Chemokines and chemokine receptors

  • Zoltán Szekanecz
  • Alisa E. Koch
Part of the Progress in Inflammation Research book series (PIR)


There is a structural and a functional classification of chemokines. The former includes four groups: CXC, CC, C and CX3C chemokines. There is a redundancy and binding promiscuity between chemokine receptors and their ligands. Recently, a functional classification distinguishing between inflammatory and homeostatic chemokines has been introduced. However, numerous effects of these chemokines overlap. For example, numerous homeostatic chemokines, which are involved in lymphocyte recruitment and lymphoid tissue organization, may also play a role in B cell migration underlying germinal center formation within the inflamed synovium. Anti-chemokine and anti-chemokine receptor targeting may be therapeutically used in future biological therapy of arthritis. In addition to the clear clinical benefit, we can learn a lot from these trials about the actions of the targeted chemokines and their receptors. Today, most data in this field are obtained from experimental models of arthritis; however, results of some human trials have also become available. Thus, it is possible that a number of specific chemokine and chemokine receptor antagonists will be administered to arthritis patients in the near future. Hopefully, some of these potential treatment modalities will be used to control inflammation, prevent joint destruction and thus will benefit our patients.


Rheumatoid Arthritis Patient Chemokine Receptor Synovial Macrophage Synovial Fluid Rheumatoid Arthritis Seron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Koch AE (2005) Chemokines and their receptors in rheumatoid arthritis. Arthritis Rheum 52: 710–721PubMedGoogle Scholar
  2. 2.
    Szekanecz Z, Kim J, Koch AE (2002) Chemokines and chemokine receptors in rheumatoid arthritis. Semin Immunol 399: 1–7Google Scholar
  3. 3.
    Szekanecz Z, Koch AE (2001) Chemokines and angiogenesis. Curr Opin Rheumatol 13: 202–208PubMedGoogle Scholar
  4. 4.
    Szekanecz Z, Szücs G, Szántó S, Koch AE (2006) Chemokines in rheumatic diseases. Curr Drug Targets 7: 91–102PubMedGoogle Scholar
  5. 5.
    Vergunst CE, Tak PP (2005) Chemokines: Their role in rheumatoid arthritis. Curr Rheumatol Rep 7: 382–388PubMedGoogle Scholar
  6. 6.
    Taub DD (1996) C-C chemokines — an overview. In: AE Koch, RM Strieter (eds): Chemokines in Disease. RG Landes Company, Austin, pp 27–54Google Scholar
  7. 7.
    Walz A, Kunkel SL, Strieter RM (1996) C-X-C chemokines — an overview. In: AE Koch, RM Strieter (eds): Chemokines in Disease. RG Landes Company, Austin, pp 1–25Google Scholar
  8. 8.
    Zlotnik A, Yoshie O (2000) Chemokines: A new classification system and their role in immunity. Immunity 12: 121–127PubMedGoogle Scholar
  9. 9.
    Moser B, Loetscher P (2001) Lymphocyte traffic control by chemokines. Nat Immunol 2: 123–128PubMedGoogle Scholar
  10. 10.
    Kunkel EJ, Butcher EC (2002) Chemokines and the tissue-specific migration of lymphocytes. Immunity 16: 1–4PubMedGoogle Scholar
  11. 11.
    Tak PP (2006) Chemokine inhibition in inflammatory arthritis. Best Pract Res Clin Rheumatol 20: 929–939PubMedGoogle Scholar
  12. 12.
    Silverman GJ, Carson DA (2003) Roles of B cells in rheumatoid arthritis. Arthritis Res Ther 5 Suppl 4: 1–6Google Scholar
  13. 13.
    De Vita S, Zaja F, Sacco S, De Candia A, Fanin R, Ferraccioli G. (2002) Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis. Arthritis Rheum 46: 2029–2033PubMedGoogle Scholar
  14. 14.
    Harris ED (1990) Rheumatoid arthritis: Pathophysiology and implications for therapy. N Engl J Med 332: 1277–1287Google Scholar
  15. 15.
    Oppenheim JJ, Zachariae COC, Mukaida N, Matsushima K (1991) Properties of the novel proinflammatory supergene “intercrine” cytokine family. Annu Rev Immunol 9: 617–648PubMedGoogle Scholar
  16. 16.
    Bacon K, Baggiolini M, Broxmeyer H, Horuk R, Lindley I, Mantovani A, Maysushima K, Murphy P, Nomiyama H, Oppenheim J et al (2002) Chemokine/chemokine receptor nomenclature. J Interferon Cytokine Res 22: 1067–1068PubMedGoogle Scholar
  17. 17.
    Strieter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J, Dzuiba J, Van Damme J, Walz A, Marriott D et al (1995) The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem 270: 27348–27357PubMedGoogle Scholar
  18. 18.
    Koch AE, Kunkel SL, Shah MR, Hosaka S, Halloran MM, Haines GK, Burdick MD, Pope RM, Strieter RM (1995) Growth related gene product alpha: A chemotactic cytokine for neutrophils in rheumatoid arthritis. J Immunol 155: 3660–3666PubMedGoogle Scholar
  19. 19.
