Up-regulation and Cytoprotective Role of Epithelial Multidrug Resistance-associated Protein 1 in Inflammatory Bowel Disease

Abstract

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. 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. Inflammatory bowel disease (IBD) 3The abbreviations used are:IBDinflammatory bowel diseaseUCulcerative colitisCDCrohn diseaseLTC4leukotriene C4ABC transportersATP-binding cassette transportersMRPmultidrug resistance-associated proteinPARPpoly(ADP-ribose)polymerasesiRNAshort interfering RNATNF-αtumor necrosis factor-αGFPgreen fluorescent protein is characterized by chronic inflammation of the gastrointestinal tract and manifests as ulcerative colitis (UC) or Crohn disease (CD) (1Fiocchi C. Gastroenterology. 1998; 115: 182-205Abstract Full Text Full Text PDF PubMed Scopus (1865) Google Scholar). The pathophysiology of IBD is characterized by a highly activated state of the mucosal immune system and excessive mucosal damage (2Duchmann R. Kaiser I. Hermann E. Mayet W. Ewe K. Meyer zum Buschenfelde K.H. Clin. Exp. Immunol. 1995; 102: 448-455Crossref PubMed Scopus (862) Google Scholar). In recent years, important progress has been made in identifying and characterizing susceptibility genes for IBD (3van Limbergen J. Russell R.K. Nimmo E.R. Satsangi J. Am. J. Gastroenterol. 2007; 102: 2820-2831Crossref PubMed Scopus (69) Google Scholar). The (putative) functions of the proteins they encode corroborate the notion that the primary cause for the development of IBD originates from a dysregulated immune response to commensal intestinal bacteria, defects in mucosal barrier function, and/or bacterial clearance. inflammatory bowel disease ulcerative colitis Crohn disease leukotriene C4 ATP-binding cassette transporters multidrug resistance-associated protein poly(ADP-ribose)polymerase short interfering RNA tumor necrosis factor-α green fluorescent protein Irrespective of the genetic cause, severe and continuous inflammation causes damage to the intestinal epithelium that may strongly affect its absorptive and secretory functions as well as its protective role against toxic compounds. Cytoprotection is provided by ATP-binding cassette (ABC) transporters that are specialized in exporting toxic compounds of foreign or endogenous origin (4Borst P. Elferink R.O. Annu. Rev. Biochem. 2002; 71: 537-592Crossref PubMed Scopus (1349) Google Scholar). P-gp/MDR1 (ABCB1), well known for its adverse role in protecting cancer cells against anti-cancer drugs (5Ueda K. Cardarelli C. Gottesman M.M. Pastan I. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 3004-3008Crossref PubMed Scopus (1046) Google Scholar), is also expressed in the healthy intestinal epithelium (6Thiebaut F. Tsuruo T. Hamada H. Gottesman M.M. Pastan I. Willingham M.C. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 7735-7738Crossref PubMed Scopus (2570) Google Scholar). Absence of Mdr1a in transgenic mice results in the spontaneous development of colitis (7Panwala C.M. Jones J.C. Viney J.L. J. Immunol. 1998; 161: 5733-5744PubMed Google Scholar). In line with this observation, specific single nucleotide polymorphisms in the ABCB1 gene have been reported to be associated with CD (8Brant S.R. Panhuysen C.I. Nicolae D. Reddy D.M. Bonen D.K. Karaliukas R. Zhang L. Swanson E. Datta L.W. Moran T. Ravenhill G. Duerr R.H. Achkar J.P. Karban A.S. Cho J.H. Am. J. Hum. Genet. 2003; 73: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 9Schwab M. Schaeffeler E. Marx C. Fromm M.F. Kaskas B. Metzler J. Stange E. Herfarth H. Schoelmerich J. Gregor M. Walker S. Cascorbi I. Roots I. Brinkmann U. Zanger U.M. Eichelbaum M. Gastroenterology. 2003; 124: 26-33Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar, 10Hoffmeyer S. Burk O. von Richter O. Arnold H.P. Brockmoller J. Johne A. Cascorbi I. Gerloff T. Roots I. Eichelbaum M. Brinkmann U. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3473-3478Crossref PubMed Scopus (2358) Google Scholar). Moreover, we recently showed that MDR1 expression is strongly reduced in the inflamed intestine of IBD patients, which may further aggravate the disease (11Blokzijl H. Vander B.S. Bok L.I. Libbrecht L. Geuken M. van den Heuvel F.A. Dijkstra G. Roskams T.A. Moshage H. Jansen P.L. Faber K.N. Inflamm. Bowel Dis. 2007; 13: 710-720Crossref PubMed Scopus (118) Google Scholar). MRP1 (multidrug resistance-associated protein 1, encoded by the ABCC1 gene) also plays a role in inflammatory responses. It transports glutathione and substrates that are conjugated to reduced glutathione, glucuronide, or sulfate as part of the detoxification machinery of (cancer) cells (12Cole S.P. Bhardwaj G. Gerlach J.H. Mackie J.E. Grant C.E. Almquist K.C. Stewart A.J. Kurz E.U. Duncan A.M. Deeley R.G. Science. 