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Enhanced Intestinal Expression of the Proteasome Subunit Low Molecular Mass Polypeptide 2 in Patients with Inflammatory Bowel Disease

  • Published:
Diseases of the Colon & Rectum

Purpose

Low molecular mass polypeptide 2 is an inducible immunoproteasome subunit. The expression of low molecular mass polypeptide 2 has not been examined in the intestine of patients with inflammatory bowel disease. This study was designed to determine whether the intestinal expression of low molecular mass polypeptide 2 was enhanced in a group of patients with inflammatory bowel disease compared with a group of control patients without inflammatory bowel disease. Moreover, we examined the association between low molecular mass polypeptide 2 expression and histologic pathology in these patients.

Methods

Twenty-one patients participated in the study. These included six control subjects without inflammatory bowel disease, eight patients with ulcerative colitis, and seven patients with Crohn’s disease. Intestinal low molecular mass polypeptide 2 expression was evaluated by immunohistochemistry, as well as by Western blot. Histology scores (0–40 severity scale) were determined on the same sections of intestine as those used for low molecular mass polypeptide 2 histochemistry.

Results

By immunohistochemistry, low molecular mass polypeptide 2 expression was significantly enhanced (P < 0.05 vs. control subjects) throughout visibly diseased areas of colon, rectum, and ileum from patients with inflammatory bowel disease. Low molecular mass polypeptide 2 expression also was increased in macroscopically normal intestine from patients with inflammatory bowel disease compared with normal tissue from control subjects. There was a significant correlation (P < 0.0001) between low molecular mass polypeptide 2 expression and histologic pathology in our patients. Western blot results confirmed that low molecular mass polypeptide 2 expression was enhanced in patients with ulcerative colitis (3.1-fold) and in patients with Crohn’s disease (3.5-fold).

Conclusions

Intestinal low molecular mass polypeptide 2 expression is significantly increased in inflammatory bowel disease. The association between intestinal low molecular mass polypeptide 2 expression and histologic pathology suggests that this proteasome subunit plays a role in the pathogenesis of inflammatory bowel disease.

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References

To the Article

  1. JD Mountz (2002) ArticleTitleSignificance of increased circulating proteasomes in autoimmune disease J Rheumatol 29 2045–2052

    Google Scholar 

  2. M Groettrup G Schmidtke (1999) ArticleTitleSelective proteasome inhibitors: modulators of antigen presentation Drug Discov Today 4 63–71 Occurrence Handle10234158 Occurrence Handle10.1016/S1359-6446(98)01292-6 Occurrence Handle1:CAS:528:DyaK1MXmtVGktLc%3D

    Article  PubMed  CAS  Google Scholar 

  3. M Groettrup S Khan K Schwartz (2002) ArticleTitleInterferon-γ inducible exchanges of 20S proteasome active site subunits: why? Biochimie 83 367–372 Occurrence Handle10.1016/S0300-9084(01)01251-2

    Article  Google Scholar 

  4. T Hayashi D Faustman (2000) ArticleTitleEssential role of human leukocyte antigen-encoded proteasome subunits in NF-κB activation and prevention of tumor necrosis factor-α induced apoptosis J Biol Chem 275 5238–5247 Occurrence Handle10671572 Occurrence Handle10.1074/jbc.275.7.5238 Occurrence Handle1:CAS:528:DC%2BD3cXhsVymtL8%3D

    Article  PubMed  CAS  Google Scholar 

  5. M Aki N Shimbara M Takashima et al. (1994) ArticleTitleInterferon-γ induces different subunit organizations and functional diversity of proteasomes J Biochem (Tokyo) 115 257–69 Occurrence Handle1:CAS:528:DyaK2cXhs1WgsbY%3D

    CAS  Google Scholar 

  6. R Stohwasser J Giesebrecht R Kraft et al. (2000) ArticleTitleBiochemical analysis of proteasomes from mouse microglia: induction of immunoproteasomes by interferon-γ and lipopolysaccharide Glia 29 355–365 Occurrence Handle10652445 Occurrence Handle10.1002/(SICI)1098-1136(20000215)29:4<355::AID-GLIA6>3.0.CO;2-4 Occurrence Handle1:STN:280:DC%2BD3c7hvFaiug%3D%3D

