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Differences in P-glycoprotein-170 expression and activity between Crohn's disease and ulcerative colitis
B Yacyshyn1, W Maksymowych, M B Bowen-Yacyshyn
1Department of Medicine, University of Alberta, Edmonton, Canada. bruce.yacyshyn@ualberta.ca
Human Immunology
|August 10, 1999
Summary
P-glycoprotein-170 (Pgp-170) expression and function are lower in ulcerative colitis (UC) intestinal lymphocytes compared to Crohn's disease. This differential Pgp-170 expression may influence Cyclosporine A efficacy in inflammatory bowel disease.
Area of Science:
- Immunology
- Gastroenterology
- Pharmacology
Background:
- The clinical efficacy of Cyclosporine A (CsA) in inflammatory bowel disease (IBD) remains debated.
- Cyclosporine A is a substrate of the P-glycoprotein-170 (Pgp-170) efflux pump, which is expressed on various immune cells.
- Differential expression of Pgp-170 could impact CsA's therapeutic effects in distinct IBD subtypes.
Purpose of the Study:
- To investigate the expression and function of Pgp-170 in lymphocytes from patients with ulcerative colitis (UC) and Crohn's disease (CD).
- To determine if Pgp-170 levels differ between UC, CD, and healthy controls.
- To explore the potential role of Pgp-170 in the variable response to CsA in IBD.
Main Methods:
- Lymphocytes (intra-epithelial, lamina propria, peripheral blood) were isolated from UC, CD, and control tissues.
- Pgp-170 surface expression was assessed using flow cytometry with the MRK-16 antibody.
- Functional Pgp-170 activity was measured via Rhodamine 123 efflux assay.
- Pgp-170 mRNA levels were quantified using RT-PCR.
Main Results:
- Significantly lower Pgp-170 surface expression was observed on UC CD3+ intestinal lymphocytes compared to controls and CD patients.
- Functional assays revealed decreased Pgp-170 activity in UC lymphocytes.
- UC samples showed fewer CD8+ intraepithelial lymphocytes (IELs), which are known to have higher intrinsic Pgp-170 function.
- Pgp-170 mRNA expression in UC IELs was below the limit of detection by RT-PCR.
- Crohn's disease exhibited greater and differential expression, function, and mRNA levels of Pgp-170 compared to UC and normal tissues.
Conclusions:
- Pgp-170 is differentially expressed and functionally active in the lymphocytes of IBD patients.
- Lower Pgp-170 expression and function in UC may contribute to the controversial clinical benefit of CsA in this condition.
- These findings suggest Pgp-170 levels could be a factor in predicting CsA response in IBD management.