1992; 258: 1650-1654Crossref PubMed Scopus (3010) Google Scholar, 13Hipfner D.R. Deeley R.G. Cole S.P. Biochim. Biophys. Acta. 1999; 1461: 359-376Crossref PubMed Scopus (379) Google Scholar). The glutathione conjugate leukotriene C4 (LTC4) has been identified as an endogenous, high affinity substrate for MRP1 (14Samuelsson B. Science. 1983; 220: 568-575Crossref PubMed Scopus (2322) Google Scholar, 15Loe D.W. Almquist K.C. Deeley R.G. Cole S.P. J. Biol. Chem. 1996; 271: 9675-9682Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar). Leukotrienes are important lipid mediators of inflammatory responses and have been implicated in the pathophysiology of both acute and chronic inflammatory diseases, including IBD (14Samuelsson B. Science. 1983; 220: 568-575Crossref PubMed Scopus (2322) Google Scholar, 16van Dullemen H. Meenan J. Stronkhorst A. Tytgat G.N. Van Deventer S.J. Scand. J. Gastroenterol. 1997; 223: S92-S98Google Scholar, 17Sharma J.N. Mohammed L.A. Inflammopharmacology. 2006; 14: 10-16Crossref PubMed Scopus (95) Google Scholar). The role of Mrp1 in the inflammatory signaling pathway is evident from studies with Mrp1-/- knock-out mice that show a strongly reduced response to arachidonic acid-induced inflammatory stimuli as measured by decreased ear edema and vascular permeability (18Wijnholds J. Evers R. van Leusden M.R. Mol C.A. Zaman G.J. Mayer U. Beijnen J.H. van der Valk M. Krimpenfort P. Borst P. Nat. Med. 1997; 3: 1275-1279Crossref PubMed Scopus (403) Google Scholar). Relevant for IBD, however, it was shown that intestinal damage was significantly aggravated in Mrp1-/- knock-out mice exposed to dextran sulfate sodium-induced colitis (19Ten Hove T. Drillenburg P. Wijnholds J. Te Velde A.A. Van Deventer S.J. Dig. Dis. Sci. 2002; 47: 2056-2063Crossref PubMed Scopus (38) Google Scholar). These animal studies suggest that Mrp1 serves a dual role during inflammation, both sending out inflammatory signals as well as protecting the intestinal epithelium. The mechanism of the latter and the relevance for IBD patients are unknown to date. In this study, we show that MRP1 expression is increased in the inflamed epithelium of patients with IBD, in particular in the intestinal crypts. We demonstrate that MRP1 protects intestinal epithelial cells against cytokine-induced cell death by exporting pro-apoptotic compounds from the cysteinyl leukotriene biosynthesis pathway. Patient Characteristics—Intestinal mucosal biopsy specimens were obtained during endoscopy following informed consent from patients with IBD. Diagnosis of IBD was established by endoscopic and histopathological examination. The Ethics Committee of the University Hospital Groningen approved the protocol (METc 2002/177c). Intestinal biopsies were obtained from macroscopically inflamed and noninflamed mucosa from 35 patients with IBD using a standard biopsy forceps. Intestinal specimens were immediately snap-frozen in liquid nitrogen for mRNA and protein analysis or liquid nitrogen-cooled isopentane for immunohistochemical staining and stored at -80 °C until further processing. Immunohistochemistry—Immunohistochemistry was performed with the mouse monoclonal antibody QCRL-3 against MRP1 on frozen sections according to the protocol described (dilution 1:10, Santa Cruz Biotechnology, Heidelberg, Germany) (20Vander B.S. Libbrecht L. Blokzijl H. Faber K.N. Moshage H. Aerts R. Van Steenbergen W. Jansen P.L. Desmet V.J. Roskams T.A. J. Pathol. 2005; 207: 471-482Crossref PubMed Scopus (71) Google Scholar). The sections were counterstained with hematoxylin. Negative controls consisted of omission of the primary antibody and were consistently negative. Cell Culture—The human colon carcinoma cell line DLD-1 was cultured as described previously (21Dijkstra G. Blokzijl H. Bok L. Homan M. van Goor H. Faber K.N. Jansen P.L. Moshage H. J. Pathol. 