    Article  PubMed  CAS  Google Scholar 

  7. U Kuckelhorn T Ruppert B Strehl et al. (2002) ArticleTitleLink between organ-specific antigen processing by 20S proteasomes and CD8+ T cell-mediated autoimmunity J Exp Med 195 983–990 Occurrence Handle10.1084/jem.20011199 Occurrence Handle1:CAS:528:DC%2BD38XivFyksLs%3D

    Article  CAS  Google Scholar 

  8. LR Fitzpatrick V Khare WA Koltun (2004) ArticleTitleImmunoproteasome induction in a lymphocyte cell line and in mice with dextran sulfate sodium-induced colitis [abstract] Gastroenterology 126 A417

    Google Scholar 

  9. LR Fitzpatrick WA Koltun (2005) ArticleTitleDextran sulfate sodium (DSS)-induced colitis is attenuated in low molecular mass polypeptide 2 (LMP2) knockout mice [abstract] Gastroenterology 128 A199–A200

    Google Scholar 

  10. LR Fitzpatrick V Khare JS Small WA Koltun (2006) ArticleTitleDextran sulfate sodium-induced colitis is associated with enhanced low molecular mass polypeptide-2 (LMP2) expression and is attenuated in LMP2 knockout mice Dig Dis Sci 51 1269–1276 Occurrence Handle16944024 Occurrence Handle10.1007/s10620-006-8047-2 Occurrence Handle1:CAS:528:DC%2BD28XptVGgtLw%3D

    Article  PubMed  CAS  Google Scholar 

  11. S Heink D Ludwig PM Kloetzel E Kruger (2005) ArticleTitleIFN-γ induced immune adaptation of the proteasome system is an accelerated and transient response Proc Natl Acad Sci USA 102 9241–9246 Occurrence Handle15944226 Occurrence Handle10.1073/pnas.0501711102 Occurrence Handle1:CAS:528:DC%2BD2MXlvF2rsrw%3D

    Article  PubMed  CAS  Google Scholar 

  12. KL Williams CR Fuller LA Dieleman et al. (2001) ArticleTitleEnhanced survival and mucosal repair after dextran sodium sulfate-induced colitis in transgenic mice that overexpress growth hormone Gastroenterology 120 925–937 Occurrence Handle11231946 Occurrence Handle10.1053/gast.2001.22470 Occurrence Handle1:CAS:528:DC%2BD3MXitlertL4%3D

    Article  PubMed  CAS  Google Scholar 

  13. CF Krieglstein WH Cerwinka FS Laroux et al. (2001) ArticleTitleRole of appendix and spleen in experimental colitis J Surg Res 101 166–175 Occurrence Handle11735272 Occurrence Handle10.1006/jsre.2001.6223 Occurrence Handle1:STN:280:DC%2BD3Mnpt1aqtg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  14. S Barcelo-Batlori M Andre C Servis et al. (2002) ArticleTitleProteomic analysis of cytokine induced proteins in human intestinal epithelial cells: implications for inflammatory bowel diseases Proteomics 2 551–560 Occurrence Handle10.1002/1615-9861(200205)2:5<551::AID-PROT551>3.0.CO;2-O

    Article  Google Scholar 

  15. D Atkins A Breuckmann GE Schmahl et al. (2004) ArticleTitleMHC class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma Int J Cancer 109 265–273 Occurrence Handle14750179 Occurrence Handle10.1002/ijc.11681 Occurrence Handle1:CAS:528:DC%2BD2cXhvVCksrc%3D

    Article  PubMed  CAS  Google Scholar 

  16. T Kamikubo T Hayashi (1996) ArticleTitleChanges in proteasome activity following transient ischemia Neurochem Int 28 209–212 Occurrence Handle8719710 Occurrence Handle10.1016/0197-0186(95)00071-2 Occurrence Handle1:CAS:528:DyaK28XislegtA%3D%3D

    Article  PubMed  CAS  Google Scholar 

  17. SR Powell P Wang H Katzeff et al. (2005) ArticleTitleOxidized and ubiquinated proteins may predict recovery of postischemic cardiac function: essential role of the proteasome Antioxid Redox Signal 7 538–546 Occurrence Handle15889999 Occurrence Handle10.1089/ars.2005.7.538 Occurrence Handle1:CAS:528:DC%2BD2MXktVWisLY%3D

