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The Journal of Immunology, 2007, 178, 7805 -7813
Copyright © 2007 by The American Association of Immunologists, Inc.

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Immunomodulatory Effects of Viral TLR Ligands on Experimental Asthma Depend on the Additive Effects of IL-12 and IL-101

Serdar Sel2,*, Michael Wegmann2,3,*, Sarper Sel*, Stefan Bauer{dagger}, Holger Garn*, Gottfried Alber{ddagger} and Harald Renz*

* Department of Clinical Chemistry and Molecular Diagnostics, Germany; {dagger} Institute of Immunology, Hospital of the Philipps-University, Marburg, Germany; and {ddagger} Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany

Based on epidemiological data, the hygiene hypothesis associates poor hygienic living conditions during childhood with a lower risk for the development of allergic diseases such as bronchial asthma. The role of viral infections, and especially of viral TLR ligands, within this context remains to be clarified. Viral TLR ligands involve dsRNA and ssRNA which are recognized by TLR-3 or TLR-7, respectively. In this study, we evaluated the impact of TLR-3 or TLR-7 activation on experimental asthma in mice. Systemic application of the synthetic TLR-3 or TLR-7 ligands polycytidylic-polyinosinic acid (p(I:C)) or R-848, respectively, during the sensitization phase prevented the production of OVA-specific IgE and IgG1 Abs and subsequently abolished all features of experimental asthma including airway hyperresponsiveness and allergic airway inflammation. Furthermore, administration of p(I:C) or R-848 to animals with already established primary allergic responses revealed a markedly reduced secondary response following allergen aerosol rechallenges. In contrast to wild-type animals, application of p(I:C) or R-848 to IL-12p35–/– mice had no effect on airway inflammation, goblet cell hyperplasia, and airway hyperresponsiveness. However, in the absence of IL-12, the numbers of eosinophils and lymphocytes in bronchoalveolar lavage fluids were still significantly reduced. These partial effects could also be abolished by neutralizing anti-IL-10 Abs in IL-12p35–/– mice. These data indicate that TLR-3 or TLR-7 activation by viral TLR ligands has both preventive as well as suppressive effects on experimental asthma which is mediated by the additive effects of IL-12 and IL-10.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by the Deutsche Forschungsgemeinschaft (Transregio 22) and the P.E. Kemkes Foundation (16/04).

2 S.S. and M.W. contributed equally to this work and appear in alphabetical order.

3 Address correspondence and reprint requests to Dr. Michael Wegmann, Biomedizinisches Forschungszentrum, Abteilung für Klinische Chemie und Molekulare Diagnostik, Hans-Meerwein-Strasse, 35033 Marburg, Germany. E-mail address: wegmann{at}med.uni-marburg.de

4 Abbreviations used in this paper: DC, dendritic cell; p(I:C), polycytidylic-polyinosinic acid; MNC, mononuclear cell; BAL, bronchoalveolar lavage; PL, peritoneal lavage; MCh, metacholine; PAS, periodic-acid Schiff; CBA, cytometric bead array; AHR, airway hyperresponsiveness; wt, wild type.




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