2004; 204: 296-303Crossref PubMed Scopus (57) Google Scholar). DLD-1 cells were treated with anti-Fas (Immunotech, Marseille, France) or human tumor necrosis factor-α (TNF-α) (R & D Systems Europe, Abingdon, UK). The LTD4 receptor antagonist MK571 (3-([[3-(2-[7-chloro-2-quinolinyl]ethenyl)-phenyl}-((3-(dimethylamino-3-oxopropyl)-thio)-methyl]thio)propanoic acid; Alexis Biochemicals, Lausen, Switzerland) was used to inhibit MRP function. The 5-lipoxygenase inhibitor AA861 (2-(12-hydroxydodeca-5,10-diynyl)-3,5,6-trimethyl-p-benzoquinone; Sigma) was used to inhibit leukotriene synthesis from arachidonic acid. siRNA-mediated Reduction of MRP1 Expression—DLD-1 cells were seeded in 6-well plates at a density of 400,000 cells per well in RPMI 1640 medium with glutamax supplemented with medium was by cells were with using according to the were obtained from and provided by D. J. University The cells were treated with after medium was supplemented with RPMI 1640 medium with to the to the cells were cultured in an at °C and for MRP1 RNA and protein expression was by and MRP1 Cell cells were seeded in 6-well plates at cells per The cells were with K. W. Deeley R.G. Cole S.P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was performed using the lipid protocol cells were to to the were and in medium were further by cell on the to cell RNA and RNA was as described Mol O. J. Geuken M. Faber K.N. Jansen P.L. M. 2002; PubMed Scopus Google Scholar). RNA was by and RNA was measured using a RNA The synthesis was performed on of RNA using in a of of was used for in a of and of and of and are described in was performed with an The expression of genes was to the endogenous cell of DLD-1 cells were by and by were using the protein system using as antibody against human (dilution Cell mouse monoclonal antibody (dilution and monoclonal antibody were used (dilution M. M. M. Wijnholds J. van A. M.C. J.H. Mol C.A. van der M. van der Valk P. Elferink Borst P. 2000; Google Scholar). and were used as The were exposed in a system The of the protein were using was according to the using a with The were performed using for obtained from the are expressed as were using and of was as of MRP1 in and Intestinal study the of inflammation on transporter expression in the intestinal we mucosal biopsies from and inflamed from patients with IBD. In an expression of and MDR1 was in biopsies from IBD patients with and with MRP1 mRNA levels were significantly increased in inflamed intestinal MDR1 expression was as described (11Blokzijl H. Vander B.S. Bok L.I. Libbrecht L. Geuken M. van den Heuvel F.A. Dijkstra G. Roskams T.A. Moshage H. Jansen P.L. Faber K.N. Inflamm. Bowel Dis. 2007; 13: 710-720Crossref PubMed Scopus (118) Google Scholar). The mRNA levels of were in and inflamed intestinal of IBD patients biopsies from patients and CD patients were expression was as a of inflammation in the biopsies in this of IBD patients, MRP1 expression was significantly increased in inflamed intestinal mucosa in both and CD and MDR1 expression was decreased in both IBD for MRP1 on biopsy with high inflammation showed a basolateral staining of intestinal epithelial cells as well as cells. MRP1 staining was in the epithelial cells the the epithelium showed staining In the from these patients for MRP1 of Inhibition of on and MRP1 levels may cell protection during gastrointestinal inflammatory Cell may be induced apoptosis in response to or as shown previously in the intestinal mucosa of IBD patients S. C. J. M. Fromm M. 2004; PubMed Scopus Google Scholar, M. M. K. T. H. M. T. S. J. Dis. 2002; PubMed Scopus Google Scholar, J. I. S. H. K. A. P. Gastroenterology. 1997; Full Text PDF PubMed Scopus Google Scholar). To study this putative function, we performed in using the human colon epithelial cell line human colon biopsies and DLD-1 cells show expression of MDR1 and including MRP1 DLD-1 cells a model for MRP1 and we of by MK571 DLD-1 cell during to anti-Fas or reported by H. S. M. A. K. H. 1998; 3: PubMed Scopus Google Scholar, S.J. Biol. 2000; PubMed Scopus Google Scholar, Cell Immunol. 2000; PubMed Scopus Google Scholar, A. J. Full Text Full Text PDF PubMed Scopus (69) Google Scholar), anti-Fas and apoptosis in DLD-1 cells in a with at and for and and of activated were detected after of or of anti-Fas MK571 strongly increased in both and cells and which was by a further in the of and The of or anti-Fas-induced apoptosis was on the of MK571 a of and anti-Fas-induced apoptosis at as as and MK571 to in DLD-1 cells. these results show that of MRP function strongly DLD-1 cells for or anti-Fas-induced of on and apoptosis of DLD-1 cells. and in DLD-1 cells treated for with or anti-Fas in the absence or of and of in DLD-1 cells treated for with or with anti-Fas with and MK571 and for are in DLD-1 cells treated with or anti-Fas in with of are expressed as Inhibition of MRP1 by RNA is a MRP and the expressed in DLD-1 cells may to a of To study the function of MRP1 in this we its expression