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Granulocyte-Macrophage Colony-Stimulating Factor Is Required for Bronchial Eosinophilia in a Murine Model of Allergic Airway Inflammation¹

Yung-Chang Su^*,, Michael S. Rolph^*, Nicole G. Hansbro, Charles R. Mackay^* and William A. Sewell^2,*,

^* Immunology and Inflammation Research Program, Garvan Institute of Medical Research and St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia; and Asthma, Allergy and Inflammation Research Centre, University of Newcastle, Newcastle, Australia

GM-CSF plays an important role in inflammation by promoting the production, activation, and survival of granulocytes and macrophages. In this study, GM-CSF knockout (GM-CSF^–/–) mice were used to investigate the role of GM-CSF in a model of allergic airway inflammation. In allergic GM-CSF^–/– mice, eosinophil recruitment to the airways showed a striking pattern, with eosinophils present in perivascular areas, but almost completely absent in peribronchial areas, whereas in wild-type mice, eosinophil infiltration appeared in both areas. In the GM-CSF^–/– mice, mucus production in the airways was also reduced, and eosinophil numbers were markedly reduced in the bronchoalveolar lavage (BAL)³ fluid. IL-5 production was reduced in the lung tissue and BAL fluid of GM-CSF^–/– mice, but IL-4 and IL-13 production, airway hyperresponsiveness, and serum IgE levels were not affected. The presence of eosinophils in perivascular but not peribronchial regions was suggestive of a cell migration defect in the airways of GM-CSF^–/– mice. The CCR3 agonists CCL5 (RANTES) and CCL11 (eotaxin-1) were expressed at similar levels in GM-CSF^–/– and wild-type mice. However, IFN- mRNA and protein were increased in the lung tissue and BAL fluid in GM-CSF^–/– mice, as were mRNA levels of the IFN--inducible chemokines CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-Tac). Interestingly, these IFN--inducible chemokines are natural antagonists of CCR3, suggesting that their overproduction in GM-CSF^–/– mice contributes to the lack of airway eosinophils. These findings demonstrate distinctive abnormalities to a model of allergic asthma in the absence of GM-CSF.

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 an Endeavour International Postgraduate Research Scholarship to Y.-C.S. from the Faculty of Medicine, University of New South Wales, and by the Co-operative Research Centre for Asthma.

² Address correspondence and reprint requests to Dr. William A. Sewell, Immunology and Inflammation Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales, Australia 2010. E-mail address: w.sewell{at}garvan.org.au

³ Abbreviations used in this paper: BAL, bronchoalveolar lavage; AHR, airway hyperresponsiveness; WT, wild type; PAS, periodic acid-Schiff; PTLN, peritracheal lymph node; PAP, pulmonary alveolar proteinosis.