IL-23 and Th17 Cells Enhance Th2-Cell–mediated Eosinophilic Airway Inflammation in Mice

Abstract
Rationale: The IL-23–IL-17A–producing CD4+ T-cell (Th17 cell) axis plays an important role in the development of chronic inflammatory diseases, including autoimmune diseases. However, the role of the IL-23–Th17 cell axis in the regulation of allergic airway inflammation is still largely unknown. Objectives: To determine the role of IL-23 and Th17 cells in allergic airway inflammation. Methods: We examined the effect of anti–IL-23 antibody on antigen-induced airway inflammation. We also investigated the effect of enforced expression of IL-23 on allergic airway inflammation by generating lung-specific IL-23 transgenic mice. Moreover, we examined the effect of adoptive transfer of antigen-specific Th17 cells on allergic airway inflammation. Measurements and Main Results: IL-23 mRNA was expressed in the lung of sensitized mice upon antigen inhalation, and the neutralization of IL-23 decreased antigen-induced eosinophil recruitment and Th2 cytokine production in the airways. The enforced expression of IL-23 in the airways significantly enhanced antigen-induced eosinophil and neutrophil recruitment into the airways; Th2 cytokine, IL-17A, and tumor necrosis factor (TNF)-α production in the airways; goblet cell hyperplasia; and airway hyperresponsiveness. Moreover, IL-23–mediated enhancement of antigen-induced Th2 cytokine production and eosinophil recruitment in the airways was still observed in the mice lacking IL-17A. Furthermore, although adoptive transfer of antigen-specific Th17 cells alone induced neutrophil but not eosinophil recruitment into the airways upon antigen inhalation, cotransfer of Th17 cells with Th2 cells significantly enhanced antigen-induced Th2-cell–mediated eosinophil recruitment into the airways and airway hyperresponsiveness. Conclusions: IL-23 and Th17 cells not only induce Th17-cell–mediated neutrophilic airway inflammation but also up-regulate Th2-cell–mediated eosinophilic airway inflammation.

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