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* Ludwig Institute for Cancer Research and Experimental Medicine Unit, Université Catholique de Louvain, Brussels, Belgium;
Industrial Toxicology and Occupational Medicine Unit, Université Catholique de Louvain, Brussels, Belgium;
Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge, U.K.;
Genaera Corporation, Plymouth Meeting, Pennsylvania; and
¶ Department of Experimental Medicine, University of Perugia, Perugia, Italy
Increased IL-9 expression, either systemically or under the control of lung-specific promoter, induces an asthma-like phenotype, including mucus overproduction, mastocytosis, lung eosinophilia, and airway hyperresponsiveness. These activities correlate with increased production of other Th2 cytokines such as IL-4, IL-5, and IL-13 in IL-9 Tg mice. To determine the exact role of IL-13 in this phenotype, mice overexpressing IL-9 were crossed with IL-13-deficient mice. In these animals, IL-9 could still induce mastocytosis and B lymphocyte infiltration of the lungs. Although IL-9-induced eosinophilia in the peritoneal cavity was not diminished in the absence of IL-13, IL-13 was required for IL-9 to increase eotaxin expression and lung eosinophilia. Mucus production and up-regulation of lung epithelial genes upon IL-9 overexpression were completely abolished in the absence of IL-13. Using hemopoietic cell transfer experiments with recipients that overexpressed IL-9 but were deficient in the IL-9 receptor (IL-9R), we could demonstrate that the effect of IL-9 on lung epithelial cells is indirect and could be fully restored by transfer of hemopoietic cells expressing IL-9R. Mucus production by lung epithelial cells was only up-regulated when hemopoietic cells simultaneously expressed functional IL-9R and IL-13 genes, indicating that IL-13 is not a cofactor but a direct mediator of the effect of IL-9 on lung epithelial cells. Taken together, these data indicate that IL-9 can promote asthma through IL-13-independent pathways via expansion of mast cells, eosinophils, and B cells, and through induction of IL-13 production by hemopoietic cells for mucus production and recruitment of eosinophils by lung epithelial cells.
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1 This work was supported in part by the Belgian Federal Service for Scientific, Technical, and Cultural Affairs, by the Actions de Recherche Concertées of the Communauté Française de Belgique and the opération Télévie. F.H. is a research associate with the Fonds National de la Recherche Scientifique, Belgium.
2 Address correspondence and reprint requests to Dr. Jean-Christophe Renauld, Ludwig Institute for Cancer Research and Experimental Medicine Unit, Université Catholique de Louvain, Avenue Hippocrate 74, Brussels, Belgium. E-mail address: Jean-Christophe.Renauld{at}bru.licr.org
3 Abbreviations used in this paper: Tg, transgenic; AHR, airway hyperresponsiveness; KO, knockout; mMCP-1, mouse mast cell protease 1; mCLCA3, mouse calcium-activated chloride channel 3; TFF2, trefoil factor 2; Retnla, resistin-like 
; WT, wild type; SPF, specific pathogen free.
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