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Chemokines in inflammatory bowel disease

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Abstract

Ulcerative colitis (UC) and Crohn’s disease (CD), collectively termed inflammatory bowel diseases (IBD), represent chronic relapsing and remitting inflammatory disorders of the gastrointestinal tract that are charcterized by leukocytic infiltration of the intestinal mucosa and submucosa. In CD, the inflammation is transmural and frequently associated with granuloma formation. Chemokines have emerged as the most important regulators of leukocyte trafficking during infection or inflammation and, therefore, have been implicated in the pathogenesis of IBD. In this review, recent advances on the role of chemokines and their receptors in mucosal immunity and inflammation are discussed, and the potential use of chemokine/chemokine-receptor antagonists as novel therapeutic targets for the treatment of human IBD is highlighted.

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References and Recommended Reading

  1. Baggiolini M: Chemokines and leukocyte traffic. Nature 1998, 392:565–568.

    Article  CAS  PubMed  Google Scholar 

  2. Zlotnik A, Yoshie O: Chemokines: a new classification system and their role in immunity. Immunity 2000, 12:121–127.

    Article  CAS  PubMed  Google Scholar 

  3. Kunkel EJ, Butcher EC: Chemokines and the tissue-specific migration of lymphocytes. Immunity 2002, 16:1–4.

    Article  CAS  PubMed  Google Scholar 

  4. Moser B, Loetscher P: Lymphocyte traffic control by chemokines. Nat Immunol 2001, 2:123–128.

    Article  CAS  PubMed  Google Scholar 

  5. Ansel KM, Ngo VN, Hyman PL, et al.: A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 2000, 406:309–314.

    Article  CAS  PubMed  Google Scholar 

  6. Carlsen HS, Baekkevold ES, Johansen FE, et al.: B cell attracting chemokine 1 (CXCL13) and its receptor CXCR5 are expressed in normal and aberrant gut associated lymphoid tissue. Gut 2002, 51:364–371.

    Article  CAS  PubMed  Google Scholar 

  7. Zabel BA, Agace WW, Campbell JJ, et al.: Human G proteincoupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. J Exp Med 1999, 190:1241–1256.

    Article  CAS  PubMed  Google Scholar 

  8. Kunkel EJ, Campbell JJ, Haraldsen G, et al.: 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 2000, 192:761–768. This paper and Papadakis et al. [9] describe the selective expression of CCL25/TECK and CCR9 that characterizes the small intestinal immune compartment. The two studies highlight the concept that regional immunity is characterized by tissue-specific expression of chemokines.

    Article  CAS  PubMed  Google Scholar 

  9. Papadakis KA, Prehn J, Nelson V, et al.: The role of thymusexpressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system. J Immunol 2000, 165:5069–5076. This paper and Kunkel et al. [8] describe the selective expression of CCL25/TECK and CCR9 that characterizes the small intestinal immune compartment. The two studies highlight the concept that regional immunity is characterized by tissue-specific expression of chemokines.

    CAS  PubMed  Google Scholar 

  10. Mora JR, Bono MR, Manjunath N, et al.: Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 2003, 424:88–93. This is the first study to demonstrate the acquisition of tissue-specific chemokine receptors by T cells mediated by specialized antigenpresenting cells. This concept might hold true for other antigenpresenting cells from other tissues, such as skin.

    Article  CAS  PubMed  Google Scholar 

  11. Homey B, Alenius H, Muller A, et al.: CCL27-CCR10 interactions regulate T cell-mediated skin inflammation [comment]. Nat Med 2002, 8:157–165.

    Article  CAS  PubMed  Google Scholar 

  12. Wurbel MA, Malissen M, Guy-Grand D, et al.: Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor gammadelta(+) gut intraepithelial lymphocytes. Blood 2001, 98:2626–2632.

    Article  CAS  PubMed  Google Scholar 

  13. Onai N, Kitabatake M, Zhang YY, et al.: Pivotal role of CCL25 (TECK)-CCR9 in the formation of gut cryptopatches and consequent appearance of intestinal intraepithelial T lymphocytes. Int Immunol 2002, 14:687–694.

