IgE+, Kit-, I-A/I-E- myeloid cells are the initial source of IL-4 after antigen challenge in a mouse model of allergic pulmonary inflammation

Abstract

Background: IL-4 is generated within hours after antigen lung challenge and influences events that take place early in the induction of pulmonary inflammation. However, the cells responsible for this early IL-4 production in the lung are unknown. Objectives: We sought to characterize the initial inflammatory events in the lung after antigen challenge and to identify cells responsible for producing IL-4 at early time points. Methods: Mice were sensitized with ovalbumin or passive IgE and challenged intranasally. Histologic measures of inflammation were used, and lung tissue cytokine production was analyzed by means of RT-PCR. Cells producing IL-4 were characterized by means of in situ hybridization and flow cytometry. Results: IL-4 mRNA was detectable 100 minutes after challenge in sensitized animals. Blockade of this early IL-4 downregulated vascular cell adhesion molecule 1 mRNA expression and attenuated the early recruitment of eosinophils to the lung. CD4-depleted and mast cell-deficient mice both expressed early IL-4. Cellular analysis revealed the presence of IL-4 protein at 100 minutes exclusively in IgE+ myeloid cells that did not express CD3, Kit, or I-A/I-E. Moreover, IL-4 production induced by means of passive IgE sensitization and abrogated in FcR γ-chain-deficient mice supports the conclusion that this IL-4 production is dependent on IgE/γ-chain interaction. Conclusion: IL-4 production by an IgE/γchain-dependent mechanism occurs rapidly after allergen challenge. At these early time points, IL-4 is produced by a myeloid cell with the characteristics of a mouse basophil (IgE+, Kit-, I-A/I-E-). These data thus suggest that strategies targeting basophils should be considered in the treatment of early lung inflammation.