Although the α7 nAChR was expressed in human mast cells, this receptor is not likely to be functional in catestatin-induced mast cell activation. Although catestatin has been shown to stimulate rat mast cell release of histamine,23 to our knowledge, this is the first study demonstrating multiple functions of wild-type catestatin and its variants in human mast cells. Our findings suggest a new role for catestatin peptides in immunoregulation of the cutaneous immune system via mast cell activation. Eicosanoids and histamine are mainly secreted by activated mast cells, and are mediators of inflammatory

reactions.21 Both LTs and PGs are critically involved in inflammatory and allergic conditions, and PGD2 and PGE2 are abundant in allergic skin inflammation selleck compound such as contact hypersensitivity.24–26

Furthermore, intracellular Ca2+ is thought to play a key role in mast cell activation, including chemotaxis and release of histamine and eicosanoids.27,28 In this report, wild-type catestatin and its variants increased intracellular Ca2+ mobilization in mast cells and caused them to migrate, degranulate, and release inflammatory mediators. These observations suggest that catestatin peptides might participate in inflammatory reactions via mast cell activation. Overall, wild-type catestatin and its variants had almost equal potencies in activating human mast cells, except for the strongest PD-0332991 supplier activity of Pro370Leu in inducing LTC4 release, and the least stimulatory capacity of Arg374Gln in degranulating mast cells. This observation partially contradicts the literature relating to catestatin peptides, where wild-type catestatin and its variants display differential potencies Mirabegron in inhibiting catecholamine release and in inducing monocyte migration.9,11 This was not the result of artificial effects of catestatin peptides, because a control peptide had no effect on mast activation. Hence, the potencies of wild-type catestatin and its variants might vary following their specific activities,

and between cell types. Mast cells accumulate and become activated at sites of inflammation, and their numbers significantly increase during wounding,29 where the levels of catestatin have been found to be enhanced.4 Although the amount of catestatin has been estimated to 20 μm in normal murine skin,4 the precise concentration of an active catestatin in human skin is not yet known. However, because the levels of catestatin increase during skin injury or inflammatory conditions,4 one could expect that catestatin might reach its optimal levels at inflammatory sites or wound sites. In this study, the concentrations used for catestatin peptides ranged from 0·02 to 10 μm, doses that have been reported to display antimicrobial activities against skin pathogens4 and Plasmodium falciparum.