Granulocyte-mediated release of histamine from mast cells. Effect of myeloperoxidase and its inhibition by antiinflammatory sulfone compounds.

During phagocytosis, neutrophilic and eosinophilic granulocytes undergo metabolic activation and degranulation. This leads to accumulation of H2O2 and myeloperoxidase (MPO) or eosinophilic peroxidase (EPO) in the extracellular environment in inflammation. In the present investigation we show that the MPO-H2O2-halide system can degranulate isolated mast cells with release of histamine and 3H-serotonin. This is accomplished both in a system containing purified human MPO and in one containing phagocytosing neutrophils. When using purified MPO and a H2O2-generating system, the release was rapid, with 50% release after less than 20 min. The direct histamine release required less (0.65-2 micrograms/ml) MPO than did the release of 3H-serotonin (1-6 micrograms/ml). The release reaction was inhibited by azide, catalase but not superoxide dismutase. Studying the effect of the antiinflammatory sulfone compounds dapsone and sulfapyridine on the MPO-mediated histamine release, we show effective inhibition of the histamine release at concentrations of 0.025-0.2 mM of sulfone. 5-aminosalicylic acid exhibited some inhibition only in the cell-free system, whereas sulfasalazine was inactive. The antiinflammatory effect of dapsone in dermatitis herpetiformis and sulfasalazine in ulcerative colitis may in part be explained by their inhibitory effects on the granulocyte-mediated histamine release from mast cells in skin and mucosal tissue.