    Wooley PH, Schaefer C, Whalen JD. Dutcher JA, Counts JF (1997) A peptide sequence from platelet factor 4 (CT-112) is effective in the treatment of type II collagen induced arthritis in mice. J Rheumatol 24: 890–898PubMedGoogle Scholar
  20. 20.
    Koch AE, Kunkel SL, Harlow LA, Johnson B, Evanoff HL, Haines GK, Burdick MD, Pope RM, Strieter RM (1994) Epithelial neutrophil activating peptide-78: A novel chemotactic cytokine for neutrophils in arthritis. J Clin Invest 94: 1012–1018PubMedGoogle Scholar
  21. 21.
    Koch AE, Kunkel SL, Burrows JC, Evanoff HL, Haines GK, Pope RM, Strieter RM (1991) Synovial tissue macrophage as a source of the chemotactic cytokine IL-8. J Immunol 147: 2187–2195PubMedGoogle Scholar
  22. 22.
    Nanki T, Hayashida K, El-Gabalawy HS, Suson S, Shi K, Girschick HJ, Yavuz S, Lipsky PE (2000) Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T-cell accumulation in rheumatoid arthritis synovium. J Immunol 165: 6590–6598PubMedGoogle Scholar
  23. 23.
    Ruth JH, Haas CS, Park CC, Amin MA, Martinez RJ, Haines GK, Shahrara S, Campbell PL, Koch AE (2006) CXCL16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway. Arthritis Rheum 54: 765–778PubMedGoogle Scholar
  24. 24.
    Nanki T, Shimaoka T, Hayashida K Taniguchi K, Yonehara S, Miyasaka N (2005) Pathogenic role of CXCL16-CXCR6 pathway in rheumatoid arthritis. Arthritis Rheum 52: 3004–3014PubMedGoogle Scholar
  25. 25.
    Deleuran B, Lemche P, Kristensen M, Chu CQ, Field M, Jensen J, Matsushima K, Stengaard-Pedersen K (1994) Localisation of interleukin 8 in the synovial membrane, cartilage-pannus junction and chondrocytes in rheumatoid arthritis. Scand J Rheumatol 23: 2–7PubMedGoogle Scholar
  26. 26.
    Koch AE, Volin MV, Woods JM, Kunkel SL, Connors MA, Harlow LA, Woodruff DC, Burdick MD, Strieter RM (2001) Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide-78 in the rheumatoid joint. Arthritis Rheum 44: 31–40PubMedGoogle Scholar
  27. 27.
    Hosaka S, Akahoshi T, Wada C, Kondo H (1994) Expression of the chemokine superfamily in rheumatoid arthritis. Clin Exp Immunol 97: 451–457PubMedGoogle Scholar
  28. 28.
    Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG, Strieter RM (1992) Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258: 1798–1801PubMedGoogle Scholar
  29. 29.
    Salcedo R, Ponce ML, Young HA, Wasserman K, Ward JM, Kleinman HK, Oppenheim JJ, Murphy WJ (2000) Human endothelial cells express CCR2 and respond to MCP-1: Direct role of MCP-1 in angiogenesis and tumor progression. Blood 96: 34–40PubMedGoogle Scholar
  30. 30.
    Castor CW, Smith EM, Hossler PA, Bignall MC, Aaron BP (1992) Detection of connective tissue activating peptide-III isoforms in synovium from osteoarthritis and rheumatoid arthritis patients: Patterns of interaction with other synovial cytokines in cell culture. Arthritis Rheum 35: 783–793PubMedGoogle Scholar
  31. 31.
    Pierer M, Rethage J, Seibl R, Lauener R, Brentano F, Wagner U, Hantzschel H, Michel BA, Gay RE, Gay S, Kyburz D (2004) Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. J Immunol 172: 1256–1265PubMedGoogle Scholar
  32. 32.
    Hanaoka R, Kasama T, Muramatsu M Yajima N, Shiozawa F, Miwa Y, Negishi M, Ide H, Miyaoka H, Uchida H et al (2003) A novel mechanism for the regulation of IFN-γ inducible protein-10 expression in rheumatoid arthritis. Arthritis Res Ther 5: R74–R81PubMedGoogle Scholar
  33. 33.
    Patel DD, Zachariah JP, Whichard LP (2001) CXCR3 and CCR5 ligands in the rheumatoid arthritis synovium. Clin Immunol 98: 39–45PubMedGoogle Scholar
  34. 34.
    Blades MC, Ingegnoli F, Wheller SK, Manzo A, Wahid S, Panayi GS, Perretti M, Pitzalis C (2002) Stromal cell-derived factor 1 (CXCL12) induces monocyte migration into human synovium transplanted onto SCID mice. Arthritis Rheum 46: 824–836PubMedGoogle Scholar
  35. 35.
