Skip to main content
Log in

Increased Expression of CCL20 in Human Inflammatory Bowel Disease

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Inflammatory bowel disease (IBD) constituting Crohn's disease (CD) and ulcerative colitis (UC) is related to a dysregulated T cell response. CCL20 attracts memory T lymphocytes and dendritic cells. We asked whether CCL20 expression is altered in IBD. Colonic biopsies were obtained from 114 subjects with IBD, non-IBD colitis, irritable bowel syndrome, and healthy controls. CCL20 and CCR6 mRNA expression was measured by Taqman-PCR, and protein secretion from colonic explant cultures (CEC) and its regulation by TNF-α by ELISA. CCL20, CCR6, and Langerin were identified by immunohistochemistry and immunofluorescence. CCL20 mRNA and protein were severalfold increased in involved CD and UC but not in non-IBD colitis. TNF-α increased and anti-TNF-α decreased CCL20 release in healthy control CEC but not in involved IBD colonic specimens. CCL20 localized to follicle-associated epithelium, and CCR6 to the adjacent mantle zone of lymphoid follicles. Furthermore, abundant numbers of Langerin+ immature dendritic cells were identified in the subepithelial space of IBD specimens. CCL20 might regulate the attraction of T lymphocytes and dendritic cells in IBD.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  1. Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR: Crohn's disease in Olmsted County, Minnesota, 1940–1993: Incidence, prevalence, and survival. Gastroenterology 114: 1161-1168, 1998

    Google Scholar 

  2. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411: 599-603, 2001

    Google Scholar 

  3. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH: A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411: 603-606, 2001

    Google Scholar 

  4. Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, Bridger S, van Deventer S, Forbes A, Nikolaus S, Lennard-Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG: Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357: 1925-1928, 2001

    Google Scholar 

  5. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G: Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276: 4812-4818, 2001

    Google Scholar 

  6. Inohara N, Ogura Y, Chen FF, Muto A, Nunez G: Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem 276: 2551-2554, 2001

    Google Scholar 

  7. Papadakis KA, Targan SR: Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med 51: 289-298, 2000

    Google Scholar 

  8. Fiocchi C: Inflammatory bowel disease: Etiology and pathogenesis. Gastroenterology 115: 182-205, 1998

    Google Scholar 

  9. Springer TA: Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm. Cell 76: 301-314, 1994

    Google Scholar 

  10. Butcher EC, Picker LJ: Lymphocyte homing and homeostasis. Science 272: 60-66, 1996

    Google Scholar 

  11. Rollins BJ: Chemokines. Blood 90: 909-928, 1997

    Google Scholar 

  12. Forster R, Schubel A, Breitfeld D, Kremmer E, Renner-Muller I, Wolf E, Lipp M: CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99: 23-33, 1999

    Google Scholar 

  13. Svensson M, Marsal J, Ericsson A, Carramolino L, Broden T, Marquez G, Agace WW: CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa. J Clin Invest 110: 1113-1121, 2002

    Google Scholar 

  14. Campbell DJ, Butcher EC: Intestinal attraction: CCL25 functions in effector lymphocyte recruitment to the small intestine. J Clin Invest 110: 1079-1081, 2002

    Google Scholar 

  15. Shibahara T, Wilcox JN, Couse T, Madara JL: Characterization of epithelial chemoattractants for human intestinal intraepithelial lymphocytes. Gastroenterology 120: 60-70, 2001

    Google Scholar 

  16. Izadpanah A, Dwinell MB, Eckmann L, Varki NM, Kagnoff MF: Regulated MIP-3alpha/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity. Am J Physiol Gastrointest Liver Physiol 280: G710-G719, 2001

    Google Scholar 

  17. Dwinell MB, Lugering N, Eckmann L, Kagnoff MF: Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells. Gastroenterology 120: 49-59, 2001

    Google Scholar 

  18. Papadakis KA, Prehn J, Moreno ST, Cheng L, Kouroumalis EA, Deem R, Breaverman T, Ponath PD, Andrew DP, Green PH, Hodge MR, Binder SW, Targan SR: Ccr9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic crohn's disease. Gastroenterology 121: 246-254, 2001

