NEUROPEPTIDE REGULATION OF PROINFLAMMATORY CYTOKINE RESPONSES

Severe traumatic injuries and infections are frequently accompanied by life-threatening,a shock and are associated with increases in the pro inflammatory cytokines, particularly tumor necrosis factor alpha (TNF- alpha). The body's first perception of injury is the nociceptive or pa ins response. This response is induced at the site of injury and if tr ansmitted systemically by sensory neuropeptides, the tachykinins, rele ased from sensory afferent c-fiber neurons. We studied the role of tac hykinins in regulating the production of proinflammatory cytokines ind uced by the administration of bacterial lipopolysaccharide. Destructio n of terminal sensory nerve endings before lipopolysaccharide administ ration abrogates tachykinin synthesis and down-regulates TNF-alpha tra nscription and secretion. In contrast, the responses of interleukins-1 and -6 are unaffected. Pretreating animals with an antagonist for the substance P-specific NK-1 receptor also down-regulated the TNF-alpha response, whereas blockade of the NK-2 receptor had no effect. These f indings indicate that substance P contributes to the induction of thos e cytokines that are involved in precipitating the shock response.