There is strong evidence for the existence of a neuroimmune axis which is regulated by a network of interacting cytokines and neuropeptides. Accordingly, pro-opiomelanocortin-derived peptide hormones such as melanocyte-stimulating hormones (MSH), adrenocorticotropin, and beta-endorphin not only could be detected in many immunocompetent cells but also turned out to be potent immunomodulating and anti-inflammatory mediators, mainly through regulating cytokine production. Thus, it was investigated whether alpha-MSH, which is known to inhibit immune and inflammatory responses, would influence the production of the cytokine synthesis inhibitor IL-10 by human PBMC. Stimulation of PBMC with alpha-MSH resulted in a significantly enhanced release of, IL-10 protein. These data were confirmed by Northern blot analysis, which demonstrated increased IL-10 mRNA expression induced by alpha-MSH. This effect of alpha-MSH was dose-dependent; maximum IL-10 release and mRNA expression were obtained at a concentration of 10(-13) M. There is also clear evidence that only the C-terminal tripeptide of alpha-MSH was required to enhance IL-10 production. In addition, alpha-MSH and its tripeptide strongly induced IL-10 in purified monocytes. In contrast, neither unstimulated nor activated T lymphocytes produced increased amounts of IL-10 in response to alpha-MSH. These findings indicate that pro-opiomelanocortin peptides such as alpha-MSH are able to up-regulate the production of suppressor factors such as IL-10 in monocytes and thereby may contribute to immunosuppression.