    Bradfield PF, Amft N, Vernon-Wilson E Exley AE, Parsonage G, Rainger GE, Nash GB, Thomas AM, Simmons DL, Salmon M et al (2003) Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12) which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. Arthritis Rheum 48: 2472–2482PubMedGoogle Scholar
  36. 36.
    Hansen IB, Ellingsen T, Hornung N, Poulsen JH, Lottenburger T, Stengaard-Pedersen K (2006) Plasma level of CXC-chemokine CXCL12 is increased in rheumatoid arthritis and is independent of disease activity and methotrexate treatment. J Rheumatol 33: 1754–1759PubMedGoogle Scholar
  37. 37.
    Pablos JL, Santiago B, Galindo M Torres C, Brehmer MT, Blanco FJ, Garcia-Lazaro FJ (2003) Synoviocyte-derived CXCL12 is displayed on endothelium and induces angiogenesis in rheumatoid arthritis. J Immunol 170: 2147–2152PubMedGoogle Scholar
  38. 38.
    Santiago B, Baleux F, Palao G, Gutierrez-Canas I, Ramirez JC, Arenzana-Seisdedos F, Pablos JL (2006) CXCL12 is displayed by rheumatoid endothelial cells through its basic amino-terminal motif on heparan sulfate proteoglycans. Arthritis Res Ther 8: R43Google Scholar
  39. 39.
    Burger D (2000) Cell contact interactions in rheumatology. The Kennedy Institute for Rheumatology, London, UK, 1-2 June 2000. Arthritis Res 2: 472–476PubMedGoogle Scholar
  40. 40.
    Joven B, Gonzalez N, Aguilar F, Santiago B, Galindo M, Alcami J (2005) Association between stromal cell derived factor 1 chemokine gene variant and radiographic progression of rheumatoid arthritis. Arthritis Rheum 52: 354–356PubMedGoogle Scholar
  41. 41.
    Gronthos S, Zannettino AC (2007) The role of the chemokine CXCL12 in osteoclastogenesis. Trends Endocrinol Metab 18: 108–113PubMedGoogle Scholar
  42. 42.
    Edwards JCW, Cambridge G, Abrahams VM (1999) Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology 97: 188–196PubMedGoogle Scholar
  43. 43.
    Manzo A, Paoletti S, Carulli M, Blades MC, Barone F, Yanni G, Fitzgerald O, Bresnihan B, Caporali R, Montecucco C (2005) Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur J Immunol 35: 1347–1359PubMedGoogle Scholar
  44. 44.
    Li T, Zhong J, Chen Y, Qiu X, Zhang T, Ma D, Han W (2006) Expression of chemokinelike factor 1 is upregulated during T lymphocyte activation. Life Sci 79: 519–524PubMedGoogle Scholar
  45. 45.
    Haringman JJ, Smeets TJ, Reinders-Blankert P, Tak PP (2006) Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis and reactive arthritis. Ann Rheum Dis 65: 294–300PubMedGoogle Scholar
  46. 46.
    Koch AE, Kunkel SL, Harlow LA Johnson B, Evanoff HL, Haines GK, Burdick MD, Pope RM, Strieter RM (1992) Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest 90: 772–779PubMedGoogle Scholar
  47. 47.
    Villiger PM, Terkeltaub R, Lotz M (1992) Production of monocyte chemoattractant protein-1 by inflamed synovial tissue and cultured synoviocytes. J Immunol 149: 722–727PubMedGoogle Scholar
  48. 48.
    Koch AE, Kunkel SL, Harlow LA Mazarakis DD, Haines GK, Burdick MD, Pope RM, Strieter RM (1994) Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest 93: 921–928PubMedGoogle Scholar
  49. 49.
    Matsui T, Akahoshi T, Namai R, Hashimoto A, Kurihara Y, Rana M, Nishimura A, Endo H, Kitasato H, Kawai S et al (2001) Selective recruitment of CCR6-expressing cells by increased production of MIP-3 alpha in rheumatoid arthritis. Clin Exp Immunol 125: 155–161PubMedGoogle Scholar
  50. 50.
    Lisignoli G, Piacentini A, Cristino S, Grassi F, Cavallo C, Cattini L, Tonnarelli B, Manferdini C, Facchini A (2007) CCL20 chemokine induces both osteoblast proliferation and osteoclast differentiation: Increased levels of CCL20 are expressed in subchondral bone tissue of rheumatoid arthritis patients. J Cell Physiol 210: 798–806PubMedGoogle Scholar
  51. 51.
    Volin MV, Shah MR, Tokuhira M, Haines GK, Woods JM, Koch AE (1998) RANTES expression and contribution to monocyte chemotaxis in arthritis. Clin Immunol Immunopathol 89: 44–53PubMedGoogle Scholar
  52. 52.
    Rathanaswami P, Hachicha M, Sadick M, Scahll TJ, McColl SR (1993) Expression of the cytokine RANTES in human rheumatoid synovial fibroblasts. Differential regulation of RANTES and interleukin-8 genes by inflammatory cytokines. J Biol Chem 268: 5834–5839PubMedGoogle Scholar
  53. 53.
