Skip to main content

Advertisement

SpringerLink
Log in

Ulcerative colitis: immune function, tissue fibrosis and current therapeutic considerations

  • Review Article
  • Published:
Langenbeck's Archives of Surgery Aims and scope Submit manuscript

Abstract

Background

Ulcerative colitis (UC) is a complex disease in which the interaction of genetic, environmental and microbial factors drives chronic intestinal inflammation that finally leads to extensive tissue fibrosis.

Discussion

The present review discusses the current knowledge on genetic susceptibility, especially of the IL-12/IL-23 pathway, the pathophysiologic role of the involved cytokines (e.g. IL-13, IL-23, TGFβ1) and immune cells (e.g. T cells, epithelial cells, fibroblasts) in UC followed by an overview on actual therapeutic considerations. These future therapies will target selectively the involved cell types by blocking their activation and its downstream signalling, by inhibiting their migration to the inflamed site and by anti-cytokine strategies. This may avoid–when initiated in time–the perpetuation of the inflammatory mechanisms thus preventing fibrosis. With respect to animal models that have guided the most productive efforts for understanding human inflammatory bowel disease, these will be shortly discussed in the respective context.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Loftus EV Jr (2004) Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 126:1504–1517

    Article  PubMed  Google Scholar 

  2. Maul J, Duchmann R (2008) Can loss of immune tolerance cause IBD? Inflamm Bowel Dis 14:S115–S116

    Article  PubMed  Google Scholar 

  3. Ardizzone S, Puttini PS, Cassinotti A, Porro GB (2008) Extraintestinal manifestations of inflammatory bowel disease. Dig Liver Dis 40:S253–S259

    Article  PubMed  Google Scholar 

  4. Duchmann R, Maul J, Heller F, Zeitz M (2003) Basic mechanisms of inflammation in ulcerative colitis. Dig Surg 20:347–349

    Google Scholar 

  5. Fichtner-Feigl S, Strober W, Geissler EK, Schlitt H (2008) Cytokines mediating the induction of chronic colitis and colitis-associated fibrosis. Mucosal Immunol 1:S24–S27

    Article  PubMed  CAS  Google Scholar 

  6. Cho JH (2008) The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol 8:458–466

    Article  PubMed  CAS  Google Scholar 

  7. Strober W, Fuss IJ, Blumberg RS (2002) The immunology of mucosal models of inflammation. Annu Rev Immunol 20:495–549

    Article  PubMed  CAS  Google Scholar 

  8. Caprilli R, Lapaquette P, Darfeuille-Michaud A (2010) Eating the enemy in Crohn's disease: an old theory revisited. J Crohn Colitis 4:377–383

    Article  Google Scholar 

  9. Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, Matsunami N, Ardlie KG, Civello D, Catanese JJ, Leong DU, Panko JM, McAllister LB, Hansen CB, Papenfuss J, Prescott SM, White TJ, Leppert MF, Krueger GG, Begovich AB (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80:273–290

    Article  PubMed  CAS  Google Scholar 

  10. Burtton P, Clayton D, Cardon L (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39:1329–1337

    Article  CAS  Google Scholar 

  11. Yu W, Lin Z, Pastor DM, Hegarty JP, Chen X, Kelly AA, Wang Y, Poritz LS, Koltun WA (2010) Genes regulated by Nkx2-3 in sporadic and inflammatory bowel disease-associated colorectal cancer cell lines. Dig Dis Sci 55:3171–3180

    Article  PubMed  CAS  Google Scholar 

  12. Goyette P, Lefebvre C, Ng A, Brant SR, Cho JH, Duerr RH, Silverberg MS, Taylor KD, Latiano A, Aumais G, Deslandres C, Jobin G, Annese V, Daly MJ, Xavier RJ, Rioux JD (2008) Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal Immunol 1:131–138

    Article  PubMed  CAS  Google Scholar 

  13. Long SA, Cerosaletti K, Wan JY, Ho J, Tatum M, Wei S, Shilling HG, Buckner JH (2011) An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4+ T cells. Genes Immun 12:116–125

