Inhibition of basophil histamine release by methotrexate

Basophil leukocytes in whole blood from 4 healthy donors, 4 atopic patients, and 10 female patients operated for breast-cancer were preincubated from 1 to 20 hrs alone or in the presence of methotrexate (MTX) or MTX and folinic acid. After preincubation, the basophil leukocytes were challenged with anti-IgE, allergens or the calcium ionophore A23187 in the presence of 25 ng/ml TPA (12-o-tetradecanoyl-phorbol-13-acetate). A 9-hr preincubation with MTX produced significant inhibition of histamine release (greater than 20%) at 500-50 micrograms/ml. This effect increased up to 20 hrs of incubation, displaying maximal activity (100% inhibition) at 500 micrograms/ml, but even submicrogram concentrations (0.5 microgram/ml) produced significant inhibition. The addition of folinic acid did not alter the inhibition. It is concluded that MTX with or without the addition of folinic acid is a potent inhibitor of histamine release induced by anti-IgE, allergens, and A23187 combined with TPA. Like glucocorticoids the mechanism of action of MTX may be linked to arachidonate metabolism, but may interrupt earlier steps in prostaglandin synthesis.