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Etanercept reduces the serum levels of macrophage chemotactic protein-1 in patients with rheumatoid arthritis

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Modern Rheumatology

Abstract

This study was performed to analyze the effect of etanercept, the soluble tumor necrosis factor-α (TNF-α) receptor, on the serum levels of several chemokines including monocyte chemotactic protein-1 (MCP-1), regulated upon activation normal T expressed and presumably secreted (RANTES), and granzyme B in rheumatoid arthritis (RA) patients. Twenty-eight patients with RA were administered etanercept once or twice a week for more than 6 months. Clinical and laboratory parameters were measured and serum levels of MCP-1, RANTES, and granzyme B were determined using enzyme-linked immunosorbent assay (ELISA) kits at baseline and at 3 and 6 months after the initial treatment. In addition, the levels of MCP-1, RANTES, and granzyme B produced by cultured synovial cells stimulated with TNF-α were measured. A significant decrease in serum MCP-1 levels was observed at 3 and 6 months after initial treatment with etanercept. Serum RANTES and granzyme B levels did not show significant changes. TNF-α induced MCP-1, RANTES, and granzyme B production in cultured synovial cells from RA patients. Serum MCP-1 levels were significantly correlated with the disease activity scores of 28 joints combined with CRP (DAS28-CRP), indicating the role of MCP-1 in the pathogenesis of rheumatoid inflammation. This study demonstrated that a reduction of MCP-1 production in RA patients was a newly determined effect of etanercept. Another cascade not associated with TNF-α may induce granzyme B and RANTES production in RA patients.

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References

  1. Arend WP, Dayer J-M. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 1995;38:151–60.

    Article  PubMed  CAS  Google Scholar 

  2. Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Ann Rev Med. 2000;51:207–29.

    Article  PubMed  CAS  Google Scholar 

  3. Woo CH, Kim TH, Choi JA, Ryu HC, Lee JE, You HJ, et al. Inhibition of receptor internalization attenuates the TNF alpha-induced ROS generation in non-phagocytic cells. Biochem Biophys Res Commun. 2006;351:972–8.

    Article  PubMed  CAS  Google Scholar 

  4. Sakon S, Xue X, Takekawa M, Sasazuki T, Okazaki T, Kojima Y, et al. NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J. 2003;22:3898–909.

    Article  PubMed  CAS  Google Scholar 

  5. Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN. Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum. 1998;41:1258–65.

    Article  PubMed  CAS  Google Scholar 

  6. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Ann Rev Immunol. 2001;19:163–96.

    Article  CAS  Google Scholar 

  7. Pittoni V, Bombardieri M, Spinelli FR, Scrivo R, Alessandri C, Conti F, et al. Anti-tumor necrosis factor (TNF) alpha treatment of rheumatoid arthritis (infliximab) selectively down regulates the production of interleukin (IL) 18 but not of IL12 and IL13. Ann Rheum Dis. 2002;61:723–5.

    Article  PubMed  CAS  Google Scholar 

  8. Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J. Effect of repeated infliximab therapy on serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with rheumatoid arthritis. J Rheumatol. 2004;31:238–42.

    PubMed  CAS  Google Scholar 

  9. Kageyama Y, Takahashi M, Torikai E, Suzuki M, Ichikawa T, Nagafusa T, et al. Treatment with anti-TNF-alpha antibody infliximab reduces serum IL-15 levels in patients with rheumatoid arthritis. Clin Rheumatol. 2007;26:505–9.

    Article  PubMed  Google Scholar 

  10. Torikai E, Kageyama Y, Suzuki M, Ichikawa T, Nagano A. The effect of infliximab on chemokines in patients with rheumatoid arthritis. Clin Rheumatol. 2007;26:1088–93.

    Article  PubMed  Google Scholar 

  11. Kageyama Y, Ichikawa T, Nagafusa T, Torikai E, Shimazu M, Nagano A. Etanercept reduces the serum levels of interleukin-23 and macrophage inflammatory protein-3 alpha in patients with rheumatoid arthritis. Rheumatol Int. 2007;28:137–43.

    Article  PubMed  CAS  Google Scholar 

  12. Zoja C, Wang JM, Bettoni S, Sironi M, Renzi D, Chiaffarino F, et al. Interleukin-1 beta and tumor necrosis factor-alpha induce gene expression and production of leukocyte chemotactic factors, colony-stimulating factors, and interleukin-6 in human mesangial cells. Am J Pathol. 1991;138:991–1003.

    PubMed  CAS  Google Scholar 

  13. Visser CE, Tekstra J, Brouwer-Steenbergen JJ, Tuk CW, Boorsma DM, Sampat-Sardjoepersad SC, et al. Chemokines produced by mesothelial cells: huGRO-alpha, IP-10, MCP-1 and RANTES. Clin Exp Immunol. 1998;112:270–5.

