Melanocortins (MCs; e.g. ACTH and α-MSH) are peptides with known anti-inflammatory properties in different tissues and systems. Our group has focused one of its interest on cellular and molecular anti-inflammatory properties of MCs in acute and chronic inflammation. We proposed a major role for MC3 receptor, in the regulation of endogenous anti-inflammation, thereby modulating macrophage activation and cytokine production. However, the possible source of MCs at the site of inflammation remains to be elucidated. Mast cells are leukocytes resident in different tissues and play an important role in triggering and development of inflammation. The aim of this study was to determine if elements of the MC system were present in murine mast cells. Bone marrow-derived mast cells (BMMC) were generated by culture of bone marrow cells for 4-6 weeks in 30% WEHI conditioned medium. Purity of the cultures was assessed by the expression of IgE receptor and CD117 and toluidine blue staining, measuring always purity ≥95%. Expression of MC receptors as well as of the pro-opiomelanocortin gene (POMC) was monitored by RT-PCR and western blotting. In some cases, cells were stimulated with LPS (1-100 ng/ml). In addition, naïve peritoneal mast cells were also used following positive isolation by magnetic selection. Expression data revealed POMC gene expression in resting BMMC and peritoneal mast cells. To highlight potential modulatory pathways, BMMC were stimulated with 100 ng/ml LPS, selected because it produced maximal TNF production: POMC gene was already up-regulated within 1-h of LPS stimulation, and mRNA content remained up to 24h. Interestingly, stressing BMMC by deprivation of WEHI conditioned medium, triggered a delayed up regulation the POMC gene, maximum at 24h. With respect to MC receptors, BMMC and peritoneal mast cells expressed detectable mRNA level for the MC1, MC3 and MC5 receptors. However, western blotting analysis allowed detection only of MC1 protein, at least in resting BMMC. In conclusion, this investigation proposes the existence of an endogenous anti-inflammatory loop operative in the periphery, possibly in conditions of tissue injury and inflammatory resolution, whereby murine mast cells could act in concert or in parallel with the macrophage to promote regain of homeostasis. Parallel studies in mice nullified for elements of this anti-inflammatory break signal confirm the pivotal role played by this system in acute and chronic inflammation. The role that MC production by the mast cells might have in these conditions remains to be determined.