrast, the responses of interleukins-1 and -6 are unaffected. Pretreating animals with an antago- nist for the substance P-specific NK-1 receptor also down-regulated the TNF-a response, whereas block- ade of the NK-2 receptor had no effect. These findings indicate that substance P contributes to the induction of those cytokines that are involved in precipitating the shock response. J. Leukoc. Biol. 63: 602-605; 1998.