    Article  PubMed  CAS  Google Scholar 

  18. K Yoshihara T Yajima C Kubo Y Yoshikai (2005) ArticleTitleThe role of interleukin-15 in colitis induced by dextran sulphate sodium in mice Gut 55 334–341 Occurrence Handle16162679 Occurrence Handle10.1136/gut.2005.076000 Occurrence Handle1:CAS:528:DC%2BD28Xis1Sjsb4%3D

    Article  PubMed  CAS  Google Scholar 

  19. M Murano K Maemura I Hirata et al. (2000) ArticleTitleTherapeutic effect of intracolonically administered nuclear factor κB (p65) antisense oligonucleotide on mouse dextran sulphate sodium (DSS)-induced colitis Clin Exp Immunol 120 51–58 Occurrence Handle10759763 Occurrence Handle10.1046/j.1365-2249.2000.01183.x Occurrence Handle1:CAS:528:DC%2BD3cXisl2mt78%3D

    Article  PubMed  CAS  Google Scholar 

  20. AK Spiik A Ridderstad LG Axelsson T Midtvedt L Bkork S Pattersen (2002) ArticleTitleAbrogated lymphocyte infiltration and lowered CD14 in dextran sulfate induced colitis in mice treated with p65 oligonucleotides Int J Colorectal Dis 17 223–232 Occurrence Handle12073070 Occurrence Handle10.1007/s00384-001-0366-3

    Article  PubMed  Google Scholar 

To the Invited Editorial

  1. D Nandi P Tahiliani A Kumar D Chandu (2005) ArticleTitleThe ubiquitin-proteasome system J Biosci 31 137–155

    Google Scholar 

  2. S Barceló-Batlori M André C Servis et al. (2002) ArticleTitleProteomic analysis of cytokine induced proteins in human intestinal epithelial cells: implications for inflammatory bowel diseases Proteomics 2 551–560 Occurrence Handle10.1002/1615-9861(200205)2:5<551::AID-PROT551>3.0.CO;2-O

    Article  Google Scholar 

  3. LR Fitzpatrick V Khare JS Small WA Koltun (2006) ArticleTitleDextran sulfate sodium-induced colitis is associated with enhanced low molecular mass polypeptide-2 (LMP2) expression and is attenuated in LMP2 knockout mice Dig Dis Sci 51 1269–1276 Occurrence Handle16944024 Occurrence Handle10.1007/s10620-006-8047-2 Occurrence Handle1:CAS:528:DC%2BD28XptVGgtLw%3D

    Article  PubMed  CAS  Google Scholar 

To the Authors Reply

  1. JD Mountz (2002) ArticleTitleSignificance of increased circulating proteasomes in autoimmune disease J Rheumatol 29 2045–2052

    Google Scholar 

  2. M Groettrup G Schmidtke (1999) ArticleTitleSelective proteasome inhibitors: modulators of antigen presentation Drug Discov Today 4 63–71 Occurrence Handle10234158 Occurrence Handle10.1016/S1359-6446(98)01292-6 Occurrence Handle1:CAS:528:DyaK1MXmtVGktLc%3D

    Article  PubMed  CAS  Google Scholar 

  3. M Groettrup S Khan K Schwartz (2002) ArticleTitleInterferon-γ inducible exchanges of 20S proteasome active site subunits: why? Biochimie 83 367–372 Occurrence Handle10.1016/S0300-9084(01)01251-2

    Article  Google Scholar 

  4. T Hayashi D Faustman (2000) ArticleTitleEssential role of human leukocyte antigen-encoded proteasome subunits in NF-κB activation and prevention of tumor necrosis factor-α induced apoptosis J Biol Chem 275 5238–47 Occurrence Handle10671572 Occurrence Handle10.1074/jbc.275.7.5238 Occurrence Handle1:CAS:528:DC%2BD3cXhsVymtL8%3D

    Article  PubMed  CAS  Google Scholar 

  5. S Barcelo-Batlori M Andre C Servis et al. (2002) ArticleTitleProteomic analysis of cytokine induced proteins in human intestinal epithelial cells: implications for inflammatory bowel diseases Proteomics 2 551–560 Occurrence Handle10.1002/1615-9861(200205)2:5<551::AID-PROT551>3.0.CO;2-O