    Wang CR, Guo HR, Liu MF (2005) RANTES promoter polymorphism as a genetic risk factor for rheumatoid arthritis in the Chinese. Clin Exp Rheumatol 23: 379–384PubMedGoogle Scholar
  54. 54.
    Buckley CD (2003) Why do leucocytes accumulate within chronically inflamed joints? Rheumatology (Oxford) 42: 1433–1444Google Scholar
  55. 55.
    Okamoto H, Koizumi K, Yamanaka H, Saito T, Kamatani N (2003) A role for TARC/ CCL17, a CC chemokine, in systemic lupus erythematosus. J Rheumatol 30: 2369–2373PubMedGoogle Scholar
  56. 56.
    Momohara S, Okamoto H, Iwamoto T, Mizumura T, Ikari K, Kawaguchi Y, Takeuchi M, Kamatani N, Tomatsu T (2007) High CCL18/PARC expression in articular cartilage and synovial tissue of patients with rheumatoid arthritis. J Rheumatol 34: 266–271PubMedGoogle Scholar
  57. 57.
    Van Lieshout AW, van der Voort R, le Blanc LM, Roelofs MF, Schreurs BW, van Riel PL, Adema GJ, Radstake TR (2006) Novel insights in the regulation of CCL18 secretion by monocytes and dendritic cells via cytokines, toll-like receptors and rheumatoid synovial fluid. BMC Immunol 19: 7–23Google Scholar
  58. 58.
    Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ (1997) A new class of membrane bound chemokine with a X3C motif. Nature 385: 640–644PubMedGoogle Scholar
  59. 59.
    Ruth JH, Volin MV, Haines GK III, Woodruff DC, Katschke KJ Jr, Woods JM, Park CC, Morel JC, Koch AE (2001) Fractalkine, a novel chemokine in rheumatoid arthritis and rat adjuvant-induced arthritis. Arthritis Rheum 44: 1568–1581PubMedGoogle Scholar
  60. 60.
    Blaschke S, Middel P, Dorner BG Blaschke V, Hummel KM, Kroczek RA, Reich K, Benoehr P, Koziolek M, Muller GA (2003) Expression of activation-induced, T cellderived, and chemokine related cytokine/lymphotactin and its functional role in rheumatoid arthritis. Arthritis Rheum 48: 1858–1872PubMedGoogle Scholar
  61. 61.
    Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer JM (1998) CCR5 is characteristic of Th1 lymphocytes. Nature 391: 344–345PubMedGoogle Scholar
  62. 62.
    Sawai H, Park YW, Robertson J, Iwai T, Goronzy JJ, Weyand CM (2005) T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis. Arthritis Rheum 52: 1392–1401PubMedGoogle Scholar
  63. 63.
    Matsunawa M, Isozaki T, Odai T, Yjima N, Takeuchi HT, Negishi M, Ide H, Adachi M, Kasama T (2006) Increased serum levels of soluble fractalkine (CX3CL1) correlate with disease activity in rheumatoid vasculitis. Arthritis Rheum 54: 3408–3416PubMedGoogle Scholar
  64. 64.
    McDermott DH, Fong AM, Yang Q Sechler JM, Cupples LA, Merrell MN, Wilson PW, D’Agostino RB, O’Donnell CJ, Patel DD et al (2003) Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J Clin Invest 111: 1241–1250PubMedGoogle Scholar
  65. 65.
    Volin MV, Woods JM, Amin MA, Connors MA, Harlow LA, Koch AE (2001) Fractalkine: A novel angiogenic chemokine in rheumatoid arthritis. Am J Pathol 159: 1521–1530PubMedGoogle Scholar
  66. 66.
    Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR (1998) The chemokine receptors CXCR3 and CCR5 mark subsets of T cells with a homing predilection for certain inflammatory sites. J Clin Invest 101: 746–750PubMedGoogle Scholar
  67. 67.
    Norii M, Yamamura M, Iwahashi M, Ueno A, Yamana J, Makino H (2006) Selective recruitment of CXCR3+ and CCR5+ T cells into synovial tissue in patients with rheumatoid arthritis. Acta Med Okayama 60: 149–157PubMedGoogle Scholar
  68. 68.
    Garcia-Lopez MA, Sanchez-Madrid F, Rodriguez-Frade JM (2001) CXCR3 chemokine receptor distribution in normal and inflamed tissues. Lab Invest 81: 409–418PubMedGoogle Scholar
  69. 69.
    Schmutz C, Hulme A, Burman A Salmon M, Ashton B, Buckley C, Middleton J (2005) Chemokine receptors in the rheumatoid synovium: Upregulation of CXCR5. Arthritis Res Ther 7: R217–R229PubMedGoogle Scholar
  70. 70.
    Katschke KJ Jr, Rottman JB, Ruth JH, Qin S, Wu L, LaRosa G, Ponath P, Park CC, Pope RM, Koch AE (2001) Differential expression of chemokine receptors on peripheral blood, synovial fluid and synovial tissue monocytes/macrophages in rheumatoid arthritis. Arthritis Rheum 44: 1022–1032PubMedGoogle Scholar
  71. 71.
