The role of IL -25 in allergic lung disease

Pornpimon Angkasekwinai, The University of Texas Graduate School of Biomedical Sciences at Houston


Allergic asthma is a chronic inflammatory disease of the airways caused by dysregulated immune responses to allergens. Despite compelling evidence that Th2-mediated immune responses orchestrate the pathogenesis of asthma diseases, the mechanisms underlying their initiation remain elusive. IL-25 (IL-17E), a novel cytokine in the IL-17 family plays a unique role in regulating type-2 immune responses. However, its biological function in allergic asthma has not been elucidated. Here, we demonstrated that IL-25 initiates allergic reactions by bridging the innate and adaptive immune responses of allergic asthma. IL-25 mRNA expression was up-regulated in lung epithelial cells upon exposure to common allergens, and mice overexpressing IL-25 in lung epithelium displayed features of allergic asthma, including eosinophilia, and epithelial and goblet cell hyperplasia. Moreover, administration of an antagonistic antibody against IL-25 in a mouse model of allergic asthma attenuated airway inflammation and antigen-specific Th2 responses induced by endogenous IL-25. In searching for IL-25-responding cells, Th2 cells that expressed the highest levels of IL-17RB, the cognate receptor for IL-25, were found to be the potential target of IL-25. Indeed, we showed that IL-25 promoted the differentiation and effector functions of Th2 cells by inducing early IL-4 production through the activation of the transcription factors JUNB and NFATc1. Interestingly, we found that the enhanced Th2 differentiation mediated by IL-25 required signals induced by a heterodimeric receptor complex composed of both IL-17RB and IL-17RA. To further elucidate the cellular mechanisms by which IL-25 amplifies type-2 immune responses, mice overexpressing IL-17RB driven by the CD4 promoter were generated. T cells isolated from IL-17RB transgenic mice and cultured with IL-25 were prone to produce prodigious amounts of Th2 cytokines. In an experimental asthma model, CD4-IL-17RB transgenic mice exhibited allergic airway inflammation, demonstrating that IL-25 enhances Th2 polarization and effector functions, thereby leading to the exacerbation of allergic asthma. We also uncovered an additional function of IL-25 to induce the up-regulation of IL-9 in IL-17RB transgenic T cells independent of IL-4. Our findings provide a novel mechanism that initiates allergic asthma and may facilitate the development of therapeutic approaches for future immune-based therapies for allergic asthma.

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Recommended Citation

Angkasekwinai, Pornpimon, "The role of IL -25 in allergic lung disease" (2009). Texas Medical Center Dissertations (via ProQuest). AAI3353987.