    Article  Google Scholar 

  6. J Leblond A Hubert-Buron C Bole-Feysot P Ducrotte P Dechelotte M Coeffier (2006) ArticleTitleRegulation of proteolysis by cytokines in the human intestinal epithelial cell line HCT-8: role of IFN-γ Biochimie 88 759–765 Occurrence Handle16488064 Occurrence Handle10.1016/j.biochi.2006.01.003 Occurrence Handle1:CAS:528:DC%2BD28Xns12lu70%3D

    Article  PubMed  CAS  Google Scholar 

  7. LR Fitzpatrick V Khare JS Small WA Koltun (2006) ArticleTitleDextran sulfate sodium-induced colitis is associated with enhanced low molecular mass polypeptide-2 (LMP2) expression and is attenuated in LMP2 knockout mice Dig Dis Sci 51 1269–1276 Occurrence Handle16944024 Occurrence Handle10.1007/s10620-006-8047-2 Occurrence Handle1:CAS:528:DC%2BD28XptVGgtLw%3D

    Article  PubMed  CAS  Google Scholar 

  8. AJ Schotellius AS Baldwin (1999) ArticleTitleA role for transcription factor NF-κB in intestinal inflammation Int J Colorectal Dis 14 18–28 Occurrence Handle10.1007/s003840050178

    Article  Google Scholar 

  9. C Jobin RB Sartor (2000) ArticleTitleNF-κB signaling proteins as therapeutic targets for inflammatory bowel diseases Inflamm Bowel Dis 6 206–213 Occurrence Handle10961593 Occurrence Handle1:STN:280:DC%2BD3M%2Fmt1Gqsg%3D%3D Occurrence Handle10.1002/ibd.3780060308

    Article  PubMed  CAS  Google Scholar 

  10. S Nancey S Holvoet I Graber et al. (2006) ArticleTitleCD8+ cytotoxic T cells induce relapsing colitis in normal mice Gastroenterology 131 485–496 Occurrence Handle16890603 Occurrence Handle10.1053/j.gastro.2006.05.018 Occurrence Handle1:CAS:528:DC%2BD28XpsFyksLs%3D

    Article  PubMed  CAS  Google Scholar 

  11. AM Westendorf D Fleissner S Deppenmeier et al. (2006) ArticleTitleAutoimmune-mediated intestinal inflammation-impact and regulation of antigen-specific CD8+ T cells Gastroenterology 131 510–524 Occurrence Handle16890605 Occurrence Handle10.1053/j.gastro.2006.05.015 Occurrence Handle1:CAS:528:DC%2BD28XpsFyksb4%3D

    Article  PubMed  CAS  Google Scholar 

  12. H Cheroutre (2006) ArticleTitleIn IBD eight can come before four Gastroenterology 131 667–669 Occurrence Handle16890619 Occurrence Handle10.1053/j.gastro.2006.06.041 Occurrence Handle1:CAS:528:DC%2BD28XpsFykt7s%3D

    Article  PubMed  CAS  Google Scholar 

  13. CG Escheveria (2002) ArticleTitleRecent advances in the identification and development of 20S proteasome inhibitors Mini Rev Med Chem 2 247–259 Occurrence Handle10.2174/1389557023406142

    Article  Google Scholar 

  14. Proteolix Inc. Website. Available at: http://www. proteolix.com. Accessed.

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Acknowledgments

The authors thank Kang Li (histologic sample preparation), Kris Garver, and Leona Gilbert (histology photographs) for assistance.

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Correspondence to Leo R. Fitzpatrick Ph.D..

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Supported by a grant from Philadelphia Health Care Trust, Philadelphia, Pennsylvania.

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Fitzpatrick, L.R., Small, J.S., Poritz, L.S. et al. Enhanced Intestinal Expression of the Proteasome Subunit Low Molecular Mass Polypeptide 2 in Patients with Inflammatory Bowel Disease. Dis Colon Rectum 50, 337–350 (2007). https://doi.org/10.1007/s10350-006-0796-7

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  • DOI: https://doi.org/10.1007/s10350-006-0796-7

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