    Google Scholar 

  19. Jugde F, Alizadeh M, Boissier C, Chantry D, Siproudhis L, Corbinais S, Quelvennec E, Dyard F, Campion JP, Gosselin M, Bretagne JF, Semana G, Heresbach D: Quantitation of chemokines (MDC, TARC) expression in mucosa from Crohn's disease and ulcerative colitis. Eur Cytokine Netw 12: 468-477, 2001

    Google Scholar 

  20. Middel P, Thelen P, Blaschke S, Polzien F, Reich K, Blaschke V, Wrede A, Hummel KM, Gunawan B, Radzun HJ: Expression of the T-cell chemoattractant chemokine lymphotactin in Crohn's disease. Am J Pathol 159: 1751-1761, 2001

    Google Scholar 

  21. Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 392: 245-252, 1998

    Google Scholar 

  22. Malmstrom V, Shipton D, Singh B, Al Shamkhani A, Puklavec MJ, Barclay AN, Powrie F: CD134L expression on dendritic cells in the mesenteric lymph nodes drives colitis in T cell-restored SCID mice. J Immunol 166: 6972-6981, 2001

    Google Scholar 

  23. Bell SJ, Rigby R, English N, Mann SD, Knight SC, Kamm MA, Stagg AJ: Migration and maturation of human colonic dendritic cells. J Immunol 166: 4958-4967, 2001

    Google Scholar 

  24. Vuckovic S, Florin TH, Khalil D, Zhang MF, Patel K, Hamilton I, Hart DN: CD40 and CD86 upregulation with divergent CMRF44 expression on blood dendritic cells in inflammatory bowel diseases. Am J Gastroenterol 96: 2946-2956, 2001

    Google Scholar 

  25. Ikeda Y, Akbar F, Matsui H, Onji M: Characterization of antigen-presenting dendritic cells in the peripheral blood and colonic mucosa of patients with ulcerative colitis. Eur J Gastroenterol Hepatol 13: 841-850, 2001

    Google Scholar 

  26. Baggiolini M, Loetscher P: Chemokines in inflammation and immunity. Immunol Today 21: 418-420, 2000

    Google Scholar 

  27. Locati M, Murphy PM: Chemokines and chemokine receptors: Biology and clinical relevance in inflammation and AIDS. Annu Rev Med 50: 425-440, 1999

    Google Scholar 

  28. Mantovani A: The chemokine system: redundancy for robust outputs. Immunol Today 20: 254-257, 1999

    Google Scholar 

  29. Campbell JJ, Hedrick J, Zlotnik A, Siani MA, Thompson DA, Butcher EC: Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279: 381-384, 1998

    Google Scholar 

  30. Campbell JJ, Haraldsen G, Pan J, Rottman J, Qin S, Ponath P, Andrew DP, Warnke R, Ruffing N, Kassam N, Wu L, Butcher EC: The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 400: 776-780, 1999

    Google Scholar 

  31. Fitzhugh DJ, Naik S, Caughman SW, Hwang ST: Cutting edge: C-C chemokine receptor 6 is essential for arrest of a subset of memory T cells on activated dermal microvascular endothelial cells under physiologic flow conditions in vitro. J Immunol 165: 6677-6681, 2000

    Google Scholar 

  32. Rossi DL, Vicari AP, Franz-Bacon K, McClanahan TK, Zlotnik A: Identification through bioinformatics of two new macrophage proinflammatory human chemokines: MIP-3alpha and MIP-3beta. J Immunol 158: 1033-1036, 1997

    Google Scholar 

  33. Hieshima K, Imai T, Opdenakker G, Van Damme J, Kusuda J, Tei H, Sakaki Y, Takatsuki K, Miura R, Yoshie O, Nomiyama H: Molecular cloning of a novel human CC chemokine liver and activation-regulated chemokine (LARC) expressed in liver. Chemotactic activity for lymphocytes and gene localization on chromosome 2. J Biol Chem 272: 5846-5853, 1997