by RNA DLD-1 cells were with and after MRP1 mRNA and protein and levels were significantly reduced to of cells. of the DLD-1 cells to anti-Fas to significantly increased levels These data show that specific of MRP1 DLD-1 cells to anti-Fas-induced apoptosis and that expressed in DLD-1 cells are to for the of MRP1 function. of MRP1 in DLD-1 we DLD-1 cell that MRP1 to this the resistance of these cells against and cell and MRP1 at its to the green fluorescent protein it has been shown that this protein its substrate S.P. K. D.W. Grant C.E. Deeley R.G. Google Scholar). and and increased MRP1 mRNA analysis a at the of the protein of MRP1 and In DLD-1 the endogenous MRP1 protein of was analysis to the of the a membrane staining in the which was detected in the DLD-1 cells of the MRP1 cell to anti-Fas or resulted in significantly and with the DLD-1 cells we observed an the expression and the of or apoptosis in these cells. These data that MRP1 is to cells from or Inhibition of the of arachidonic cysteinyl LTC4 is a high affinity substrate for MRP1 that is to the LTD4 after We MRP function results in the of a pro-apoptotic compound the of an The inhibitor AA861 was used to leukotriene synthesis from arachidonic acid. AA861 in DLD-1 cells of DLD-1 cells with anti-Fas and of however, results in a in is to the of pro-apoptotic arachidonic D. A. C. R. L. F. M. F. P. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U. S. A. 2000; 97: PubMed Scopus Google Scholar). is the that the in cells is significantly that in cells DLD-1 cells were with and of a in was observed the of AA861 in the cells was reduced to levels with DLD-1 cells These data that leukotriene synthesis by AA861 results in the of a compound in DLD-1 cells. AA861 the of an pro-apoptotic compound in DLD-1 which is a substrate for MRP1 a of LTC4 biosynthesis and and the and of the used in this In this study, we show that the transporter MRP1 is induced in inflamed intestinal epithelial cells of patients with IBD. of MRP function increased and apoptosis of DLD-1 cells. of MRP1 expression by RNA DLD-1 cells for anti-Fas-induced and apoptosis was reduced in DLD-1 cells MRP1 or when the of its high affinity was by of MRP1 is known for its to tumor cells by an of drugs that apoptosis or necrosis of these cells P. Evers R. M. Wijnholds J. Biochim. Biophys. Acta. 1999; 1461: PubMed Scopus Google Scholar). 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Acta. 2002; PubMed Scopus Google Scholar). apoptosis of and its and epithelial cells have been shown to be to these compounds M. S. 2003; Google Scholar). and as the line of we found that the biosynthesis of leads to a in or anti-Fas-induced apoptosis in DLD-1 cells with an MRP function. LTC4 is a high affinity substrate of we suggest that this is the pro-apoptotic compound during inflammatory D.W. Almquist K.C. Deeley R.G. Cole S.P. J. Biol. Chem. 1996; 271: 9675-9682Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar). and have also been shown to be to LTC4 with high affinity M. D. PubMed Scopus Google Scholar, M. J. D. J. Exp. PubMed Scopus Google Scholar), and both transporters are expressed in human intestinal and DLD-1 cells. a of MRP1 in DLD-1 cells leads to of these cells for anti-Fas-induced and/or for the of MRP1 these data show that MRP1 has an important role in protecting the intestinal epithelium during inflammation. data well with by M. K. T. J. Gastroenterol. 1995; PubMed Scopus Google observed that of LTC4 synthesis is associated with decreased intestinal damage induced by acid-induced colitis. In addition, Mrp1-/- mice have been shown to severe colitis after of dextran sulfate (19Ten Hove T. Drillenburg P. Wijnholds J. Te Velde A.A. Van Deventer S.J. Dig. Dis. Sci. 2002; 47: 2056-2063Crossref PubMed Scopus (38) Google Scholar, M. K. T. J. Gastroenterol. 1995; PubMed Scopus Google Scholar). role of MRP1 against inflammation-induced cell death may be to intestinal epithelial cells. we found that in of patients with severe cells high levels of MRP1 J.E. Libbrecht L. Geuken M. Jansen P.L. Roskams T.A. J. Pathol. 2003; PubMed Scopus Google Scholar). to the intestinal cells are in of during to in when they are exposed to toxic and MRP1 may be an important of during inflammation. In data show a function of which is protection of intestinal epithelial cells against inflammation-induced MRP1 expression is increased in intestinal epithelial in particular the which may to the intestinal We S. P. Cole for the of the and G. L. The for the mouse monoclonal antibody with