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Am J Physiol Gastrointest Liver Physiol 289: G890-G897, 2005; doi:10.1152/ajpgi.00015.2005
0193-1857/05 $8.00
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INFLAMMATION/IMMUNITY/MEDIATORS

Eosinophils alter colonic epithelial barrier function: role for major basic protein

Glenn T. Furuta,1,2 Edward E. S. Nieuwenhuis,5 Jorn Karhausen,2 Gerald Gleich,4 Richard S. Blumberg,5 James J. Lee,6 and Steven J. Ackerman3

1Combined Program in Pediatric Gastroenterology and Nutrition and 2Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Harvard Medical School, Boston, Masssachusetts; 3Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois; 4Department of Dermatology, University of Utah, Salt Lake City, Utah; 5Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts; and 6Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Scottsdale, Arizona

Submitted 13 January 2005 ; accepted in final form 6 June 2005

Mucosal eosinophils increase in a number of gastrointestinal diseases that are often associated with altered epithelial barrier function, including food allergic enteropathies and inflammatory bowel diseases. Although eosinophils are known to secrete biologically active mediators including granule proteins, their role in gastrointestinal diseases is uncertain. The aim of this study was to determine the impact of eosinophils on intestinal barrier function. Epithelial barrier function was determined in a coculture of eosinophils and T84 epithelial cells and in a murine model of T helper (Th) type 2-mediated colitis. Coculture conditions resulted in decreased transepithelial resistance (TER) and increased transepithelial flux. Cell-free coculture supernatants contained a ≥5-kDa soluble factor that also diminished TER; these supernatants contained the eosinophil-granule proteins major basic protein (MBP) and eosinophil-derived neurotoxin (EDN). T84 barrier function decreased significantly when basolateral surfaces were exposed to native human MBP but not EDN. Additional studies identified downregulation of the tight junctional molecule occludin as at least one mechanism for MBP action. MBP-null mice were protected from inflammation associated with oxazolone colitis compared with wild-type mice. In conclusion, MBP decreases epithelial barrier function and in this manner contributes to the pathogenesis of inflammatory bowel diseases.

tight junction; eosinophilic gastroenteritis; food allergy


Address for reprint requests and other correspondence: G. T. Furuta, 300 Longwood Ave., Hunnewell Ground Floor, Boston, MA 02115 (e-mail: gfuruta{at}zeus.bwh.harvard.edu)






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