A gene-dosage effect for interleukin-4 receptor α-chain expression has an impact on Th2-mediated allergic inflammation during bronchopulmonary mycosis

Abstract

Interleukin (IL)-4 and IL-13 are key factors in the pathogenesis of bronchopulmonary mycosis induced in mice by infection with Cryptococcus 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 pulmonary C. neoformans infection. 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. © 2008 by the Infectious Diseases Society of America. All rights reserved.