    Google Scholar 

  34. Hromas R, Gray PW, Chantry D, Godiska R, Krathwohl M, Fife K, Bell GI, Takeda J, Aronica S, Gordon M, Cooper S, Broxmeyer HE, Klemsz MJ: Cloning and characterization of exodus, a novel beta-chemokine. Blood 89: 3315-3322, 1997

    Google Scholar 

  35. Liao F, Rabin RL, Smith CS, Sharma G, Nutman TB, Farber JM: CC-chemokine receptor 6 is expressed on diverse memory subsets of T cells and determines responsiveness to macrophage inflammatory protein 3 alpha. J Immunol 162: 186-194, 1999

    Google Scholar 

  36. Dieu-Nosjean MC, Vicari A, Lebecque S, Caux C: Regulation of dendritic cell trafficking: A process that involves the participation of selective chemokines. J Leukoc Biol 66: 252-262, 1999

    Google Scholar 

  37. Dieu-Nosjean MC, Massacrier C, Homey B, Vanbervliet B, Pin JJ, Vicari A, Lebecque S, Dezutter-Dambuyant C, Schmitt D, Zlotnik A, Caux C: Macrophage inflammatory protein 3alpha is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J Exp Med 192: 705-718, 2000

    Google Scholar 

  38. Iwasaki A, Kelsall BL: Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3alpha, MIP-3beta, and secondary lymphoid organ chemokine. J Exp Med 191: 1381-1394, 2000

    Google Scholar 

  39. Bohr J, Olesen M, Tysk C, Jarnerot G: Collagenous and lymphocytic colitis: A clinical and histopathological review. Can J Gastroenterol 14: 943-947, 2000

    Google Scholar 

  40. Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muller-Lissner SA: Functional bowel disorders and functional abdominal pain. Gut 45 (Suppl 2):II43-II47, 1999

    Google Scholar 

  41. Oldach D: “Real-time” polymerase chain reaction. Gastroenterology 116: 763-764, 1999

    Google Scholar 

  42. Freeman WM, Walker SJ, Vrana KE: Quantitative RT-PCR: Pitfalls and potential. Biotechniques 26: 112-115, 1999

    Google Scholar 

  43. Schreiber S, Heinig T, Thiele HG, Raedler A: Immunoregulatory role of interleukin 10 in patients with inflammatory bowel disease. Gastroenterology 108: 1434-1444, 1995

    Google Scholar 

  44. Kaser A, Dunzendorfer S, Offner FA, Ryan T, Schwabegger A, Cruikshank WW, Wiedermann CJ, Tilg H: A role for interleukin 16 in the cross-talk between dendritic cells and T cells. J Immunol 163: 3232-3238, 1999

    Google Scholar 

  45. Dieu-Nosjean MC, Massacrier C, Vanbervliet B, Fridman WH, Caux C: IL-10 induces CCR6 expression during Langerhans cell development while IL-4 and IFN-gamma suppress it. J Immunol 167: 5594-5602, 2001

    Google Scholar 

  46. Carramolino L, Kremer L, Goya I, Varona R, Buesa JM, Gutierrez J, Zaballos A, Martinez A, Marquez G: Down-regulation of the beta-chemokine receptor CCR6 in dendritic cells mediated by TNF-alpha and IL-4. J Leukoc Biol 66: 837-844, 1999

    Google Scholar 

  47. Ebert LM, McColl SR: Up-regulation of CCR5 and CCR6 on distinct subpopulations of antigen-activated CD4+ T lymphocytes. J Immunol 168: 65-72, 2002

    Google Scholar 

  48. Yang SK, Eckmann L, Panja A, Kagnoff MF: Differential and regulated expression of C-X-C, C-C, and C-chemokines by human colon epithelial cells. Gastroenterology 113: 1214-1223, 1997

    Google Scholar 

  49. Eckmann L, Jung HC, Schurer-Maly C, Panja A, Morzycka-Wroblewska E, Kagnoff MF: Differential cytokine expression by human intestinal epithelial cell lines: regulated expression of interleukin 8. Gastroenterology 105: 1689-1697, 1993

