HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0803109v1 183/8/5293    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Durrant, D. M. Articles by Metzger, D. W. PubMed PubMed Citation Articles by Durrant, D. M. Articles by Metzger, D. W. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Pneumonia

Development of Allergen-Induced Airway Inflammation in the Absence of T-bet Regulation Is Dependent on IL-17¹

Douglas M. Durrant,^* Sarah L. Gaffen, Erik P. Riesenfeld, Charles G. Irvin, and Dennis W. Metzger^2*

^*Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208; University of Pittsburgh, Division of Rheumatology and Clinical Immunology, Pittsburgh, PA 15261; and University of Vermont, Department of Medicine, Burlington, VT 05405

Dysfunctional expression of T-bet, a transcription factor that is critical for IFN- production, has been implicated in the development of asthma. To investigate in detail the mechanisms responsible for exacerbated disease in the absence of T-bet expression, BALB/c wild-type (WT) and T-bet^–/– mice were used in a murine model of OVA-induced allergic lung inflammation. Following OVA challenge, T-bet^–/– mice displayed increased histological inflammation in the lungs as well as greater thickening of the bronchiole linings, increased numbers of eosinophils and neutrophils in the lung, and enhanced airway hyperresponsiveness, compared with WT mice. However, the production of Th2 cytokines in T-bet^–/– mice did not appear to be significantly greater than in WT mice. Interestingly, a marked increase in the levels of the proinflammatory cytokine IL-17 was observed in T-bet^–/– mice. Neutralization of pulmonary IL-17 in T-bet^–/– mice by anti-IL-17 mAb treatment during OVA challenge resulted in decreased levels of neutrophilic infiltration into the airways and decreased airway inflammation, essentially reversing the development of allergic asthma development. These findings indicate that IL-17 is a key mediator of airway inflammation in the absence of T-bet. The results of this study suggest a possible target for therapeutic intervention of human asthma.

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 National Institutes of Health Grants R01 AI41715 (to D.W.M.) and R01 AR054389 and DE018822 (to S.L.G.).

² Address correspondence and reprint requests to Dr. Dennis W. Metzger, Center for Immunology and Microbial Disease, MC-151, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208. E-mail address: Metzged{at}mail.amc.edu

³ Abbreviations used in this paper: WT, wild type; BAL, bronchoalveolar lavage; CBA, cytometric bead array; Ct, cycle threshold; i.n., intranasal; Mch, methacholine; ROR, retinoic acid-related orphan receptor.

⁴ The online version of this article contains supplemental material.