    Article  PubMed  CAS  Google Scholar 

  14. Bekker-Jensen S, Danielsen JR, Fugger K, Gromova I, Nerstedt A, Lukas C, Bartek J, Lukas J, Mailand N (2010) HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes. Nat Cell Biol 12:80–86

    Article  PubMed  CAS  Google Scholar 

  15. Chan I, Liu L, Hamada T, Sethuraman G, McGrath JA (2007) The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1. Exp Dermatol 16:881–890

    Article  PubMed  CAS  Google Scholar 

  16. Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, Doi T, Shimotohno K, Harada T, Nishida E, Hayashi H, Sugano S (2003) Large-scale identification and characterization of human genes that activate NF-[kappa]B and MAPK signaling pathways. Oncogene 22:3307–3318

    Article  PubMed  CAS  Google Scholar 

  17. Franke A, Balschun T, Karlsen TH, Hedderich J, May S, Lu T, Schuldt D, Nikolaus S, Rosenstiel P, Krawczak M, Schreiber S (2008) Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet 40:713–715

    Article  PubMed  CAS  Google Scholar 

  18. Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C, Barrett JC, Cummings FR, Drummond H, Lees CW, Onnie CM, Hanson CE, Blaszczyk K, Inouye M, Ewels P, Ravindrarajah R, Keniry A, Hunt S, Carter M, Watkins N, Ouwehand W, Lewis CM, Cardon L, Lobo A, Forbes A, Sanderson J, Jewell DP, Mansfield JC, Deloukas P, Mathew CG, Parkes M, Satsangi J (2008) Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet 40:710–712

    Article  PubMed  CAS  Google Scholar 

  19. Brand S (2009) Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut 58:1152–1167

    Article  PubMed  CAS  Google Scholar 

  20. Deusch K, Mauthe B, Reiter C, Riethmüller G, Classen M (1993) CD4-antibody treatment of inflammatory bowel disease: one year follow-up. Gastroenterology 104:A691

    Google Scholar 

  21. Emmrich J, Seyfarth M, Fleig WE, Emmrich F (1991) Treatment of inflammatory bowel disease with anti-CD4 monoclonal antibody. Lancet 338:570–571

    Article  PubMed  CAS  Google Scholar 

  22. Kozuch PL, Hanauer SB (2006) General principles and pharmacology of biologics in inflammatory bowel disease. Gastroenterol Clin North Am 35:757–773

    Article  PubMed  Google Scholar 

  23. Plevy S, Salzberg B, Van Assche G, Regueiro M, Hommes D, Sandborn W, Hanauer S, Targan S, Mayer L, Mahadevan U, Frankel M, Lowder J (2007) A phase I study of visilizumab, a humanized anti-CD3 monoclonal antibody, in severe steroid-refractory ulcerative colitis. Gastroenterology 133:1414–1422

    Article  PubMed  CAS  Google Scholar 

  24. Baumgart DC, Targan SR, Dignass AU, Mayer L, Assche GV, Hommes DW, Hanauer SB, Mahadevan U, Reinisch W, Plevy SE, Salzberg BA, Buchman AL, Mechkov GM, Krastev ZA, Lowder JN, Frankel MB, Sandborn WJ (2010) Prospective randomized open-label multicenter phase I/II dose escalation trial of visilizumab (HuM291) in severe steroid-refractory ulcerative colitis. Inflamm Bowel Dis 16:620–629

    PubMed  Google Scholar 

  25. Sandborn W, Colombel J, Frankel MB, Hommes D, Lowder J, Mayer L, Plevy SE, Stokkers P, Travis S, Van Assche GA, Targan S (2009) A placebo-controlled trial of visilizumab in patients with intravenous (IV) steroid refractory ulcerative colitis (UC). Gastroenterology 136:A64

    Google Scholar 

  26. Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DG, Baerg RD, Tremaine WJ, Johnson T, Diehl NN, Zinsmeister AR (2001) Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 121:1088–1094

    Article  PubMed  CAS  Google Scholar 

  27. Rutgeerts P, Lemmens L, Van Assche G, Noman M, Borghini-Fuhrer I, Goedkoop R (2003) Treatment of active Crohn's disease with onercept (recombinant human soluble p55 tumour necrosis factor receptor): results of a randomized, open-label, pilot study. Aliment Pharmacol Ther 17:185–192

