Antigen-specific production of interleukin (IL)-13 and IL-5 cooperate to mediate IL-4Rα-independent airway hyperreactivity

Abstract

The pathogenesis of human asthma and the development of key features of pulmonary allergy in mouse models has been critically linked to IL-13. Analyses of the receptor components employed by IL-13 have shown that delivery of this cytokine to the airways of naive IL-4Rα gene targeted (IL-4Rα-/-) mice fails to induce disease, suggesting that this membrane protein is critical for transducing IL-13-mediated responses. The current study demonstrates that, in contrast to naive mice, T helper 2 bias, airways hyperreactivity (AHR) and tissue eosinophilia develop in Ovalbumin-sensitized IL-4Rα-/- mice and that these responses can be inhibited by the IL-13 antagonist sIL-13Rα2Fc. Therefore, antigen stimulation induces an IL-13-regulated response that is independent of IL-4Rα. To determine the role of IL-5 and eosinophils in the development of disease in antigen-exposed IL-4Rα-/- mice, pulmonary allergy was examined in mice deficient in both factors. IL-4Rα/IL-5-/- mice were significantly defective in their ability to produce IL-13 and failed to develop AHR, suggesting that IL-5 indirectly regulates AHR in allergic IL-4Rα-/- mice by an IL-13-dependent mechanism. Collectively, these results demonstrate that IL-13-dependent processes regulating the development of AHR and T helper bias persist in the in the lungs of allergic IL-4Rα-/- mice.