    Article  CAS  PubMed  Google Scholar 

  14. Svensson M, Marsal J, Ericsson A, et al.: CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa [comment]. J Clin Invest 2002, 110:1113–1121. This study showed that CCL25 mediates the homing of mucosally activated CD8+ T lymphocytes to the small intestinal epithelium.

    Article  CAS  PubMed  Google Scholar 

  15. Papadakis KA, Landers C, Prehn J, et al.: CC chemokine receptor 9 expression defines a subset of peripheral blood lymphocytes with mucosal T cell phenotype and Th1 or Tregulatory 1 cytokine profile. J Immunol 2003, 171:159–165.

    CAS  PubMed  Google Scholar 

  16. Papadakis KA, Prehn J, Moreno ST, et al.: CCR9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic Crohn’s disease. Gastroenterology 2001, 121:246–254. The CCL25/CCR9 system is involved in the pathogenesis of small bowel inflammatory diseases, such as Crohn’s or celiac disease.

    Article  CAS  PubMed  Google Scholar 

  17. Tanaka Y, Imai T, Baba M, et al.: Selective expression of liver and activation-regulated chemokine (LARC) in intestinal epithelium in mice and humans. Eur J Immunol 1999, 29:633–642.

    Article  CAS  PubMed  Google Scholar 

  18. 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 2000, 191:1381–1394.

    Article  CAS  PubMed  Google Scholar 

  19. Cook DN, Prosser DM, Forster R, et al.: CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue. Immunity 2000, 12:495–503.

    Article  CAS  PubMed  Google Scholar 

  20. Varona R, Villares R, Carramolino L, et al.: CCR6-deficient mice have impaired leukocyte homeostasis and altered contact hypersensitivity and delayed-type hypersensitivity responses. J Clin Invest 2001, 107:R37-R45.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Sierro F, Dubois B, Coste A, et al.: Flagellin stimulation of intestinal epithelial cells triggers CCL20-mediated migration of dendritic cells. Proc Natl Acad Sci U S A 2001, 98:13722–13727.

    Article  CAS  PubMed  Google Scholar 

  23. Agace WW, Amara A, Roberts AI, et al.: Constitutive expression of stromal derived factor-1 by mucosal epithelia and its role in HIV transmission and propagation. Curr Biol 2000, 10:325–328.

    Article  CAS  PubMed  Google Scholar 

  24. Reinecker HC, Loh EY, Ringler DJ, et al.: Monocytechemoattractant protein 1 gene expression in intestinal epithelial cells and inflammatory bowel disease mucosa. Gastroenterology 1995, 108:40–50.

    Article  CAS  PubMed  Google Scholar 

  25. MacDermott RP, Sanderson IR, Reinecker HC: The central role of chemokines (chemotactic cytokines) in the immunopathogenesis of ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis 1998, 4:54–67.

    Article  CAS  PubMed  Google Scholar 

  26. Papadakis KA, Targan SR: The role of chemokines and chemokine receptors in mucosal inflammation. Inflamm Bowel Diss 2000, 6:303–313.

    Article  CAS  Google Scholar 

  27. Muehlhoefer A, Saubermann LJ, Gu X, et al.: Fractalkine is an epithelial and endothelial cell-derived chemoattractant for intraepithelial lymphocytes in the small intestinal mucosa. J Immunol 2000, 164:3368–3376.

    CAS  PubMed  Google Scholar 

  28. Ancuta P, Rao R, Moses A, et al.: Fractalkine preferentially mediates arrest and migration of CD16+ monocytes. J Exp Med 2003, 197:1701–1707.

    Article  CAS  PubMed  Google Scholar 

  29. Lucas AD, Chadwick N, Warren BF, et al.: The transmembrane form of the CX3CL1 chemokine fractalkine is expressed predominantly by epithelial cells in vivo. Am J Pathol 2001, 158:855–866.

    CAS  PubMed  Google Scholar 

  30. Kurth I, Willimann K, Schaerli P, et al.: Monocyte selectivity and tissue localization suggests a role for breast and kidney-expressed chemokine (BRAK) in macrophage development. J Exp Med 2001, 194:855–861.

