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Originally published In Press as doi:10.1074/jbc.M110424200 on November 30, 2001

J. Biol. Chem., Vol. 277, Issue 6, 4406-4412, February 8, 2002
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Enterocyte Expression of the Eotaxin and Interleukin-5 Transgenes Induces Compartmentalized Dysregulation of Eosinophil Trafficking*

Anil MishraDagger §, Simon P. HoganDagger §, Eric B. BrandtDagger , Norbert Wagner, Michael W. CrossmanDagger , Paul S. Foster||, and Marc E. RothenbergDagger **

From the Dagger  Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, the  Cologne Institute for Genetics, University of Cologne, Cologne 50931, Germany, and the || Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 0200, Australia

Eosinophils accumulate in the gastrointestinal tract in a number of medical disorders, but the mechanisms involved are largely unknown. To understand the significance of cytokine expression by enterocytes, enterocyte transgenic mice that overexpressed the eosinophil-selective cytokines eotaxin and interleukin (IL)-5 were generated. Transgenic mice, generated by utilizing the rat intestinal fatty acid-binding protein promoter (Fabpi), overexpressed the mRNA for these cytokines in the small intestine. Overexpression of IL-5 resulted in marked increases of eosinophils in the bone marrow and blood, whereas eotaxin overexpression resulted in similar levels compared with nontransgenic control mice. In contrast, both IL-5 and eotaxin transgenic mice had significant accumulation of eosinophils in the gastrointestinal mucosa compared with control mice. Eotaxin-induced gastrointestinal eosinophilia was substantially higher than that induced by IL-5 and was especially prominent within the lamina propria of the villi. Interestingly, genetic rescue of eotaxin deficiency (by transgenic overexpression of eotaxin in eotaxin gene-targeted mice) resulted in significant restoration of gastrointestinal eosinophil levels. Finally, the intestinal eosinophilia induced by the eotaxin transgene was beta 7 integrin-dependent. Taken together, these results demonstrate that expression of eotaxin and IL-5 in intestinal epithelium induces compartmentalized dysregulation of eosinophil trafficking and the important role of the beta 7 integrin in gastrointestinal allergic responses.

* This work was supported in part by a National Health Medical Research Council (Australia) C. J. Martin postdoctoral fellowship (to S. P. H.), National Institutes of Health Grants R01 AI42242-03 and R01 AI45898-02 (both to M. E. R.), a grant from the Human Frontier Science Program (to M. E. R and P. S. F.), and Deutsche Forschungsgemeinschaft Grant WAII27/1-3 (to N. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

** To whom correspondence should be addressed: Div. of Allergy and Immunology, Dept. of Pediatrics, Children's Hospital Medical Center, Cincinnati, OH 45229. Tel.: 513-636-7210; Fax: 513-636-3310; E-mail: rothenberg@chmcc.org.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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