Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:124

Article

He, Rui^1,2  Kim, Hye Young^1,2  Yoon, Juhan^1,2  Oyoshi, Michiko K.^1,2  MacGinnitie, Andrew^1,2  Goya, Sho³  Freyschmidt, Eva-Jasmin^1,2  Bryce, Paul^1,2  McKenzie, Andrew N. J.⁴  Umetsu, Dale T.^1,2  Oettgen, Hans C.^1,2  Geha, Raif S.^1,2 

[1] Harvard Univ, Childrens Hosp, Sch Med, Div Immunol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

[3] Osaka Univ, Grad Sch Med, Dept Resp Med Allergy & Rheumat Dis, Osaka, Japan

[4] MRC, Mol Biol Lab, Cambridge, MA USA

关键词: IL-17;    T(H)2 cytokines;    atopic dermatitis;    asthma;   

DOI  :  10.1016/j.jaci.2009.07.040

来源: Elsevier

【 摘 要 】

Background: Atopic dermatitis (AD) is characterized by local and systemic T(H)2 responses to cutaneously introduced allergens and is a risk factor for asthma. Blockade of T(H)2 cytokines has been suggested as therapy for AD. Objectives: We sought to examine the effect of the absence of IL-4 and IL-13 on the T(H)17 response to epicutaneous sensitization in a murine model of allergic skin inflammation with features of AD. Methods: Wild-type, IL4 knockout (KO), IL13 KO and IL4/13 double KO (DKO) mice were subjected to epicutaneous sensitization with ovalbumin (OVA) or saline and airway challenged with OVA. Systemic immune responses to OVA, skin and airway inflammation, and airway hyperresponsiveness were examined. Results: OVA-sensitized DKO mice exhibited impaired T(H)2-driven responses with undetectable OVA-specific IgE levels and severely diminished eosinophil infiltration at sensitized skin sites but intact dermal infiltration with CD4(+) cells. DKO mice mounted exaggerated IL-17A but normal IFN-gamma and IL-5 systemic responses. Airway challenge of these mice with OVA caused marked upregulation of IL-17 mRNA expression in the lungs, increased neutrophilia in bronchoalveolar lavage fluid, airway inflammation characterized by mononuclear cell infiltration with no detectable eosinophils, and bronchial hyperresponsiveness to methacholine that were reversed by IL-17 blockade. IL-4, but not IL-13, was identified as the major T(H)2 cytokine that downregulates the IL-17 response in epicutaneously sensitized mice. Conclusion: Epicutaneous sensitization in the absence of IL-4/IL-13 induces an exaggerated T(H)17 response systemically and in lungs after antigen challenge that results in airway inflammation and airway hyperresponsiveness. (J Allergy Clin Immunol 2009;124:761-70.)

【 授权许可】

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