Mechanism of interleukin-25 (IL-17E)- induced pulmonary inflammation and airways hyper-reactivity

Suresh Mahalingam, T Sharkhuu, Klaus Matthaei, E Forbes, S Hogan, P Hansbro, Paul Foster

    Research output: Contribution to journalArticle

    87 Citations (Scopus)

    Abstract

    Background - IL‐25, a novel member of the IL‐17 cytokine family, promotes CD4+ T‐helper 2 lymphocyte‐like (Th type‐2) inflammatory responses in the lung. Although IL‐25 up‐regulates IL‐13 in the lung, the contribution of this and other type 2 cytokine signalling pathways to the induction and persistence of airways hyper‐reactivity (AHR) and allergic inflammation are unclear.
    Objective - To determine the downstream factors employed by IL‐25 to induce Th type‐2 pulmonary inflammation and AHR.
    Methods - IL‐25 was delivered to the airways of BALB/c mice by intra‐tracheal (i.t.) instillation and AHR and Th type‐2 inflammatory responses were characterized in wild type (WT) and Th type‐2‐cytokine and ‐signalling pathway‐deficient (−/−) mice.
    Results IL‐25 treatment resulted in AHR, eosinophilic inflammation, mucus hypersecretion and a progressive increase in the production of Th type‐2 cytokines in the lungs. Levels of arginase‐I (arg‐I) and eotaxin were also elevated by IL‐25 treatment. A significant reduction in AHR, and attenuation of mucus production was observed in IL‐25‐treated IL‐13−/−, IL‐4 receptor alpha (IL‐4Rα−/−)‐ and signal‐transducer‐and‐activator‐of‐transcription‐factor‐6 (STAT6−/−)‐deficient mice. AHR was also inhibited in IL‐4−/−‐ and IL‐5/eotaxin(1)−/−‐ deficient mice treated with IL‐25, however, mucus hypersecretion was not completely ablated. IL‐25 promoted Th type‐2 responses by directly acting on naïve T cells.
    Conclusion - IL‐25 potently (single dose) induces sustained AHR and acute pulmonary inflammation with eosinophilia. IL‐25‐induced AHR is dependent on the production of Th type‐2 cytokines, and removal of IL‐13 and its signal transduction pathway prevents IL‐25‐induced airways inflammation and AHR. IL‐25 potently induces inflammatory cascades that may exacerbate allergic airways inflammation by promoting Th type‐2 cytokine responses in conjunction with the up‐regulation of factors (eotaxin and arg‐I) that can amplify inflammation associated with allergic disorders. Dysregulation in IL‐25 production may predispose to features of allergic airways disease.
    Original languageEnglish
    Pages (from-to)1575-1583
    Number of pages9
    JournalClinical and Experimental Allergy
    Volume36
    Issue number1
    DOIs
    Publication statusPublished - 2006

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