Two groups of mediators, the neuropeptides substance P and K and the monocyte-derived cytokines, interact in the neural regulation of immunological and inflammatory responses. Substance P, substance K, and the carboxyl-terminal peptide SP(4-11) induce the release of interleukin-1, tumor necrosis factor-α, and interleukin-6 from human blood monocytes. The neuropeptide effects occur at low doses, are specific as shown by inhibition studies with a substance P antagonist, and require de novo protein synthesis. Since monocyte-derived cytokines regulate multiple cellular functions in inflammation and immunity and since neuropeptides can be released from peripheral nerve endings into surrounding tissues, these findings identify a potent mechanism for nervous system regulation of host defense responses.