Regulation of cockroach antigen-induced allergic airway hyperreactivity by the CXCR3 ligand CXCL9.
Allergic airway disease is characterized by a robust lymphocytic infiltrate, elaboration of Th2-type inflammatory mediators, pulmonary eosinophil accumulation, and airway hyperreactivity. The CXCR3 ligands, CXCL9 (monokine induced by IFN-gamma) and CXCL10 (IFN-inducible protein, 10 kDa), are IFN-gamma-inducible, Th1-type chemokines. As CXCL10 has been previously shown to participate in the modulation of allergic inflammation, we were interested in investigating the possible role that CXCL9 may play in this inflammatory response. Expression of CXCL9 was primarily identified in airway epithelial cells by immunohistochemical staining. Airway neutralization of CXCL9 at the time of allergen challenge significantly increased airway hyperreactivity, airway eosinophil accumulation, and IL-4 levels in the bronchoalveolar lavage while significantly decreasing airway levels of IL-12. In contrast, introduction of exogenous CXCL9 into the airway at the time of allergen challenge dramatically reduced airway hyper-reactivity and eosinophil accumulation. Moreover, pulmonary levels of IL-4 were significantly reduced, whereas levels of IL-12 were significantly increased, with exogenous CXCL9 treatment. In lymphocytes restimulated with CXCL9 and allergen in vitro, CXCL9 down-regulated IL-4 expression and up-regulated IFN-gamma expression, suggesting that CXCL9 is able to direct activated lymphocytes toward a Th1-type phenotype. Additionally, CXCL9 was shown to inhibit CC chemokine ligand 11-induced eosinophil chemotaxis in in vitro assays. Taken together, our results demonstrate that the CXCR3 ligand CXCL9 is involved in regulation of the allergic response in the lung by regulation of lymphocyte activation and eosinophil recruitment.
Thomas
Molly S
MS
Department of Pathology, University of Michigan, 1309 Catherine, Ann Arbor, MI 48109, USA.
Kunkel
Steven L
SL
Lukacs
Nicholas W
NW
D000485:Allergens / Q000276:immunology*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000209:etiology*; D054413:Chemokine CCL11; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019742:Chemokines, CC / Q000037:antagonists & inhibitors; D019743:Chemokines, CXC / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D003058:Cockroaches / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004804:Eosinophils / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C
D000485:Allergens; C515456:CCL11 protein, human; C114753:CXCL10 protein, human; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019742:Chemokines, CC; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; C485969:Cxcl9 protein, mouse; D016207:Cytokines