Interleukin‐33 amplifies IgE synthesis and triggers mast cell degranulation via interleukin‐4 in naïve mice

Abstract

Background The regulation and function of IgE in healthy individuals and in antigen‐naïve animals is not well understood. IL‐33 administration increases serum IgE in mice with unknown mechanism. We tested the hypothesis that IL‐33 provides an antigen‐independent stimulus for IgE production and mast cell degranulation. Methods IL‐33 was administered to naïve wild‐type (WT), nude and ST2^−/−, IL‐4^−/−, IL4Rα^−/− and T‐or B‐cell‐specific IL‐4Rα^−/− mice. IgEand cytokines were quantified by ELISA. T‐ and B‐lymphocyte numbers and CD40L expression were determined by flow cytometry. Anaphylaxis was measured by temperature, mast cell degranulation and histamine release. Results IL‐33 enhanced IgE production in naïve WT, T‐IL‐4Rα^−/− but not in ST2^−/−, IL‐4^−/−, IL‐4Rα^−/− or B‐cell‐specific IL‐4Rα^−/− mice, demonstrating IL‐33 specificity and IL‐4 dependency. Moreover, IL‐4 was required for IL‐33‐induced B‐cell proliferation and T‐cell CD40L expression, which promotes IgE production. IL‐33‐induced IL‐4 production was mainly from innate cells including mast cells and eosinophils. IL‐33 increased mast cell surface IgE and triggered degranulation and systemic anaphylaxis in allergen‐naïve WT but not in IL‐4Rα^−/− mice. Conclusion IL‐33 amplifies IgE synthesis and triggers anaphylaxis in naïve mice via IL‐4, independent of allergen. IL‐33 may play an important role in nonatopic allergy and idiopathic anaphylaxis.