IL-13 mediates in vivo IL-9 activities on lung epithelial cells but not on hematopoietic cells.
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.
Steenwinckel
Valérie
V
Ludwig Institute for Cancer Research and Experimental Medicine Unit, Université Catholique de Louvain, Avenue Hippocrate 74, Brussels, Belgium.
Louahed
Jamila
J
Orabona
Ciriana
C
Huaux
François
F
Warnier
Guy
G
McKenzie
Andrew
A
Lison
Dominique
D
Levitt
Roy
R
Renauld
Jean-Christophe
JC
D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000096:biosynthesis / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018793:Interleukin-13 / Q000172:deficiency / Q000276:immunology*; D016906:Interleukin-9 / Q000172:deficiency / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009093:Mucus / Q000276:immunology / Q000378:metabolism; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053651:Receptors, Interleukin-9 / Q000172:deficiency / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; C508448:Il9r protein, mouse; D018793:Interleukin-13; D016906:Interleukin-9; D053651:Receptors, Interleukin-9