Up-regulation and cytoprotective role of epithelial multidrug resistance-associated protein 1 in inflammatory bowel disease.
MRP1 (multidrug resistance-associated protein 1) is well known for its role in providing multidrug resistance to cancer cells. In addition, MRP1 has been associated with both pro- and anti-inflammatory functions in nonmalignant cells. The pro-inflammatory function is evident from the fact that MRP1 is a high affinity transporter for cysteinyl-leukotriene C4 (LTC4), a lipid mediator of inflammation. It remains unexplained, however, why the absence of Mrp1 leads to increased intestinal epithelial damage in mice treated with dextran-sodium sulfate, a model for inflammatory bowel disease (IBD). We found that MRP1 expression is induced in the inflamed intestine of IBD patients, e.g. Crohn disease and ulcerative colitis. Increased MRP1 expression was detected at the basolateral membrane of intestinal epithelial cells. To study a putative role for MRP1 in protecting epithelial cells against inflammatory cues, we manipulated MRP1 levels in human epithelial DLD-1 cells and exposed these cells to cytokines and anti-Fas. Inhibition of MRP1 (by MK571 or RNA interference) resulted in increased cytokine- and anti-Fas-induced apoptosis of DLD-1 cells. Opposite effects, e.g. protection of DLD-1 cells against cytokine- and anti-Fas-induced apoptosis, were observed after recombinant MRP1 overexpression. Inhibition of LTC4 synthesis reduced anti-Fas-induced apoptosis when MRP1 function was blocked, suggesting that LTC4 is the pro-apoptotic compound exported by epithelial MRP1 during inflammation. These data show that MRP1 protects intestinal epithelial cells against inflammation-induced apoptotic cell death and provides a functional role for MRP1 in the inflamed intestinal epithelium of IBD patients.
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9700 RB, Groningen, The Netherlands.
Hans
H
Blokzijl
Axel
A
van Steenpaal
Sara
S
Vander Borght
Lisette I H
LI
Bok
Louis
L
Libbrecht
Marieke
M
Tamminga
Mariska
M
Geuken
Tania A D
TA
Roskams
Gerard
G
Dijkstra
Han
H
Moshage
Peter L M
PL
Jansen
Klaas Nico
KN
Faber
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology; D016264:Dextran Sulfate / Q000633:toxicity; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017997:Leukotriene C4 / Q000378:metabolism*; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference
D016207:Cytokines; D016264:Dextran Sulfate; D018836:Inflammation Mediators; D020024:Leukotriene Antagonists; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; C059141:verlukast; C421109:multidrug resistance-associated protein 1