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Published online 13 November 2006 doi:10.1084/jem.20061401
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 12, 2715-2725
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ARTICLE

 Interleukin-17 is a negative regulator of established allergic asthma

Silvia Schnyder-Candrian1,2, Dieudonnée Togbe1, Isabelle Couillin1, Isabelle Mercier1, Frank Brombacher4, Valérie Quesniaux1, Francois Fossiez3, Bernhard Ryffel1, and Bruno Schnyder1,2

1 Université d' Orléans, Centre national de la Recherche Scientifique (CNRS), Molecular Immunology and Embryology, 45071 Orléans, France
2 Biomedical Research Foundation, SBF, 9548 Matzingen, Switzerland
3 Schering Plough Inc., 69571 Dardilly, France
4 Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 7925 Cape Town, South Africa

CORRESPONDENCE Bruno Schnyder: schnyder{at}cnrs-orleans.fr

T helper (Th)17 cells producing interleukin (IL)-17 play a role in autoimmune and allergic inflammation. Here, we show that IL-23 induces IL-17 in the lung and IL-17 is required during antigen sensitization to develop allergic asthma, as shown in IL-17R–deficient mice. Since IL-17 expression increased further upon antigen challenge, we addressed its function in the effector phase. Most strikingly, neutralization of IL-17 augmented the allergic response in sensitized mice. Conversely, exogenous IL-17 reduced pulmonary eosinophil recruitment and bronchial hyperreactivity, demonstrating a novel regulatory role of IL-17. Mechanistically, IL-17 down modulated eosinophil-chemokine eotaxin (CCL11) and thymus- and activation-regulated chemokine/CCL17 (TARC) in lungs in vivo and ex vivo upon antigen restimulation. In vitro, IL-17 reduced TARC production in dendritic cells (DCs)—the major source of TARC—and antigen uptake by DCs and IL-5 and IL-13 production in regional lymph nodes. Furthermore, IL-17 is regulated in an IL-4–dependent manner since mice deficient for IL-4R{alpha} signaling showed a marked increase in IL-17 concentration with inhibited eosinophil recruitment. Therefore, endogenous IL-17 is controlled by IL-4 and has a dual role. Although it is essential during antigen sensitization to establish allergic asthma, in sensitized mice IL-17 attenuates the allergic response by inhibiting DCs and chemokine synthesis.

Abbreviations used: BAL, bronchoalveolar lavage; EPO, eosinophil peroxidase; Penh, enhanced respiratory pause; TARC, thymus- and activation-regulated chemokine/CCL17; Th cell, T helper cell; T reg cell, T regulatory.


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