    Article  PubMed  CAS  Google Scholar 

  14. Harigai M, Hara M, Yoshimura T, Leonard EJ, Inoue K, Kashiwazaki S. Monocyte chemoattractant protein-1 (MCP-1) in inflammatory joint diseases and its involvement in the cytokine network of rheumatoid synovium. Clin Immunol Immunopathol. 1993;69:83–91.

    Article  PubMed  CAS  Google Scholar 

  15. Guilloton F, Jean C, de Thonel A, Laurent G, Quillet-Mary A. Granzyme B induction signaling pathway in acute myeloid leukemia cell lines stimulated by tumor necrosis factor alpha and Fas ligand. Cell Signal. 2007;19:1132–40.

    Article  PubMed  CAS  Google Scholar 

  16. Kageyama Y, Takahashi M, Nagafusa T, Torikai E, Nagano A. Etanercept reduces the oxidative stress marker levels in patients with rheumatoid arthritis. Rheumatol Int. 2008;28:245–51.

    Article  PubMed  CAS  Google Scholar 

  17. Takahashi M, Ohishi T, Aoshima H, Kawana K, Kushida K, Inoue T, Horiuchi K. The Maillard protein cross-link pentosidine in urine from diabetic patients. Diabetologia. 1993;36:664–7.

    Article  PubMed  CAS  Google Scholar 

  18. Catrina AI, Lampa J, Ernestam S, Klint E, Bratt J, Klareskog L, et al. Anti-tumor necrosis factor (TNF)-alpha therapy (etanercept) down-regulates serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis. Rheumatology (Oxford). 2002;41:484–9.

    Article  CAS  Google Scholar 

  19. Valente AJ, Graves DT, Vialle-Valentin CE, Delgado R, Schwartz CJ. Purification of a monocyte chemotactic factor secreted by nonhuman primate vascular cells in culture. Biochemistry. 1988;27:4162–8.

    Article  PubMed  CAS  Google Scholar 

  20. Huffnagle GB, Strieter RM, Standiford TJ, McDonald RA, Burdick MD, Kunkel SL, et al. The role of monocyte chemotactic protein-1 (MCP-1) in the recruitment of monocytes and CD4+ T cells during a pulmonary Cryptococcus neoformans infection. J Immunol. 1995;155:4790–7.

    PubMed  CAS  Google Scholar 

  21. Husson H, Carideo EG, Cardoso AA, Lugli SM, Neuberg D, Munoz O, et al. MCP-1 modulates chemotaxis by follicular lymphoma cells. Br J Haematol. 2001;115:554–62.

    Article  PubMed  CAS  Google Scholar 

  22. Allavena P, Bianchi G, Zhou D, van Damme J, Jílek P, Sozzani S, et al. Induction of natural killer cell migration by monocyte chemotactic protein-1, -2 and -3. Eur J Immunol. 1994;24:3233–6.

    Article  PubMed  CAS  Google Scholar 

  23. Taub DD, Sayers TJ, Carter CR, Ortaldo JR. Alpha and beta chemokines induce NK cell migration and enhance NK-mediated cytolysis. J Immunol. 1995;155:3877–88.

    PubMed  CAS  Google Scholar 

  24. Carr MW, Roth SJ, Luther E, Rose SS, Springer TA. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci USA. 1994;91:3652–6.

    Article  PubMed  CAS  Google Scholar 

  25. Pulsatelli L, Dolzani P, Piacentini A, Silvestri T, Ruggeri R, Gualtieri G, et al. Chemokine production by human chondrocytes. J Rheumatol. 1999;26:1992–2001.

    PubMed  CAS  Google Scholar 

  26. Vogel CF, Nishimura N, Sciullo E, Wong P, Li W, Matsumura F. Modulation of the chemokines KC and MCP-1 by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Arch Biochem Biophys. 2007;461:169–75.

    Article  PubMed  CAS  Google Scholar 

  27. Antoniades HN, Neville-Golden J, Galanopoulos T, Kradin RL, Valente AJ, Graves DT. Expression of monocyte chemoattractant protein 1 mRNA in human idiopathic pulmonary fibrosis. Proc Natl Acad Sci USA. 1992;89:5371–80.

    Article  PubMed  CAS  Google Scholar 

  28. Daly C, Rollins BJ. Monocyte chemoattractant protein-1 (CCL2) in inflammatory disease and adaptive immunity: therapeutic opportunities and controversies. Microcirculation. 2003;10:247–57.

    PubMed  CAS  Google Scholar 

  29. Ellingsen T, Buus A, Stengaard-Pedersen K. Plasma monocyte chemoattractant protein 1 is a marker for joint inflammation in rheumatoid arthritis. J Rheumatol. 2001;28:41–6.

    PubMed  CAS  Google Scholar 

  30. Hayashida K, Nanki T, Girschick H, Yavuz S, Ochi T, Lipsky PE. Synovial stromal cells from rheumatoid arthritis patients attract monocytes by producing MCP-1 and IL-8. Arthritis Res. 2001;3:118–26.

    Article  PubMed  CAS  Google Scholar 

  31. Koch AE, Kunkel SL, Harlow LA, Johnson B, Evanoff HL, Haines GK, et al. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest. 1992;90:772–9.

