Mast cells play a major role in the initiation of inflammation and allergic reactions. As cell numbers are tightly controlled by the interplay of factors affecting cell proliferation, development, and death the regulation of mast cell number may be important. Melanocyte-stimulating hormone inhibits most forms of inflammation by an unknown mechanism. In the present study, we have found that the α-melanocyte-stimulating hormone (α-MSH) inhibited endotoxin-mediated nuclear transcription factor κB (NF-κB) activation in different cells correlated with the expression of α-MSH receptors. We have also found for the first time that it induces cell death alone or in endotoxin-stimulated mast cells. α-MSH-mediated apoptosis was not observed in NF-κB overexpressed cells. The inhibitory effect of α-MSH was mediated through generation of cAMP, as inhibitors of adenylate cyclase and of protein kinase A reversed its inhibitory effect. Overall, our results suggest that NF-κB is the key molecule involved in α-MSH-mediated cell death and this may help to regulate mast cell-mediated inflammation.
