Identification of a cooperative mechanism involving interleukin-13 and eotaxin-2 in experimental allergic lung inflammation.
Pulmonary eosinophilia, a hallmark pathologic feature of allergic lung disease, is regulated by interleukin-13 (IL-13) as well as the eotaxin chemokines, but the specific role of these cytokines and their cooperative interaction are only partially understood. First, we elucidated the essential role of IL-13 in the induction of the eotaxins by comparing IL-13 gene-targeted mice with wild type control mice by using an ovalbumin-induced model of allergic airway inflammation. Notably, ovalbumin-induced expressions of eotaxin-1 and eotaxin-2 mRNA in the lungs were almost completely dependent upon IL-13. Second, in order to address the specific role of eotaxin-2 in IL-13-induced pulmonary eosinophilia, we generated eotaxin-2 gene-deficient mice by homologous recombination. Notably, in contrast to observations made in eotaxin-1-deficient mice, eotaxin-2-deficient mice had normal base-line eosinophil levels in the hematopoietic tissues and gastrointestinal tract. However, following intratracheal IL-13 administration, eotaxin-2-deficient mice showed a profound reduction in airway eosinophilia compared with wild type mice. Most interestingly, the level of peribronchial lung tissue eosinophils in IL-13-treated eotaxin-2-deficient mice was indistinguishable from wild type mice. Furthermore, IL-13 lung transgenic mice genetically engineered to be deficient in eotaxin-2 had a marked reduction of luminal eosinophils. Mechanistic analysis identified IL13-induced eotaxin-2 expression by macrophages in a distinct lung compartment (luminal inflammatory cells) compared with eotaxin-1, which was expressed solely in the tissue. Taken together, these results demonstrate a cooperative mechanism between IL-13 and eotaxin-2. In particular, IL-13 mediates allergen-induced eotaxin-2 expression, and eotaxin-2 mediates IL-13-induced airway eosinophilia.
Pope
Samuel M
SM
Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Fulkerson
Patricia C
PC
Blanchard
Carine
C
Akei
Hiroko Saito
HS
Nikolaidis
Nikolaos M
NM
Zimmermann
Nives
N
Molkentin
Jeffery D
JD
Rothenberg
Marc E
ME
D000818:Animals; D001483:Base Sequence; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D019742:Chemokines, CC / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004804:Eosinophils / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D017403:In Situ Hybridization; D007249:Inflammation / Q000378:metabolism*; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D014018:Tissue Distribution
C515456:CCL11 protein, human; C515484:CCL24 protein, human; C515457:Ccl11 protein, mouse; C515485:Ccl24 protein, mouse; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D019742:Chemokines, CC; D018793:Interleukin-13