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IL-12 Contributes to Allergen-Induced Airway Inflammation in Experimental Asthma¹

Isabelle Meyts^*,¶, Peter W. Hellings^*, Greet Hens^*, Bart M. Vanaudenaerde, Bert Verbinnen^*, Hubertine Heremans, Patrick Matthys, Dominique M. Bullens^*, Lut Overbergh, Chantal Mathieu, Kris De Boeck^¶ and Jan L. Ceuppens^2,*,||

^* Laboratory of Experimental Immunology and Laboratory of Pneumology, University Hospitals, Faculty of Medicine, Katholieke Universiteit Leuven, Laboratory of Immunobiology, Rega Institute, Faculty of Medicine, Katholieke Universiteit Leuven, Laboratory of Experimental Medicine and Endocrinology, Faculty of Medicine, Katholieke Universiteit Leuven, and ^¶ Department of Pediatrics and ^|| Department of Internal Medicine, University Hospitals, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium

Lack of sufficient IL-12 production has been suggested to be one of the basic underlying mechanisms in atopy, but a potential role of IL-12 in established allergic airway disease remains unclear. We took advantage of a mouse model of experimental asthma to study the role of IL-12 during the development of bronchial inflammation. Administration of anti-IL-12p35 or anti-IL-12p40 mAb to previously OVA-sensitized BALB/c mice concomitantly with exposure to nebulized OVA, abolished both the development of bronchial hyperresponsiveness to metacholine as well as the eosinophilia in bronchoalveolar lavage fluid and peripheral blood. Anti-IL-12 treatment reduced CD4⁺ T cell numbers and IL-4, IL-5, and IL-13 levels in the bronchoalveolar lavage fluid and the mRNA expression of IL-10, eotaxin, RANTES, MCP-1, and VCAM-1 in the lung. Anti-IL-12p35 treatment failed to show these effects in IFN- knockout mice pointing to the essential role of IFN- in IL-12-induced effects. Neutralization of IL-12 during the sensitization process aggravated the subsequent development of allergic airway inflammation. These data together with recent information on the role of dendritic cells in both the sensitization and effector phase of allergic respiratory diseases demonstrate a dual role of IL-12. Whereas IL-12 counteracts Th2 sensitization, it contributes to full-blown allergic airway disease upon airway allergen exposure in the postsensitization phase, with enhanced recruitment of CD4⁺ T cells and eosinophils and with up-regulation of Th2 cytokines, chemokines, and VCAM-1. IFN--producing cells or cells dependent on IFN- activity, play a major role in this unexpected proinflammatory effect of IL-12 in allergic airway disease.

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 grants of the Fonds Wetenschappelijk Onderzoek (FWO) Vlaanderen G.0255.05 and of the research council of the Katholieke Universiteit Leuven. I.M. and G.H. are recipients of fellowships from the FWO, and P.M., D.M.B., and P.W.H. are postdoctoral fellows of the FWO. B.V. is a recipient of a fellowship of the Innovatie door Wetenschap en Technologie.

² Address correspondence and reprint requests to Dr. Jan L. Ceuppens, Laboratory of Experimental Immunology, Onderwijs en Navorsing, Herestraat 49, B-3000 Leuven, Belgium. E-mail address: Jan.Ceuppens{at}uz.kuleuven.ac.be

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; DC, dendritic cell; KO, knockout; MCh, metacholine; PenH, enhanced pause; BAL, bronchoalveolar lavage; sVCAM-1, soluble VCAM-1.

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