Estradiol activates mast cells via a non-genomic estrogen receptor-α and calcium influx

Background: Allergic airway diseases are more common in females than in males during early adulthood. A relationship between female hormones and asthma prevalence and severity has been suggested, but the cellular and molecular mechanisms are not understood. Objective: To elucidate the mechanism(s) by which estrogens enhance the synthesis and release of mediators of acute hypersensitivity. Methods: Two mast cell/basophil cell lines (RBL-2H3 and HMC-1) and primary cultures of bone marrow derived mast cells, all of which naturally express estrogen receptor-α, were examined. Cells were incubated with physiological concentrations of 17-β-estradiol with and without IgE and allergens. Intracellular Ca²⁺ concentrations and the release of β-hexosaminidase and leukotriene C₄ were quantified. Results: Estradiol alone induced partial release of the preformed, granular protein β-hexosaminidase from RBL-2H3, BMMC and HMC-1, but not from BMMC derived from estrogen receptor-α knock-out mice. The newly synthesized LTC₄ was also released from RBL-2H3. Estradiol also enhanced IgE-induced degranulation and potentiated LTC₄ production. Intracellular Ca²⁺ concentration increased prior to and in parallel with mediator release. Estrogen receptor antagonists or Ca²⁺ chelation inhibited these estrogenic effects. Conclusion: Binding of physiological concentrations of estradiol to a membrane estrogen receptor-α initiates a rapid onset and progressive influx of extracellular Ca²⁺, which supports the synthesis and release of allergic mediators. Estradiol also enhances IgE-dependent mast cell activation, resulting in a shift of the allergen dose response.