Enterocyte expression of the eotaxin and IL-5 transgenes induces compartmentalized dysregulation of eosinophil trafficking

doi:10.1074/jbc.M110424200

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Papers In Press, published online ahead of print November 30, 2001
J. Biol. Chem, 10.1074/jbc.M110424200
Submitted on October 30, 2001
Revised on November 30, 2001
Accepted on November 29, 2001

Enterocyte expression of the eotaxin and IL-5 transgenes induces compartmentalized dysregulation of eosinophil trafficking

Anil Mishra, Simon P. Hogan, Eric B. Brandt, Norbert Wagner, Michael W. Crossman, Paul S. Foster, and Marc E. Rothenberg

Div. of Allergen and Clinical Immunology, Childrens Hospital Medical Center, Cincinnati, OH 45229

Corresponding Author: rothenberg{at}chmcc.org

Eosinophils accumulate in the gastrointestinal tract in a number of medical disorders but the mechanisms involved are largely unknown. In order to understand the significance of cytokine expression by enterocytes, enterocyte transgenic mice that overexpressed the eosinophil selective cytokines eotaxin and IL-5 were generated. Transgenic mice, generated by utilizing the rat intestinal fatty acid binding protein promoter (Fabpi), over-expressed 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 to non-transgenic 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 b7-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 b7-integrin in gastrointestinal allergic responses.

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