    Article  PubMed  CAS  Google Scholar 

  28. Travis S, Yap LM, Hawkey C, Warren B, Lazarov M, Fong T, Tesi RJ (2005) RDP58 is a novel and potentially effective oral therapy for ulcerative colitis. Inflamm Bowel Dis 11:713–719

    Article  PubMed  Google Scholar 

  29. Lofberg R, Neurath M, Ost A, Pettersson S (2002) Topical NFkB antisense oligonucleotides in patients with active distal colonic IBD. A randomised controlled pilot trial. Gastroenterology 122:A60

    Article  Google Scholar 

  30. Danese S, Angelucci E, Malesci A, Caprilli R (2008) Biological agents for ulcerative colitis: hypes and hopes. Med Res Rev 28:201–218

    Article  PubMed  CAS  Google Scholar 

  31. Van Assche G, Sandborn WJ, Feagan BG, Salzberg BA, Silvers D, Monroe PS, Pandak WM, Anderson FH, Valentine JF, Wild GE, Geenen DJ, Sprague R, Targan SR, Rutgeerts P, Vexler V, Young D, Shames RS (2006) Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial. Gut 55:1568–1574

    Article  PubMed  CAS  Google Scholar 

  32. Creed TJ, Probert CSJ, Norman MN, Moorghen M, Shepherd NA, Hearing SD, Dayan CM, THE BASBUC INVESTIGATORS1 (2006) Basiliximab for the treatment of steroid-resistant ulcerative colitis: further experience in moderate and severe disease. Aliment Pharmacol Ther 23:1435–1442

    Article  PubMed  CAS  Google Scholar 

  33. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, Vyhnálek P, Zádorová Z, Palmer T, Donoghue S (2003) Natalizumab for active Crohn's disease. N Engl J Med 348:24–32

    Article  PubMed  CAS  Google Scholar 

  34. Gordon FH, Hamilton MI, Donoghue S, Greenlees C, Palmer T, Rowley-Jones D, Dhillon AP, Amlot PL, Pounder RE (2002) A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin. Aliment Pharmacol Ther 16:699–705

    Article  PubMed  CAS  Google Scholar 

  35. Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JWD, Dubé R, Cohen A, Steinhart AH, Landau S, Aguzzi RA, Fox IH, Vandervoort MK (2005) Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med 352:2499–2507

    Article  PubMed  CAS  Google Scholar 

  36. Van Deventer SJH, Wedel MK, Baker BF, Xia S, Chuang E, Miner PB (2006) A phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis. Aliment Pharmacol Ther 23:1415–1425

    Article  PubMed  CAS  Google Scholar 

  37. Suzuki K, Kawauchi Y, Palaniyandi SS, Veeraveedu PT, Fujii M, Yamagiwa S, Yoneyama H, Han GD, Kawachi H, Okada Y, Ajioka Y, Watanabe K, Hosono M, Asakura H, Aoyagi Y, Narumi S (2007) Blockade of interferon-gamma-inducible protein-10 attenuates chronic experimental colitis by blocking cellular trafficking and protecting intestinal epithelial cells. Pathol Int 57:413–420

    Article  PubMed  CAS  Google Scholar 

  38. Bendelac A, Savage PB, Teyton L (2007) The biology of NKT cells. Annu Rev Immunol 25:297–336

    Article  PubMed  CAS  Google Scholar 

  39. Brigl M, Brenner MB (2004) CD1: antigen presentation and T cell function. Annu Rev Immunol 22:817–890

    Article  PubMed  CAS  Google Scholar 

  40. Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W (2004) Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 113:1490–1497

    PubMed  CAS  Google Scholar 

  41. van Dieren JM, van der Woude CJ, Kuipers EJ, Escher JC, Samsom JN, Blumberg RS, Nieuwenhuis EES (2007) Roles of CD1d-restricted NKT cells in the intestine. Inflamm Bowel Dis 13:1146–1152

    Article  PubMed  Google Scholar 

  42. Omata F, Birkenbach M, Matsuzaki S, Christ AD, Blumberg RS (2001) The expression of IL-12 p40 and its homologue, Epstein-Barr virus-induced gene 3, in inflammatory bowel disease. Inflamm Bowel Dis 7:215–220

