Critical Role for P-Glycoprotein Expression in Hematopoietic Cells in the FVB.Mdr1a/ Model of Colitis

Staley, Elizabeth M.*; Dimmitt, Reed A.; Schoeb, Trenton R.; Tanner, Scott M.§; Lorenz, Robin G.§

Journal of Pediatric Gastroenterology & Nutrition: December 2011 - Volume 53 - Issue 6 - p 666–673
doi: 10.1097/MPG.0b013e31822860f1
Original Articles: Gastroenterology

Objective: P-glycoprotein (P-gp), the functional product of the multidrug resistance gene (MDR), is a transmembrane protein that extrudes substrates from the intracellular environment. P-gp is expressed on the apical surface of epithelial cells and on cells from the hematopoietic lineage. Human MDR polymorphisms have been associated with the increased risk of inflammatory bowel disease, and FVB/N animals deficient in mdr1a expression develop spontaneous colitis. Previous studies using adult bone marrow chimeras indicated that colitis development in this animal model was contingent on P-gp deficiency in radiation-resistant epithelial cells; however, the use of adult animals may mask the role of hematopoietic immune cells in colitis initiation, due to preexisting epithelial abnormalities.

Subjects and Methods: To assess the importance of P-gp expression in intestinal epithelial and hematopoietic-derived cells on colitis induction in FVB.mdr1a−/− animals, we developed a neonatal model of bone marrow reconstitution. FVB/N and FVB.mdr1a−/− adult and neonatal animals were lethally irradiated and reconstituted with bone marrow from FVB/N or FVB.mdr1a−/− donors. Animals were observed for 20 weeks.

Results: Adult FVB/N animals deficient in P-gp expression in hematopoietically derived immune cells developed colitis similar to adult animals deficient in P-gp expression in radiation-resistant epithelial/stromal cells. Neonatal animals deficient in P-gp expression in hematopoietically derived immune cells developed a more histologically significant colitis than those deficient in P-gp expression in epithelial tissue.

Conclusions: The use of a neonatal model of bone marrow reconstitution has revealed a critical role for P-gp expression in hematopoietically derived immune cells in colitis development in the FVB.mdr1a−/− model.

*Department of Microbiology

Department of Pediatrics

Department of Genetics

§Department of Pathology, University of Alabama at Birmingham.

Address correspondence and reprint requests to Dr Robin G. Lorenz, Department of Pathology, University of Alabama at Birmingham, 1825 University Blvd, SHEL 602, Birmingham, AL 35243-2182 (e-mail: rlorenz@uab.edu).

Received 6 January, 2011

Accepted 8 June, 2011

Drs Staley and Dimmitt participated equally in the study.

This work was supported in part by NIH grants R01 DK059911, P01 DK071176, and the Molecular Pathology and Human Cell Tissue Core of the University of Alabama at Birmingham Digestive Diseases Research Development Center (P30 DK064400). E.M.S. received partial salary support from T32 AI07051 and R.A.D. received partial support from K08 HD046506. S.M.T. is a recipient of a UAB-Hughes Med into Grad Fellowship. Aspects of this project were conducted in biomedical research space that was constructed with funds supported in part by NIH grant C06RR020136.

The authors report no conflicts of interest.

Copyright 2011 by ESPGHAN and NASPGHAN