    Borzi RM, Mazzetti I, Cattini L, Uguccioni M, Baggiolini M, Facchini A (2000) Human chondrocytes express functional chemokine receptors and release matrix-degrading enzymes in response to C-X-C and C-C chemokines. Arthritis Rheum 43: 1734–1741PubMedGoogle Scholar
  72. 72.
    Ruth JH, Rottman JB, Katschke KJ Jr, Qin S, Wu L, LaRosa G, Ponath P, Pope RM, Koch AE (2001) Selective lymphocyte chemokine receptor expression in the rheumatoid joint. Arthritis Rheum 44: 2750–2760PubMedGoogle Scholar
  73. 73.
    Prahalad S (2006) Negative association between the chemokine receptor CCR5-Δ32 polymorphism and rheumatoid arthritis: A metaanalysis. Genes Immun 7: 264–268PubMedGoogle Scholar
  74. 74.
    Galligan CL, Matsuyama W, Matsukawa A, Mizuta H, Hodge DR, Yoshimura T (2004) Up-regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis. Arthritis Rheum 50: 1806–1814PubMedGoogle Scholar
  75. 75.
    Patterson AM, Siddall H, Chamberlain G, Gardner L, Middleton J (2002) Expression of the Duffy antigen/receptor for chemokines (DARC) by the inflamed synovial endothelium. J Pathol 197: 108–116PubMedGoogle Scholar
  76. 76.
    Mullazehi M, Mathsson L, Lampa J, Ronnelid J (2006) Surface-bound anti-type II collagen-containing immune complexes induce production of tumor necrosis factor alpha, interleukin-1β and interleukin-8 from peripheral blood monocytes via Fcγ receptor IIA. Arthritis Rheum 54: 1759–1771PubMedGoogle Scholar
  77. 77.
    Rantapaa-Dahlqvist S, Boman K, Tarkowski A, Hallmans G (2007) Upregulation of monocyte chemoattractant protein-1 expression in anti-citrulline antibody and immunoglobulin M rheumatoid factor positive subjects precedes onset of inflammatory response and development of overt rheumatoid arthritis. Ann Rheum Dis 66: 121–123PubMedGoogle Scholar
  78. 78.
    Loetscher P, Dewald B, Baggiolini M, Seitz M (1994) Monocyte chemoattractant protein 1 and interleukin 8 production by rheumatoid synoviocytes: Effects of anti-rheumatic drugs. Cytokine 6: 162–170PubMedGoogle Scholar
  79. 79.
    Lopez-Armada MJ, Sanchez-Pernaute O, Largo R, Diez-Ortego I, Palacios I, Egido J, Herrero-Beaumont G (2002) Modulation of cell recruitment by anti-inflammatory agents in antigen-induced arthritis. Ann Rheum Dis 61: 1027–1030PubMedGoogle Scholar
  80. 80.
    Volin MV, Campbell PL, Connors MA, Woodruff DC, Koch AE (2002) The effect of sulfasalazine on rheumatoid arthritis synovial tissue chemokine production. Exp Mol Pathol 73: 84–92PubMedGoogle Scholar
  81. 81.
    Ho CY, Wong CK, Li EK, Tam LS, Lam CW (2003) Suppressive effect of combination treatment of leflunomide and methotrexate on chemokine expression in patients with rheumatoid arthritis. Clin Exp Immunol 133: 132–138PubMedGoogle Scholar
  82. 82.
    Ellingsen T, Hornung N, Moller BK, Poulsen JH, Stengaard-Pedersen K (2007) Differential effect of methotrexate on the increased CCR2 density on circulating CD4 T lymphocytes and monocytes in active chronic rheumatoid arthritis, with down regulation only on monocytes in responders. Ann Rheum Dis 66: 151–157PubMedGoogle Scholar
  83. 83.
    Taylor PC, Peters AM, Paleolog E, Chapman PT, Elliott MJ, McCloskey R, Feldmann M, Maini RN (2000) Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum 43: 38–47PubMedGoogle Scholar
  84. 84.
    Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J (2006) Regulation of serum chemokines following infliximab therapy in patients with rheumatoid arthritis. Clin Exp Rheumatol 24: 529–533PubMedGoogle Scholar
  85. 85.
    Torikai E, Kageyama Y, Suzuki M, Ichikawa T, Nagano A (2006) The effect of infliximab in chemokines in patients with rheumatoid arthritis. Clin Rheumatol 26: 1088–1093PubMedGoogle Scholar
  86. 86.
    Kageyama Y, Torikai E, Nagano A (2006) Anti-tumor necrosis factor.alpha antibody treatment reduces serum CXCL16 levels in patients with rheumatoid arthritis. Rheumatol Int 27: 467–472Google Scholar
  87. 87.
    Nissinen R, Leirisalo-Repo M, Peltomaa R, Palosuo T, Vaarala A (2004) Cytokine and chemokine receptor profile of peripheral blood mononuclear cells during treatment with infliximab in patients with active rheumatoid arthritis. Ann Rheum Dis 63: 681–687PubMedGoogle Scholar
  88. 88.
