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.
Similar content being viewed by others
References
To the Article
JD Mountz (2002) ArticleTitleSignificance of increased circulating proteasomes in autoimmune disease J Rheumatol 29 2045–2052
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
To the Invited Editorial
D Nandi P Tahiliani A Kumar D Chandu (2005) ArticleTitleThe ubiquitin-proteasome system J Biosci 31 137–155
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
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
To the Authors Reply
JD Mountz (2002) ArticleTitleSignificance of increased circulating proteasomes in autoimmune disease J Rheumatol 29 2045–2052
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
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
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
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
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
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
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
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
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
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
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
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
Proteolix Inc. Website. Available at: http://www. proteolix.com. Accessed.
Acknowledgments
The authors thank Kang Li (histologic sample preparation), Kris Garver, and Leona Gilbert (histology photographs) for assistance.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by a grant from Philadelphia Health Care Trust, Philadelphia, Pennsylvania.
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10350-006-0796-7