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Neutrophil Defensins Induce Histamine Secretion from Mast Cells: Mechanisms of Action¹

A. Dean Befus^2,*, Connie Mowat, Mark Gilchrist^*, Jing Hu, Samuel Solomon and Andrew Bateman

^* Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Immunology Research Group, University of Calgary, Calgary, Alberta, Canada; and Department of Medicine, Obstetrics and Gynecology, Endocrine Laboratory, Royal Victoria Hospital/McGill University, Montreal, Quebec, Canada

Defensins are endogenous antimicrobial peptides stored in neutrophil granules. Here we report that a panel of defensins from human, rat, guinea pig, and rabbit neutrophils all have histamine-releasing activity, degranulating rat peritoneal mast cells with EC₅₀ ranging from 70 to 2500 nM, and between 45 and 60% of the total histamine released. The EC₅₀ for defensin-induced histamine secretion correlates with their net basic charge at neutral pH. There is no correlation between histamine release and antimicrobial potency. Degranulation induced by defensins has characteristics similar to those of activation by substance P. The maximum percent histamine release is achieved in <10 s, and it can be markedly inhibited by pertussis toxin (100 ng/ml) and by pretreatment of mast cells with neuraminidase. These properties differ from those for degranulation induced by IgE-dependent Ag stimulation and by the calcium ionophore A23187. GTPase activity, a measure of G protein activation, was induced in a membrane fraction from mast cells following treatment with defensin. Thus, neutrophil defensins are potent mast cell secretagogues that act in a manner similar to substance P and 48/80, through a rapid G protein-dependent response that is mechanistically distinct from Ag/IgE-dependent mast cell activation. Defensins may provide important pathways for communication between neutrophils and mast cells in defenses against microbial agents and in acute inflammatory responses.