A Gene-Dosage Effect for Interleukin-4 Receptor α-Chain Expression Has an Impact on Th2-Mediated Allergic Inflammation during Bronchopulmonary Mycosis

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Interleukin (IL)-4 and IL-13 are key factors in the pathogenesis of bronchopulmonary mycosis induced in mice by infection withCryptococcus neoformans. Both cytokines use the IL-4 receptor α-chain (IL-4Rα). In this study, we investigated the role played by IL-4Rα expression in susceptibility to pulmonaryC. neoformansinfection. IL-4Rα−/− mice were extremely resistant. To characterize the effect of IL-4Rα expression level on disease outcome, we generated IL-4Rα+/− first-generation (F1) mice. IL-4Rα+/− mice showed intermediate levels of IL-4Rα expression, in contrast to higher levels in wild-type mice and no expression in IL-4Rα−/− mice, indicating biallelic expression of the gene for IL-4Rα(Il4ra). Concomitant with intermediate IL-4Rα expression, F1 mice showed intermediate susceptibility associated with altered Th2/Th17 cytokine production, decreased immunoglobulin E levels, and reduced allergic inflammation. This indicates a gene-dosage effect of IL-4Rα expression on susceptibility to bronchopulmonary mycosis. These data provide the basis for novel therapies antagonizing IL-4Rα in Th2-related pulmonary infection and possibly also in asthma.

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