    Aeberli D, Seitz M, Juni P, Villiger PM (2005) Increase of peripheral CXCR3 positive T lymphocytes upon treatment of RA patients with TNF-alpha inhibitors. Rheumatology (Oxford) 44: 172–175Google Scholar
  89. 89.
    van der Voort R, van Lieshout AW, Toonen LW Sloetjes AW, van den Berg WB, Figdor CG, Radstake TR, Adema GJ (2005) Elevated CXCL16 expression by synovial macrophages recruits memory T cells into rheumatoid joints. Arthritis Rheum 52: 1381–1391PubMedGoogle Scholar
  90. 90.
    Newton SM, Mackie SL, Martineau AR, Wilkinson KA, Kampmann B, Fischer C, Dutta S, Levin M, Wilkinson RJ, Pasvol G (2008) Reduction of chemokine secretion in response to mycobacteria in infliximab-treated patients. Clin Vaccine Immunol 15: 506–512PubMedGoogle Scholar
  91. 91.
    Sato M, Miyazaki T, Nagaya T, Murata Y, Ida N, Maeda K, Seo H (1996) Antioxidants inhibit tumor necrosis factor-alpha mediated stimulation of interleukin-8, monocyte chemoattractant protein-1, and collagenase expression in cultured human synovial cells. J Rheumatol 23: 432–438PubMedGoogle Scholar
  92. 92.
    Yokota K, Miyazaki T, Hirano M, Akiyama Y, Mimura T (2006) Simvastatin inhibits production of interleukin-6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-alpha in fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Rheumatol 33: 463–471PubMedGoogle Scholar
  93. 93.
    Wang Y, Wei D, Lai Z, Le Y (2006) Triptolide inhibits CC chemokines expressed in ratd adjuvant-induced arthritis. Int Immunopharmacol 6: 1825–1832PubMedGoogle Scholar
  94. 94.
    Ahmed S, Pakozdi A, Koch AE (2006) Regulation of interleukin-1β-induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 54: 2393–2401PubMedGoogle Scholar
  95. 95.
    Ospelt C, Kurowska/Stolarska M, Neidhart M, Michel BA, Gay RE, Laufer S, Gay S (2008) The dual inhibitor of lipoxygenase and cyclooxygenase ML3000 decreases the expression of CXCR3 ligands. Ann Rheum Dis 67: 524–529PubMedGoogle Scholar
  96. 96.
    Hounoki H, Sugiyama E, Mohamed SG, Shinoda K, Taki H, Abdel-Aziz HO, Maruyama M, Kobayashi M, Miyahara T (2008) Activation of peroxisome proliferator-activated receptor gamma inhibits TNF-alpha mediated osteoclast differentiation in human peripheral monocytes in part via suppression of monocyte chemoattractant protein-1 expression. Bone 42: 765–774PubMedGoogle Scholar
  97. 97.
    Akahoshi T, Endo H, Kondo H, Kashiwazaki S, Kasahara T, Mukaida N, Harada A, Matsushima K (1994) Essential involvement of interleukin-8 in neutrophil recruitment in rabbits with acute experimental arthritis induced by lipopolysaccharide and interleukin-1. Lymphokine Cytokine Res 13: 113–116PubMedGoogle Scholar
  98. 98.
    Halloran MM, Woods JM, Strieter RM, Szekanecz Z, Volin MV, Hosaka S, Haines GK III, Kunkel SL, Burdick MD, Walz A, Koch AE (1999) The role of an epithelial neutrophil-activating peptide-78-like protein in rat adjuvant-induced arthritis. J Immunol 162: 7492–7500PubMedGoogle Scholar
  99. 99.
    Kasama T, Strieter RM, Lukacs NW, Lincoln PL, Burdick MD, Kunkel SL (1995) Interleukin-10 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis. J Clin Invest 95: 2868–2876PubMedGoogle Scholar
  100. 100.
    Salomon I, Netzer N, Wildbaum G, Schif-Zuck S, Maor G, Karin N (2002) Targeting the function of IFNγ-inducible protein 10 suppresses ongoing adjuvant arthritis. J Immunol 169: 2865–2873Google Scholar
  101. 101.
    Skov L, Beurskens FJ, Zachariae CO, Reitamo S, Teeling J, Satijn D, Knudsen KM, Boot EP, Hudson D, Baadsgaard O, Parren PW, van de Winkel JG (2008) IL-8 as antibody therapeutic target in inflammatory diseases: Reduction of clinical activity in palmoplantar pustulosis. J Immunol 181: 669–679PubMedGoogle Scholar
  102. 102.
    Chintalacharuvu SR, Wang JX, Giaconia JM, Venkataraman C (2005) An essential role for CCL3 in the development of collagen-induced arthritis. Immunol Lett 100: 202–204PubMedGoogle Scholar
  103. 103.