    Article  PubMed  CAS  Google Scholar 

  43. Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17:629–638

    Article  PubMed  CAS  Google Scholar 

  44. Gauvreau GM, Boulet L, Cockcroft DW, FitzGerald JM, Carlsten C, Davis BE, Deschesnes F, Duong M, Durn BL, Howie KJ, Hui L, Kasaian MT, Killian KJ, Strinich TX, Watson RM, Y N, Zhou S, Raible D, O'Byrne PM (2011) The effects of IL-13 blockade on allergen-induced airway responses in mild atopic asthma. Am J Respir Crit Care Med (in press)

  45. Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA (2001) CD4+CD25 high regulatory cells in human peripheral blood. J Immunol 167:1245–1253

    PubMed  CAS  Google Scholar 

  46. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G (2001) Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 193:1303–1310

    Article  PubMed  CAS  Google Scholar 

  47. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH (2001) Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 193:1285–1294

    Article  PubMed  CAS  Google Scholar 

  48. Maul J, Loddenkemper C, Mundt P, Berg E, Giese T, Stallmach A, Zeitz M, Duchmann R (2005) Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology 128:1868–1878

    Article  PubMed  CAS  Google Scholar 

  49. Epple H, Loddenkemper C, Kunkel D, Tröger H, Maul J, Moos V, Berg E, Ullrich R, Schulzke J, Stein H, Duchmann R, Zeitz M, Schneider T (2006) Mucosal but not peripheral FOXP3+ regulatory T cells are highly increased in untreated HIV infection and normalize after suppressive HAART. Blood 108:3072–3078

    Article  PubMed  CAS  Google Scholar 

  50. Yu QT, Saruta M, Avanesyan A, Fleshner PR, Banham AH, Papadakis KA (2007) Expression and functional characterization of FOXP3+ CD4+ regulatory T cells in ulcerative colitis. Inflamm Bowel Dis 13:191–199

    Article  PubMed  Google Scholar 

  51. Makita S, Kanai T, Oshima S, Uraushihara K, Totsuka T, Sawada T, Nakamura T, Koganei K, Fukushima T, Watanabe M (2004) CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol 173:3119–3130

    PubMed  CAS  Google Scholar 

  52. Rieger K, Loddenkemper C, Maul J, Fietz T, Wolff D, Terpe H, Steiner B, Berg E, Miehlke S, Bornhäuser M, Schneider T, Zeitz M, Stein H, Thiel E, Duchmann R, Uharek L (2006) Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD. Blood 107:1717–1723

    Article  PubMed  CAS  Google Scholar 

  53. Zhang X, Izikson L, Liu L, Weiner HL (2001) Activation of CD25(+)CD4(+) regulatory T cells by oral antigen administration. J Immunol 167:4245–4253

    PubMed  CAS  Google Scholar 

  54. Gad M, Brimnes J, Claesson MH (2003) CD4+ T regulatory cells from the colonic lamina propria of normal mice inhibit proliferation of enterobacteria-reactive, disease-inducing Th1-cells from scid mice with colitis. Clin Exp Immunol 131:34–40

    Article  PubMed  CAS  Google Scholar 

  55. Read S, Malmström V, Powrie F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192:295–302

    Article  PubMed  CAS  Google Scholar 

  56. Mottet C, Uhlig HH, Powrie F (2003) Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 170:3939–3943

    PubMed  CAS  Google Scholar 

  57. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  PubMed  CAS  Google Scholar 

  58. Bluestone JA, Abbas AK (2003) Natural versus adaptive regulatory T cells. Nat Rev Immunol 3:253–257

    Article  PubMed  CAS  Google Scholar 

  59. Hori S (2010) Developmental plasticity of Foxp3+ regulatory T cells. Curr Opin Immunol 22:575–582

    Article  PubMed  CAS  Google Scholar 

  60. Saruta M, Yu QT, Fleshner PR, Mantel P, Schmidt-Weber CB, Banham AH, Papadakis KA (2007) Characterization of FOXP3+CD4+ regulatory T cells in Crohn's disease. Clin Immunol 125:281–290

