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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 42-50, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.4832

Interleukin-17 Orchestrates the Granulocyte Influx into Airways after Allergen Inhalation in a Mouse Model of Allergic Asthma

Peter W. Hellings, Ahmad Kasran, Zhanju Liu, Philippe Vandekerckhove, Anja Wuyts, Lutgart Overbergh, Chantal Mathieu and Jan L. Ceuppens

Laboratory of Experimental Immunology, Department of Otorhinolaryngology-Head and Neck Surgery, Laboratory of Hematology, and Laboratory of Molecular Immunology, Rega Institute, Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Department of Internal Medicine, University Hospitals, Faculty of Medicine, University of Leuven, Leuven, Belgium

Address correspondence to: Jan Ceuppens, Laboratory of Experimental Immunology, Onderwijs en Navorsing, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: Jan.Ceuppens{at}med.kuleuven.ac.be

Interleukin (IL)-17 is produced by activated memory CD4+ cells and induces cytokines and chemokines that stimulate neutrophil generation and recruitment. Here, we investigated the involvement of IL-17 in the bronchial influx of neutrophils in experimental allergic asthma. Inhalation of nebulized ovalbumin (OVA) by sensitized mice with bronchial eosinophilic inflammation resulting from chronic OVA exposure induced early IL-17 mRNA expression in inflamed lung tissue, concomitant with a prominent bronchial neutrophilic influx. Anti–IL-17 monoclonal antibodies (mAb) injected before allergen inhalation strongly reduced bronchial neutrophilic influx, in a manner equally as potent as the anti-inflammatory dexamethasone. Remarkably, anti–IL-17 mAb significantly enhanced IL-5 levels in both BAL fluid and serum, and aggravated allergen-induced bronchial eosinophilia. In another series of experiments, anti–IL-17 mAb were given repeatedly during the inhalatory challenge phase with OVA of sensitized mice. This treatment regimen abated bronchial neutrophilia in parallel with reduction of bone marrow and blood neutrophilia. In addition, anti–IL-17 mAb treatment elevated eosinophil counts in the bone marrow and bronchial IL-5 production, without alteration of allergen-induced bronchial hyperresponsiveness. In summary, our results demonstrate that IL-17 expression in airways is upregulated upon allergen inhalation, and constitutes the link between allergen-induced T cell activation and neutrophilic influx. Because neutrophils may be important in airway remodeling in chronic severe asthma, targeting IL-17 may hold therapeutic potential in human asthma.

Abbreviations: bronchoalveolar lavage, BAL • bronchial hyperresponsiveness, BHR • bone marrow, BM • enzyme-linked immunosorbent assay, ELISA • eosinophil peroxidase, EPO • experimental units, EU • granulocyte macrophage colony-stimulating factor, G-CSF • hematoxylin and eosin, H&E • interferon-{gamma}, IFN-{gamma} • interleukin, IL • monoclonal antibodies, mAb • methacholine, MCh • May-Grünwald-Giemsa, MGG • myeloperoxidase, MPO • ovalbumin, OVA • enhanced pause, Penh • T helper 2, Th2 • tumor necrosis factor, TNF




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