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

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Sharkhuu, T.
Matthaei, K.
Forbes, E.
Mahalingam, S.
Hogan, S.
Hansbro, P.
Foster, P.
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2006
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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-4Ra-/-)- 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 naﶥ 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.

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Clinical and Experimental Allergy

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36

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12

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Immunology not elsewhere classified

Immunology

Nutrition and Dietetics

Public Health and Health Services

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