Naturally Occurring Imidazole Peptides, Carnosine and Anserine Inhibit the Degranulation of Mast Cells and Basophils by Modulating Intracellular Signaling

Abstract

Imidazole peptides possess multiple functions, including antioxidant effects, although their biological activities are largely unclear. Their production in humans and animals suggests their physiological roles and validates their safety for pharmaceutical or supplemental use. This study investigated the in vitro anti-anaphylactic potential of two histidine-containing dipeptides, carnosine and anserine in mast cells and basophils. Carnosine and anserine reduced mast cell degranulation elicited by anti-ovalbumin monoclonal IgE and ovalbumin or ionomycin in rat basophilic leukemia RBL2H3 cells without affecting cell viability. In contrast, interleukin-4 production following stimulation was enhanced in the presence of carnosine. Carnosine and anserine strongly inhibited Akt phosphorylation and moderately inhibited ERK phosphorylation. However, these peptides enhanced the increase in phosphorylated JNK levels upon IgE stimulation. The phosphorylation levels of p38 were not affected by carnosine or anserine. To determine the effect of carnosine on basophils, we established a method for detecting IgE-dependent activation in primary cultured mouse splenic basophils via CD63 expression for the first time. Carnosine treatment significantly reduced the increase in CD63 surface expression, a marker of degranulation, in mouse splenic basophils stimulated with anti-IgE. Flow cytometory analysis revealed that mean fluorescence intensities for non-stimulated, anti-IgE-stimulated, and carnosine-pre-treated/anti-IgE-stimulated basophils were 3853 ± 320, 5548 ± 282, and 3853 ± 203, respectively. The findings indicate carnosine and anserine suppress mast cell and basophil IgE-dependent degranulation. The proposed mechanism of the inhibitory effect is the suppression of the activation of phosphoinositide 3-kinase–Akt. Carnosine and anserine may exert anti-anaphylactic effects under physiological and pathological conditions and serve as safe potential drug candidates.