    Article  PubMed  CAS  Google Scholar 

  61. Takahashi M, Nakamura K, Honda K, Kitamura Y, Mizutani T, Araki Y, Kabemura T, Chijiiwa Y, Harada N, Nawata H (2006) An inverse correlation of human peripheral blood regulatory T cell frequency with the disease activity of ulcerative colitis. Dig Dis Sci 51:677–686

    Article  PubMed  Google Scholar 

  62. Holmén N, Lundgren A, Lundin S, Bergin A, Rudin A, Sjövall H, Ohman L (2006) Functional CD4+CD25high regulatory T cells are enriched in the colonic mucosa of patients with active ulcerative colitis and increase with disease activity. Inflamm Bowel Dis 12:447–456

    Article  PubMed  Google Scholar 

  63. Sumida Y, Nakamura K, Kanayama K, Akiho H, Teshima T, Takayanagi R (2008) Preparation of functionally preserved CD4+ CD25high regulatory T cells from leukapheresis products from ulcerative colitis patients, applicable to regulatory T-cell transfer therapy. Cytotherapy 10:698–710

    Article  PubMed  CAS  Google Scholar 

  64. Buruiana FE, Solà I, Alonso-Coello P (2010) Recombinant human interleukin 10 for induction of remission in Crohn's disease. In: Alonso-Coello P (ed) Cochrane Database of Systematic Reviews, The Cochrane Collaboration. Wiley, Chichester, UK

    Google Scholar 

  65. Schreiber S, Fedorak RN, Wild G, Gangl A, Targan SR, Jacyna M, Wright JP, Kilian A, Cohard M, LeBeaut A, Tremaine W (1998) Ulcerative Colitis IL-10 Cooperative Study Group. Safety and tolerance of rHuIL-10 treatment in patients with mild/moderate active ulcerative colitis. Gastroenterology 114:A1080–A1081

    Google Scholar 

  66. Steidler L, Rottiers P, Coulie B (2009) Actobiotics™ as a novel method for cytokine delivery. Ann N Y Acad Sci 1182:135–145

    Article  PubMed  CAS  Google Scholar 

  67. Gregori S, Roncarolo MG, Bacchetta R (2011) Methods for in vitro generation of human type 1 regulatory T cells. Methods Mol Biol 677:31–46

    Article  PubMed  CAS  Google Scholar 

  68. Desreumaux P, Beaugerie L, Bouhnik Y, Nachury M, Hebuterne X, Foussat A, Clerget-Chossat N, Forte M, Lemann M (2010) Crohn's disease and autologous type 1 regulatory T (Tr1) lmyphocytes (CATS1) cellular therapy open label phase I study. Gut 59:A73

    Google Scholar 

  69. Iwakura Y, Ishigame H (2006) The IL-23/IL-17 axis in inflammation. J Clin Invest 116:1218–1222

    Article  PubMed  CAS  Google Scholar 

  70. Wiekowski MT, Leach MW, Evans EW, Sullivan L, Chen S, Vassileva G, Bazan JF, Gorman DM, Kastelein RA, Narula S, Lira SA (2001) Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death. J Immunol 166:7563–7570

    PubMed  CAS  Google Scholar 

  71. Becker C, Dornhoff H, Neufert C, Fantini MC, Wirtz S, Huebner S, Nikolaev A, Lehr H, Murphy AJ, Valenzuela DM, Yancopoulos GD, Galle PR, Karow M, Neurath MF (2006) Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J Immunol 177:2760–2764

    PubMed  CAS  Google Scholar 

  72. Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M, Lehr H, Hirth S, Weigmann B, Wirtz S, Ouyang W, Neurath MF, Becker C (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206:1465–1472

    Article  PubMed  CAS  Google Scholar 

  73. Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, Johanns J, Blank M, Rutgeerts P (2008) A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology 135:1130–1141

    Article  PubMed  CAS  Google Scholar 

  74. West K (2009) CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr Opin Investig Drugs 10:491–504

    PubMed  CAS  Google Scholar 

  75. Debril M, Renaud J, Fajas L, Auwerx J (2001) The pleiotropic functions of peroxisome proliferator-activated receptor gamma. J Mol Med 79:30–47

