Interleukin-33 amplifies IgE synthesis and triggers mast cell degranulation via interleukin-4 in naive mice

Background The regulation and function of IgE in healthy individuals and in antigen-naive 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 naive wild-type (WT), nude and ST2-/-, IL-4-/-, IL4Ra-/- and T-or B-cell-specific IL-4Ra-/- 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 naive WT, T-IL-4Ra-/- but not in ST2-/-, IL-4-/-, IL-4Ra-/- or B-cell-specific IL-4Ra-/- 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-naive WT but not in IL-4Ra-/- mice. Conclusion IL-33 amplifies IgE synthesis and triggers anaphylaxis in naive mice via IL-4, independent of allergen. IL-33 may play an important role in nonatopic allergy and idiopathic anaphylaxis.