Decreased P-glycoprotein (P-gp/MDR1) expression in inflamed human intestinal epithelium is independent of PXR protein levels
Hans Blokzijl MD
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorSara Vander Borght
Department of Morphology and Molecular Pathology, University of Leuven, Belgium
Search for more papers by this authorLisette I.H. Bok
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorLouis Libbrecht MD, PhD
Department of Morphology and Molecular Pathology, University of Leuven, Belgium
Search for more papers by this authorMariska Geuken
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorFiona A.J. van den Heuvel MD
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorGerard Dijkstra MD, PhD
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorTania A.D. Roskams MD, PhD
Department of Morphology and Molecular Pathology, University of Leuven, Belgium
Search for more papers by this authorHan Moshage PhD
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorPeter L.M. Jansen MD, PhD
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorCorresponding Author
Klaas Nico Faber PhD
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Department of Gastroenterology and Hepatology, University Medical Center Groningen, PO-Box 30.001, 9700 RB Groningen, The NetherlandsSearch for more papers by this authorHans Blokzijl MD
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorSara Vander Borght
Department of Morphology and Molecular Pathology, University of Leuven, Belgium
Search for more papers by this authorLisette I.H. Bok
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorLouis Libbrecht MD, PhD
Department of Morphology and Molecular Pathology, University of Leuven, Belgium
Search for more papers by this authorMariska Geuken
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorFiona A.J. van den Heuvel MD
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorGerard Dijkstra MD, PhD
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorTania A.D. Roskams MD, PhD
Department of Morphology and Molecular Pathology, University of Leuven, Belgium
Search for more papers by this authorHan Moshage PhD
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorPeter L.M. Jansen MD, PhD
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorCorresponding Author
Klaas Nico Faber PhD
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Department of Gastroenterology and Hepatology, University Medical Center Groningen, PO-Box 30.001, 9700 RB Groningen, The NetherlandsSearch for more papers by this authorAbstract
Background: Altered P-glycoprotein expression (P-gp/MDR1) and/or function may contribute to the pathogenesis of gastrointestinal inflammatory disorders. Low intestinal mRNA levels of the pregnane X receptor (PXR) have been linked to low MDR1 mRNA levels in patients with ulcerative colitis (UC). Here we compared intestinal MDR1 mRNA and protein expression in uninflamed and inflamed intestinal epithelium (IE) of patients with gastrointestinal inflammatory disorders to healthy controls.
Methods: Intestinal mucosal biopsies were obtained from patients with Crohn's disease (CD, n = 20), UC (n = 10), diverticulitis (n = 3), collagenous colitis (n = 3), and healthy controls (n = 10). MDR1, iNOS, MRP1, CYP3A4, and PXR expression was determined using real-time reverse-transcriptase polymerase chain reaction (RT-PCR), Western blotting, and/or immunohistochemistry. Furthermore, MDR1 expression was determined in human intestinal biopsies and the human colon carcinoma cell line DLD-1 after exposure to cytokines (TNF-α, IFN-γ, and/or IL-1β).
Results: MDR1 mRNA levels in uninflamed colon of UC patients were comparable to healthy controls, while they were slightly decreased in ileum and slightly increased in colon of CD patients. MDR1 expression, however, was strongly decreased in inflamed IE of CD, UC, collagenous colitis, and diverticulitis patients. A cytokine-dependent decrease of MDR1 expression was observed in human intestinal biopsies, but not in DLD-1 cells. Remarkably, PXR protein levels were equal in uninflamed and inflamed tissue of CD and UC patients despite low PXR mRNA levels in inflamed tissue.
Conclusions: MDR1 expression is strongly decreased in inflamed IE of patients with gastrointestinal disorders and this is independent of PXR protein levels. Low MDR1 levels may aggravate intestinal inflammation.
(Inflamm Bowel Dis 2007)
Supporting Information
This article includes Supplementary Material available via the Internet at http://www.interscience.wiley.com/jpages/1078-0998/suppmat .
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| jws-ibd.20088.fig1.TIF67 KB | Supporting Information file jws-ibd.20088.fig1.TIF |
| jws-ibd.20088.fig2.TIF64.4 KB | Supporting Information file jws-ibd.20088.fig2.TIF |
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