    Article  PubMed  CAS  Google Scholar 

  76. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358:771–774

    Article  PubMed  CAS  Google Scholar 

  77. Jackson SM, Parhami F, Xi X, Berliner JA, Hsueh WA, Law RE, Demer LL (1999) Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. Arterioscler Thromb Vasc Biol 19:2094–2104

    Article  PubMed  CAS  Google Scholar 

  78. Yang XY, Wang LH, Chen T, Hodge DR, Resau JH, DaSilva L, Farrar WL (2000) Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor γ (PPARγ) agonists. J Biol Chem 275:4541–4544

    Article  PubMed  CAS  Google Scholar 

  79. Dubuquoy L, Rousseaux C, Thuru X, Peyrin-Biroulet L, Romano O, Chavatte P, Chamaillard M, Desreumaux P (2006) PPARγ as a new therapeutic target in inflammatory bowel diseases. Gut 55:1341–1349

    Article  PubMed  CAS  Google Scholar 

  80. Lefebvre M, Paulweber B, Fajas L, Woods J, McCrary C, Colombel J, Najib J, Fruchart J, Datz C, Vidal H, Desreumaux P, Auwerx J (1999) Peroxisome proliferator-activated receptor gamma is induced during differentiation of colon epithelium cells. J Endocrinol 162:331–340

    Article  PubMed  CAS  Google Scholar 

  81. Dubuquoy L, Jansson EÅ, Deeb S, Rakotobe S, Karoui M, Colombel J, Auwerx J, Pettersson S, Desreumaux P (2003) Impaired expression of peroxisome proliferator-activated receptor [gamma] in ulcerative colitis. Gastroenterology 124:1265–1276

    Article  PubMed  CAS  Google Scholar 

  82. Saubermann LJ, Nakajima A, Wada K, Zhao S, Terauchi Y, Kadowaki T, Aburatani H, Matsuhashi N, Nagai R, Blumberg RS (2002) Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2 cytokine response and prevent acute colitis. Inflamm Bowel Dis 8:330–339

    Article  PubMed  Google Scholar 

  83. Su CG, Wen X, Bailey ST, Jiang W, Rangwala SM, Keilbaugh SA, Flanigan A, Murthy S, Lazar MA, Wu GD (1999) A novel therapy for colitis utilizing PPAR-γ ligands to inhibit the epithelial inflammatory response. J Clin Invest 104:383–389

    Article  PubMed  CAS  Google Scholar 

  84. Takagi T, Naito Y, Tomatsuri N, Handa O, Ichikawa H, Yoshida N, Yoshikawa T (2002) Pioglitazone, a PPAR-gamma ligand, provides protection from dextran sulfate sodium-induced colitis in mice in association with inhibition of the NF-kappaB-cytokine cascade. Redox Rep 7:283–289

    Article  PubMed  CAS  Google Scholar 

  85. Lewis JD, Lichtenstein GR, Deren JJ, Sands BE, Hanauer SB, Katz JA, Lashner B, Present DH, Chuai S, Ellenberg JH, Nessel L, Wu GD (2008) Rosiglitazone for active ulcerative colitis. Gastroenterology 134:688–695

    Article  PubMed  CAS  Google Scholar 

  86. Nissen SE, Wolski K (2010) Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Arch Intern Med 170:1191–1201

    Article  PubMed  CAS  Google Scholar 

  87. Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, Kelman JA (2010) Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 304:411–418

    Article  PubMed  CAS  Google Scholar 

  88. Rousseaux C, Lefebvre B, Dubuquoy L, Lefebvre P, Romano O, Auwerx J, Metzger D, Wahli W, Desvergne B, Naccari GC, Chavatte P, Farce A, Bulois P, Cortot A, Colombel JF, Desreumaux P (2005) Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator–activated receptor-γ. J Exp Med 201:1205–1215

    Article  PubMed  CAS  Google Scholar 

  89. Seibold F, Brandwein S, Simpson S, Terhorst C, Elson CO (1998) pANCA represents a cross-reactivity to enteric bacterial antigens. J Clin Immunol 18:153–160

