In the present study, we have investigated the proopiomelanocortin (POMC)-derived neuropeptide alpha -MSH for its ability to modulate activation of human mast cells. The in vitro ability of purified human skin mast cells to secrete various types of mast cell mediators was monitored in response to alpha -MSH at the mRNA and at the protein level. Picomolar concentrations of alpha -MSH induced a dose-dependent release of histamine from isolated human skin mast cells and from skin punch biopsies. However, no effect of alpha -MSH was seen regarding the expression of IL-1, IL-6, IL-8, TGF-beta, and TNF-alpha. Melanocortin receptor MC-1 was identified at the transcriptional level by RT-PCR analysis but not at the protein level, whereas, in leukemic human mast cells (HMC-1), the mRNAs and the proteins for the MC-1 and MC- receptor were identified. These results suggest that alpha -MSH may selectively induce acute inflammary effects via secretion of histamine.