    Article  CAS  PubMed  Google Scholar 

  31. Grimm MC, Elsbury SK, Pavli P, Doe WF: Enhanced expression and production of monocyte chemoattractant protein-1 in inflammatory bowel disease mucosa. J Leukocyte Biol 1996, 59:804–812.

    CAS  PubMed  Google Scholar 

  32. Mazzucchelli L, Hauser C, Zgraggen K, et al.: Differential in situ expression of the genes encoding the chemokines MCP-1 and RANTES in human inflammatory bowel disease. J Pathol 1996, 178:201–206.

    Article  CAS  PubMed  Google Scholar 

  33. Uguccioni M, Gionchetti P, Robbiani DF, et al.: Increased expression of IP-10, IL-8, MCP-1, and MCP-3 in ulcerative colitis. Am J Pathol 1999, 155:331–336.

    CAS  PubMed  Google Scholar 

  34. Kunkel EJ, Kim CH, Lazarus NH, et al.: CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells. J Clin Invest 2003, 111:1001–1010. CCR10 expression by circulating IgA plasmablasts and by plasma cells in diverse mucosal sites unifies the role of CCR10 and its mucosal epithelial ligand CCL28/MEC in the homing of IgA-producing cells to diverse mucosal tissues after local immunization.

    Article  CAS  PubMed  Google Scholar 

  35. Bowman EP, Kuklin NA, Youngman KR, et al.: The intestinal chemokine thymus-expressed chemokine (CCL25) attracts IgA antibody-secreting cells [comment]. J Exp Med 2002, 195:269–275.

    Article  CAS  PubMed  Google Scholar 

  36. Gerszten RE, Garcia-Zepeda EA, Lim YC, et al.: MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 1999, 398:718–723.

    Article  CAS  PubMed  Google Scholar 

  37. MacDermott RP: Chemokines in the inflammatory bowel diseases. J Clin Immunol 1999, 19:266–272.

    Article  CAS  PubMed  Google Scholar 

  38. Binion DG, West GA, Ina K, Ziats NP, et al.: Enhanced leukocyte binding by intestinal microvascular endothelial cells in inflammatory bowel disease. Gastroenterology 1997, 112:1895–1907.

    Article  CAS  PubMed  Google Scholar 

  39. Danese S, de la Motte C, Sturm A, et al.: Platelets trigger a CD40-dependent inflammatory response in the microvasculature of inflammatory bowel disease patients. Gastroenterology 2003, 124:1249–1264. This study showed that activated platelets upregulate expression of ICAM-1, VCAM-1, and CXCL8/IL-8 by human intestinal microvascular endothelial cells (HIMEC) through CD40L-CD40 interactions. This study also showed high levels of CCL5/RANTES in platelet-HIMEC cocultures, which mediated T-cell adhesion to HIMEC.

    Article  CAS  PubMed  Google Scholar 

  40. Grimm MC, Elsbury SK, Pavli P, Doe WF: Interleukin 8: cells of origin in inflammatory bowel disease. Gut 1996, 38:90–98.

    CAS  PubMed  Google Scholar 

  41. Keshavarzian A, Fusunyan RD, Jacyno M, et al.: Increased interleukin-8 (IL-8) in rectal dialysate from patients with ulcerative colitis: evidence for a biological role for IL-8 in inflammation of the colon. Am J Gastroenterol 1999, 94:704–712.

    Article  CAS  PubMed  Google Scholar 

  42. Daig R, Andus T, Aschenbrenner E, et al.: Increased interleukin 8 expression in the colon mucosa of patients with inflammatory bowel disease. Gut 1996, 38:216–222.

    CAS  PubMed  Google Scholar 

  43. Z’Graggen K, Walz A, Mazzucchelli L, et al.: The C-X-C chemokine ENA-78 is preferentially expressed in intestinal epithelium in inflammatory bowel disease. Gastroenterology 1997, 113:808–816.

    Article  CAS  PubMed  Google Scholar 

  44. Wedemeyer J, Lorentz A, Goke M, et al.: Enhanced production of monocyte chemotactic protein 3 in inflammatory bowel disease mucosa [comment]. Gut 1999, 44:629–635.

    Article  CAS  PubMed  Google Scholar 

  45. Garcia-Zepeda EA, Rothenberg ME, Ownbey RT, et al.: Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med 1996, 2:449–456.