    Article  PubMed  CAS  Google Scholar 

  90. Shih DQ, Targan SR (2008) Immunopathogenesis of inflammatory bowel disease. World J Gastroenterol 14:390–400

    Article  PubMed  CAS  Google Scholar 

  91. Targan SR, Karp LC (2005) Defects in mucosal immunity leading to ulcerative colitis. Immunol Rev 206:296–305

    Article  PubMed  CAS  Google Scholar 

  92. Mizoguchi E, Mizoguchi A, Chiba C, Niles JL, Bhan AK (1997) Antineutrophil cytoplasmic antibodies in T-cell receptor alpha-deficient mice with chronic colitis. Gastroenterology 113:1828–1835

    Article  PubMed  CAS  Google Scholar 

  93. Mizoguchi A, Mizoguchi E, Chiba C, Bhan AK (1996) Role of appendix in the development of inflammatory bowel disease in TCR-alpha mutant mice. J Exp Med 184:707–715

    Article  PubMed  CAS  Google Scholar 

  94. Rieder F, Fiocchi C (2009) Intestinal fibrosis in IBD - a dynamic, multifactorial process. Nat Rev Gastroenterol Hepatol 6:228–235

    Article  PubMed  CAS  Google Scholar 

  95. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A (2006) IL-13 signaling through the IL-13[alpha]2 receptor is involved in induction of TGF-[beta]1 production and fibrosis. Nat Med 12:99–106

    Article  PubMed  CAS  Google Scholar 

  96. Fichtner-Feigl S, Young CA, Kitani A, Geissler EK, Schlitt H, Strober W (2008) IL-13 signaling via IL-13R[alpha]2 induces major downstream fibrogenic factors mediating fibrosis in chronic TNBS colitis. Gastroenterology 135:2003–2013.e7

    Article  PubMed  CAS  Google Scholar 

  97. Kobori A, Yagi Y, Imaeda H, Ban H, Bamba S, Tsujikawa T, Saito Y, Fujiyama Y, Andoh A (2010) Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis. J Gastroenterol 45:999–1007

    Article  PubMed  CAS  Google Scholar 

  98. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:479–490

    Article  PubMed  CAS  Google Scholar 

  99. Rankin AL, Mumm JB, Murphy E, Turner S, Yu N, McClanahan TK, Bourne PA, Pierce RH, Kastelein R, Pflanz S (2010) IL-33 induces IL-13-dependent cutaneous fibrosis. J Immunol 184:1526–1535

    Article  PubMed  CAS  Google Scholar 

  100. Sponheim J, Pollheimer J, Olsen T, Balogh J, Hammarstrom C, Loos T, Kasprzycka M, Sorensen DR, Nilsen HR, Kuchler AM, Vatn MH, Haraldsen G (2010) Inflammatory bowel disease-associated interleukin-33 is preferentially expressed in ulceration-associated myofibroblasts. Am J Pathol 177:2804–2815

    Article  PubMed  CAS  Google Scholar 

  101. Otte J, Rosenberg IM, Podolsky DK (2003) Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 124:1866–1878

    Article  PubMed  CAS  Google Scholar 

  102. Fedorak RN, Gangl A, Elson CO, Rutgeerts P, Schreiber S, Wild G, Hanauer SB, Kilian A, Cohard M, LeBeaut A, Feagan B (2000) Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group. Gastroenterology 119:1473–1482

    Article  PubMed  CAS  Google Scholar 

  103. Sinha A, Nightingale J, West KP, Berlanga-Acosta J, Playford RJ (2003) Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 349:350–357

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This work was supported by the Deutsche Forschungsgemeinschaft grant SFB633.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Medicine I (Gastroenterology/Rheumatology/Infectious Diseases), Charité–Universitätsmedizin Berlin, Campus Benjamin Franklin, 12200, Berlin, Germany

    Jochen Maul & Martin Zeitz

  2. Medizinische Klinik I, Charité–Campus Benjamin Franklin, 12200, Berlin, Germany

    Martin Zeitz

Authors
  1. Jochen Maul
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Zeitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin Zeitz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maul, J., Zeitz, M. Ulcerative colitis: immune function, tissue fibrosis and current therapeutic considerations. Langenbecks Arch Surg 397, 1–10 (2012). https://doi.org/10.1007/s00423-011-0789-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00423-011-0789-4

Keywords

Search

Navigation