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* Division of Allergy and Immunology,
Division of Gastroenterology, Hepatology and Nutrition,
Division of Pathology, and
Division of Biomedical Informatics, Department of Pediatrics, University of Cincinnati College of Medicine, CCHMC, Cincinnati, OH 45229;
¶ Division of Pulmonary Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259;
|| Department of Medical Sciences, University of Uppsala, Uppsala, Sweden
Clinical studies have demonstrated a link between the eosinophil-selective chemokines, eotaxins (eotaxin-1/CCL11 and eotaxin-2/CCL24), eosinophils, and the inflammatory bowel diseases, Crohn’s disease and ulcerative colitis (UC). However, the cellular source and individual contribution of the eotaxins to colonic eosinophilic accumulation in inflammatory bowel diseases remain unclear. In this study we demonstrate, by gene array and quantitative PCR, elevated levels of eotaxin-1 mRNA in the rectosigmoid colon of pediatric UC patients. We show that elevated levels of eotaxin-1 mRNA positively correlated with rectosigmoid eosinophil numbers. Further, colonic eosinophils appeared to be degranulating, and the levels positively correlated with disease severity. Using the dextran sodium sulfate (DSS)-induced intestinal epithelial injury model, we show that DSS treatment of mice strongly induced colonic eotaxin-1 and eotaxin-2 expression and eosinophil levels. Analysis of eosinophil-deficient mice defined an effector role for eosinophils in disease pathology. DSS treatment of eotaxin-2–/– and eotaxin-1/2–/– mice demonstrated that eosinophil recruitment was dependent on eotaxin-1. In situ and immunofluorescence analysis-identified eotaxin-1 expression was restricted to intestinal F4/80+CD11b+ macrophages in DSS-induced epithelial injury and to CD68+ intestinal macrophages and the basolateral compartment of intestinal epithelial cells in pediatric UC. These data demonstrate that intestinal macrophage and epithelial cell-derived eotaxin-1 plays a critical role in the regulation of eosinophil recruitment in colonic eosinophilic disease such as pediatric UC and provides a basis for targeting the eosinophil/eotaxin-1 axis in UC.
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 in part by Crohn’s Colitis Foundation of American Career Development Award 2007 (to S.P.H.), Digestive Disease Health Center Pilot and Feasibility Research Grant of the National Institutes of Health-supported Cincinnati Children’s Hospital Research Foundation Digestive Health Center (1P30DK078392-01) (to S.P.H.), and National Institutes of Health Grant R01 DK058259 (to L.D.).
2 Address correspondence and reprint requests to Dr. Simon P. Hogan, Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, ML7028, Cincinnati OH 45229. E-mail address: simon.hogan{at}cchmc.org
3 Abbreviations used in this paper: IBD, Inflammatory bowel disease; CD, Crohn’s disease; DSS, dextran sodium sulphate; EPO, eosinophil peroxidase; GI, gastrointestinal; hpf, high-powered field; UC, ulcerative colitis; UCHIS, UC histologic index of severity; WT, wild type.
4 The online version of this article contains supplemental material.
This article has been cited by other articles:
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  A. Munitz, L. Seidu, E. T. Cole, R. Ahrens, S. P. Hogan, and M. E. Rothenberg Resistin-Like Molecule {alpha} Decreases Glucose Tolerance during Intestinal Inflammation J. Immunol., February 15, 2009; 182(4): 2357 - 2363. [Abstract] [Full Text] [PDF]
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