    Google Scholar 

  50. Jung HC, Eckmann L, Yang SK, Panja A, Fierer J, Morzycka-Wroblewska E, Kagnoff MF: A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J Clin Invest 95: 55-65, 1995

    Google Scholar 

  51. Zaballos A, Varona R, Gutierrez J, Lind P, Marquez G: Molecular cloning and RNA expression of two new human chemokine receptor-like genes. Biochem Biophys Res Commun 227: 846-853, 1996

    Google Scholar 

  52. Greaves DR, Wang W, Dairaghi DJ, Caroline Dieu M, de Saint-Vis B, Franz-Bacon K, Rossi D, Caux C, McClanahan T, Gordon S, Zlotnik A, Schall TJ: CCR6, a CC chemokine receptor that interacts with macrophage inflammatory protein 3α and is highly expressed in human dendritic cells. J Exp Med 186: 837-844, 1997

    Google Scholar 

  53. Baba M, Imai T, Nishimura M, Kakizaki M, Takagi S, Hieshima K, Nomiyama H, Yoshie O: Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC. J Biol Chem 272: 14893-14898, 1997

    Google Scholar 

  54. Kaser A, Mairinger T, Vogel W, Tilg H: Infliximab in severe steroid-refractory ulcerative colitis: a pilot study. Wien Klin Wochenschr 113: 930-933, 2001

    Google Scholar 

  55. Middleton J, Neil S, Wintle J, Clark-Lewis I, Moore H, Lam C, Auer M, Hub E, Rot A: Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91: 385-395, 1997

    Google Scholar 

  56. Kwon JH, Keates S, Bassani L, Mayer LF, Keates AC: Colonic epithelial cells are a major site of macrophage inflammatory protein 3alpha (MIP-3alpha) production in normal colon and inflammatory bowel disease. Gut 51: 818-826, 2002

    Google Scholar 

  57. Varona R, Villares R, Carramolino L, Goya I, Zaballos A, Gutierrez J, Torres M, Martinez A, Marquez G: CCR6-deficient mice have impaired leukocyte homeostasis and altered contact hypersensitivity and delayed-type hypersensitivity responses. J Clin Invest 107:R37-R45, 2001

    Google Scholar 

  58. Dieu MC, Vanbervliet B, Vicari A, Bridon JM, Oldham E, Ait-Yahia S, Briere F, Zlotnik A, Lebecque S, Caux C: Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med 188: 373-386, 1998

    Google Scholar 

  59. Teramoto K, Miura S, Tsuduki Y, Hokari R, Watanabe C, Inamura T, Ogawa T, Hosoe N, Ishii H: Increased lymphocyte trafficking to the colonic mucosa is dependent on MAdCAM-1 and C-C chemokine mLARC in DSS-induced mice experimental colitis. Gastroenterology (Suppl):T1116, 2003 (abstr)

  60. Kunkel EJ, Campbell JJ, Haraldsen G, Pan J, Boisvert J, Roberts AI, Ebert EC, Vierra MA, Goodman SB, Genovese MC, Wardlaw AJ, Greenberg HB, Parker CM, Butcher EC, Andrew DP, Agace WW: Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J Exp Med 192: 761-768, 2000

    Google Scholar 

  61. Papadakis KA, Prehn J, Nelson V, Cheng L, Binder SW, Ponath PD, Andrew DP, Targan SR: The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system. J Immunol 165: 5069-5076, 2000

    Google Scholar 

  62. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, Vyhnalek P, Zadorova Z, Palmer T, Donoghue S: Natalizumab for active Crohn's disease. N Engl J Med 348: 24-32, 2003

    Google Scholar 

  63. Best WR, Becktel JM, Singleton JW, Kern F Jr: Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology 70: 439-444, 1976

    Google Scholar 

  64. Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 330: 1841-1845, 1994

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Herbert Tilg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaser, A., Ludwiczek, O., Holzmann, S. et al. Increased Expression of CCL20 in Human Inflammatory Bowel Disease. J Clin Immunol 24, 74–85 (2004). https://doi.org/10.1023/B:JOCI.0000018066.46279.6b

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:JOCI.0000018066.46279.6b

Navigation