Enterocyte expression of the eotaxin and interleukin-5 transgenes induces compartmentalized dysregulation of eosinophil trafficking.
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.
Mishra
Anil
A
Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Hogan
Simon P
SP
Brandt
Eric B
EB
Wagner
Norbert
N
Crossman
Michael W
MW
Foster
Paul S
PS
Rothenberg
Marc E
ME
D000818:Animals; D001483:Base Sequence; D002451:Cell Compartmentation; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D004064:Digestive System / Q000166:cytology; D020895:Enterocytes / Q000378:metabolism*; D004804:Eosinophils / Q000166:cytology*; D007150:Immunohistochemistry; D039641:Integrin beta Chains; D016023:Integrins / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019076:Transgenes
C515457:Ccl11 protein, mouse; C515458:Ccl11 protein, rat; D054413:Chemokine CCL11; D019742:Chemokines, CC; D017931:DNA Primers; D039641:Integrin beta Chains; D016023:Integrins; D015848:Interleukin-5; C091368:integrin beta7