    Ogata H, Takeya M, Yoshimura T, Takagi K, Takahashi K (1997) The role of monocyte chemoattractant protein-1 (MCP-1) in the pathogenesis of collagen-induced arthritis in rats. J Pathol 182: 106–114PubMedGoogle Scholar
  104. 104.
    Schrier DJ, Schimmer RC, Flory CM, Tung DK, Ward PA (1998) Role of chemokines and cytokines in a reactivation model of arthritis in rats induced by injection with streptococcal cell walls. Leukoc Biol 63: 359–363Google Scholar
  105. 105.
    Gong JH, Ratkay LG, Waterfield JD, Clark-Lewis I (1997) An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model. J Exp Med 186: 131–137PubMedGoogle Scholar
  106. 106.
    Barnes DA, Tse J, Kaufhold M, Owen M, Hesselgesser J, Strieter R, Horuk R, Perez HD (1998) Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J Clin Invest 101: 2910–2919PubMedGoogle Scholar
  107. 107.
    Inoue T, Yamashita M, Higaki M (2001) The new antirheumatic drug KE-298 suppresses MCP-1 and RANTES production in rats with adjuvant-induced arthritis and in IL-1-stimulated synoviocytes of patients with rheumatoid arthritis. Rheumatol Int 20: 149–153PubMedGoogle Scholar
  108. 108.
    Haringman JJ, Gerlag DM, Smeets TJ, Baeten D, van den Bosch F, Bresnihan B, Breedveld FC, Dinant HJ, Legay F, Gram H et al (2006) A randomized, controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum 54: 2387–2392PubMedGoogle Scholar
  109. 109.
    Nanki T, Urasaki Y, Imai T, Nishimura M, Muramoto K, Kubota T, Miyasaka N (2004) Inhibition of fractalkine ameliorates murine collagen-induced arthritis. J Immunol 173: 7010–7016PubMedGoogle Scholar
  110. 110.
    Bursill CA, Cai S, Channon KM, Greaves DR (2003) Adenoviral-mediated delivery of a viral chemokine binding protein blocks CC-chemokine activity in vitro and in vivo. Immunobiology 207: 187–196PubMedGoogle Scholar
  111. 111.
    Gong JH, Yan R, Waterfield JD, Clark-Lewis I (2004) Post-onset inhibition of murine arthritis using combined chemokine antagonist therapy. Rheumatology 43: 39–42PubMedGoogle Scholar
  112. 112.
    Youssef S, Maor G, Wildbaum G, Grabie N, Gour-Lavie A, Karin N (2000) C-C chemokine-encoding DNA vaccines enhance breakdown of tolerance to their gene products and treat ongoing adjuvant arthritis. J Clin Invest 106: 361–371PubMedGoogle Scholar
  113. 113.
    Matsukawa A, Yoshimura T, Fujiwara K, Maeda T, Ohkawara S, Yoshinaga M (1999) Involvement of growth-related protein in LPS-induced rabbit arthritis. Lab Invest 79: 591–600PubMedGoogle Scholar
  114. 114.
    Podolin PL, Bolognese BJ, Foley JJ, Schmidt DB, Buckley PT, Widdowson KL, Jin Q, White JR, Lee JM, Goodman RB et al (2002) A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit. J Immunol 169: 6435–6444PubMedGoogle Scholar
  115. 115.
    Cunha TM, Barsante MM, Guerrero AT, Verri WA jr, Ferreira SH, Coelho FM, Bertini R, Di Giacinto C, Allegretti M, Cunha FQ, Teixeira MM (2008) Treatment with DF 2162, a non-competitive allosteric inhibitor of CXCR1/2, diminishes neutrophil influx and inflammatory hypernociception in mice. Br J Pharmacol 154: 460–470PubMedGoogle Scholar
  116. 116.
    Brown CR, Blaho VA, Loiacono CM (2003) Susceptibility to experimental Lyme arthritis correlates with KC and monocyte chemoattractant protein-1 production in joints and requires neutrophil recruitment via CXCR2. J Immunol 171: 893–901PubMedGoogle Scholar
  117. 117.
    Gao P, Zhou XY, Yashiro-Ohtani Y, Yang YF, Sugimoto N, Ono S, Nakanishi T, Obika S, Imanishi T, Egawa T et al (2003) The unique target specificity of a nonpeptide chemokine receptor antagonist: Selective blockade of two Th1 chemokine receptors CCR5 and CXCR3. J Leukoc Biol 73: 273–280PubMedGoogle Scholar
  118. 118.
    Hatse S, Princen K, Bridger G, DeClerq E, Schols D (2002) Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4. FEBS Lett 527: 255–262PubMedGoogle Scholar
  119. 119.
    Tamamura H, Fujii N (2005) The therapeutic potential of CXCR4 antagonists in the treatment of HIV infection, cancer metastasis and rheumatoid arthritis. Expert Opin Ther Targets 9: 1267–1282PubMedGoogle Scholar
  120. 120.