    Article  CAS  PubMed  Google Scholar 

  46. Strober W, Fuss IJ, Blumberg RS: The immunology of mucosal models of inflammation. Ann Rev Immunol 2002, 20:495–549.

    Article  CAS  Google Scholar 

  47. Grimm M, Doe W: Chemokines in inflammatory bowel disease mucosa: expression of RANTES, macrophage inflammatory protein (MIP)-1, and interferon-inducible protein 10 by macrophages, lymphocytes, endothelial cells, and granulomas. Inflamm Bowel Dis 1996, 2:88–96.

    Article  Google Scholar 

  48. Agace WW, Roberts AI, Wu L, et al.: Human intestinal lamina propria and intraepithelial lymphocytes express receptors specific for chemokines induced by inflammation. Eur J Immunol 2000, 30:819–826.

    Article  CAS  PubMed  Google Scholar 

  49. Scheerens H, Hessel E, de Waal-Malefyt R, et al.: Characterization of chemokines and chemokine receptors in two murine models of inflammatory bowel disease: IL-10-/-mice and Rag-2-/-mice reconstituted with CD4+CD45RBhigh T cells. Eur J Immunol 2001, 31:1465–1474.

    Article  CAS  PubMed  Google Scholar 

  50. Qin S, Rottman JB, Myers P, et al.: The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 1998, 101:746–754.

    CAS  PubMed  Google Scholar 

  51. Romagnani P, Annunziato F, Lasagni L, et al.: Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity. J Clin Invest 2001, 107:53–63.

    CAS  PubMed  Google Scholar 

  52. Olsson J, Poles M, Spetz AL, et al.: Human immunodeficiency virus type 1 infection is associated with significant mucosal inflammation characterized by increased expression of CCR5, CXCR4, and beta-chemokines. J Infect Dis 2000, 182:1625–1635.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  54. Kolios G, Wright KL, Jordan NJ, et al.: C-X-C and C-C chemokine expression and secretion by the human colonic epithelial cell line, HT-29: differential effect of T lymphocytederived cytokines. Eur J Immunol 1999, 29:530–536.

    Article  CAS  PubMed  Google Scholar 

  55. Shibahara T, Wilcox JN, Couse T, Madara JL: Characterization of epithelial chemoattractants for human intestinal intraepithelial lymphocytes [comment]. Gastroenterology 2001, 120:60–70.

    Article  CAS  PubMed  Google Scholar 

  56. Sasaki S, Yoneyama H, Suzuki K, et al.: Blockade of CXCL10 protects mice from acute colitis and enhances crypt cell survival. Eur J Immunol 2002, 32:3197–3205. This study showed a protective effect of CXCL10 blockade in a murine model of acute colitis that was independent of inflammatory cell recruitment to the colonic mucosa.

    Article  CAS  PubMed  Google Scholar 

  57. Andres PG, Beck PL, Mizoguchi E, et al.: Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type immune response in the intestine. J Immunol 2000, 164:6303–6312.

    CAS  PubMed  Google Scholar 

  58. Lukacs NW, Miller AL, Hogaboam CM: Chemokine receptors in asthma:searching for the correct immune targets. J Immunol 2003, 171:11–15.

    CAS  PubMed  Google Scholar 

  59. Singh UP, Singh S, Taub DD, Lillard JW: Inhibition of IFNgamma-inducible protein-10 abrogates colitis in IL10-/-mice. J Immunol 2003, 171:1401–1406.

    CAS  PubMed  Google Scholar 

  60. Ajuebor MN, Hogaboam CM, Kunkel SL, et al.: The chemokine RANTES is a crucial mediator of the progression from acute to chronic colitis in the rat. J Immunol 2001, 166:552–558. Both studies showed that chemokine or chemokine receptor blockade can be therapeutic in an animal model of colitis.

    CAS  PubMed  Google Scholar 

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  1. Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, D-4063, 90048, Los Angeles, CA, USA

    Konstantinos A. Papadakis MD

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Papadakis, K.A. Chemokines in inflammatory bowel disease. Curr Allergy Asthma Rep 4, 83–89 (2004). https://doi.org/10.1007/s11882-004-0048-7

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