    Pease JR, Horuk R (2005) CCR1 antagonists in clinical development. Expert Opin Investig Drugs 14: 785–796PubMedGoogle Scholar
  121. 121.
    Gladue RP, Tylaska LA, Brissette WH, Lira PD, Kath JC, Poss CS, Brown MF, Paradis TJ, Conklyn MJ, Ogborne KT (2003) CP-481,715, a potent and selective CCR1 antagonist with potential therapeutic implications for inflammatory diseases. J Biol Chem 278: 40473–40480PubMedGoogle Scholar
  122. 122.
    Haringman JJ, Kraan MC, Smeets TJM, Zwinderman KH, Tak PP (2003) Chemokine blockade and chronic inflammatory disease: Proof of concept in patients with rheumatoid arthritis. Ann Rheum Dis 62: 715–721PubMedGoogle Scholar
  123. 123.
    Quinones MP, Estrada CA, Kalkonde Y, Ahuja SK, Kuziel WA, Mack M, Ahuja SS (2005) The complex role of the chemokine receptor CCR2 in collagen-induced arthritis: Implications for therapeutic targeting of CCR2 in rheumatoid arthritis. J Mol Med 83: 672–681PubMedGoogle Scholar
  124. 124.
    Quinones MP, Jimenez F, Martinez H, Estrada CA, Willmon O, Dudley M, Kuziel WA, Melby PC, Reddick RL, Ahuja SK et al (2006) CC chemokine receptor (CCR)-2 prevents arthritis development following infection by Mycobacterium avium. J Mol Med 84: 503–512PubMedGoogle Scholar
  125. 125.
    Amat M, Benjamim CF, Williams LM, Prats N, Terricabras E, Beleta J, Kunkel SL, Godessart N (2006) Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo. Br J Pharmacol 149: 666–675PubMedGoogle Scholar
  126. 126.
    Plater-Zyberk C, Hoogewerf AJ, Proudfoot AE, Power CA, Wells TN (1997) Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol Lett 57: 117–120PubMedGoogle Scholar
  127. 127.
    Shahrara S, Proudfoot AE, Woods JM Ruth JH, Amin MA, Park CC, Haas CS, Pope RM, Haines GK, Zha YY et al (2005) Amelioration of rat adjuvant-induced arthritis by Met-RANTES. Arthritis Rheum 52: 1907–1919PubMedGoogle Scholar
  128. 128.
    Yang YF, Mukai T, Gao P Yamaguchi N, Ono S, Iwaki H, Obika S, Imanishi T, Tsujimura T, Hamaoka T et al (2002) A non-peptide CCR5 antagonist inhibits collageninduced arthritis by modulating T cell migration without affecting any collagen T cell responses. Eur J Immunol 32: 2124–2132PubMedGoogle Scholar
  129. 129.
    Brühl H, Cihak J, Plachy J, Kunz-Schughart L, Niedermeier M, Denzel A, Rodriguez-Gomez M, Talke Y, Luckow B, Stangassinger M, Mack M (2007) Targeting of Gr-1+, CCR2+ monocytes in collagen-induced arthritis. Arthritis Rheum 56: 2975–2985PubMedGoogle Scholar
  130. 130.
    Quinones MP, Ahuja SK, Jimenez F Schaefer J, Garavito E, Rao A, Chenaux G, Reddick RL, Kuziel WA, Ahuja SS (2004) Experimental arthritis in CC chemokine receptor 2-null mice closely mimics severe human rheumatoid arthritis. J Clin Invest 113: 856–866PubMedGoogle Scholar
  131. 131.
    Bao L, Zhu Y, Zhu J, Lindgren JU (2005) Decreased IgG production but increased MIP-1β expression in collagen-induced arthritis in C-C chemokine receptor 5-deficient mice. Cytokine 31: 64–71PubMedGoogle Scholar
  132. 132.
    Clucas AT, Shah A, Zhang YD, Chow VF, Gladue RP (2007) Phase I evaluation of the safety, pharmacokinetics and pharmacodynamics of CP-481,715. Clin Pharmacokinet 46: 757–766PubMedGoogle Scholar
  133. 133.
    Vergunst CE, Gerlag DM, Lopatinskaya L, Klareskog L, Smith MD, van den Bosch F, Dinant HJ, Lee Y, Wyant T, Jacobson EW et al (2008) Modulation of CCR2 in rheumatoid arthritis: A double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum 58: 1931–1939PubMedGoogle Scholar
  134. 134.
    Meanwell NA, Kadow JF (2007) Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS. Curr Opin Investig Drugs 8: 669–681PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2009

Authors and Affiliations

  • Zoltán Szekanecz
    • 1
  • Alisa E. Koch
    • 2
    • 3
  1. 1.Department of Rheumatology, Institute of MedicineUniversity of Debrecen Medical and Health Science CenterDebrecenHungary
  2. 2.Veterans’ AdministrationAnn Arbor Healthcare SystemAnn ArborUSA
  3. 3.Department of Internal Medicine, Division of RheumatologyUniversity of Michigan Health SystemAnn ArborUSA

Personalised recommendations