    Article  PubMed  CAS  Google Scholar 

  32. Koch AE, Kunkel SL, Harlow LA, Mazarakis DD, Haines GK, Burdick MD, et al. Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest. 1994;93:921–8.

    Article  PubMed  CAS  Google Scholar 

  33. Ogata H, Takeya M, Yoshimura T, Takagi K, Takahashi K. The role of monocyte chemoattractant protein-1 (MCP-1) in the pathogenesis of collagen-induced arthritis in rats. J Pathol. 1997;182:106–14.

    Article  PubMed  CAS  Google Scholar 

  34. Gong JH, Ratkay LG, Waterfield JD, Lewis IC. An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model. J Exp Med. 1997;186:131–7.

    Article  PubMed  CAS  Google Scholar 

  35. Haringman JJ, Gerlag DM, Smeets TJ, Baeten D, van den Bosch F, Bresnihan B, et al. A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:2387–92.

    Article  PubMed  CAS  Google Scholar 

  36. Yoo JK, Kwon H, Khil LY, Zhang L, Jun HS, Yoon JW. IL-18 Induces monocyte chemotactic protein-1 production in macrophages through the phosphatidylinositol 3-kinase/Akt and MEK/ERK1/2 pathways. J Immunol. 2005;175:8280–6.

    PubMed  CAS  Google Scholar 

  37. Badolato R, Ponzi AN, Millesimo M, Notarangelo LD, Musso T. Interleukin-15 (IL-15) induces IL-8 and monocyte chemotactic protein 1 production in human monocytes. Blood. 1997;90:2804–9.

    PubMed  CAS  Google Scholar 

  38. Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J. Regulation of serum chemokines following infliximab therapy in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2006;24:529–33.

    PubMed  CAS  Google Scholar 

  39. Taylor PC, Peters AM, Paleolog E, Chapman PT, Elliott MJ, McCloskey R, et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum. 2000;43:38–47.

    Article  PubMed  CAS  Google Scholar 

  40. Luster AD. Chemokines–chemotactic cytokines that mediate inflammation. N Engl J Med. 1998;338:436–45.

    Article  PubMed  CAS  Google Scholar 

  41. Baggiolini M. Chemokines and leukocyte traffic. Nature. 1998;392:565–8.

    Article  PubMed  CAS  Google Scholar 

  42. Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12:121–7.

    Article  PubMed  CAS  Google Scholar 

  43. Inoue T, Yamashita M, Higaki M. The new antirheumatic drug KE-298 suppresses monocyte chemoattractant protein (MCP)-1 and RANTES production in rats with adjuvant-induced arthritis and in IL-1-stimulated synoviocytes of patients with rheumatoid arthritis. Rheumatol Int. 2001;20:149–53.

    Article  PubMed  CAS  Google Scholar 

  44. Plater-Zyberk C, Hoogewerf AJ, Proudfoot AE, Power CA, Wells TN. Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol Lett. 1997;57:117–20.

    Article  PubMed  CAS  Google Scholar 

  45. Barnes DA, Tse J, Kaufhold M, Owen M, Hesselgesser J, Strieter R, et al. Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J Clin Invest. 1998;101:2910–9.

    Article  PubMed  CAS  Google Scholar 

  46. Boiardi L, Macchioni P, Meliconi R, Pulsatelli L, Facchini A, Salvarani C. Relationship between serum RANTES levels and radiological progression in rheumatoid arthritis patients treated with methotrexate. Clin Exp Rheumatol. 1999;17:419–25.

    PubMed  CAS  Google Scholar 

  47. Liu CC, Persechini PM, Young JD. Perforin and lymphocyte-mediated cytolysis. Immunol Rev. 1995;146:145–75.

    Article  PubMed  CAS  Google Scholar 

  48. Ronday HK, van der Laan WH, Tak PP, de Roos JA, Bank RA, TeKoppele JM, et al. Human granzyme B mediates cartilage proteoglycan degradation and is expressed at the invasive front of the synovium in rheumatoid arthritis. Rheumatology (Oxford). 2001;40:55–61.

    Article  CAS  Google Scholar 

  49. Tak PP, Spaeny-Dekking L, Kraan MC, Breedveld FC, Froelich CJ, Hack CE. The levels of soluble granzyme A and B are elevated in plasma and synovial fluid of patients with rheumatoid arthritis (RA). Clin Exp Immunol. 1999;116:366–70.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Heisei Memorial Hospital, 123-1 Mizugami, Fujieda, 426-8662, Japan

    Yasunori Kageyama, Hayato Kobayashi & Norihiko Kato

  2. Department of Orthopaedic Surgery, Shimazu Clinic, 2-7-23 Takayanagi, Fujieda, 426-0041, Japan

    Masahiro Shimazu

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  1. Yasunori Kageyama
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  2. Hayato Kobayashi
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  4. Masahiro Shimazu
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Correspondence to Yasunori Kageyama.

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Kageyama, Y., Kobayashi, H., Kato, N. et al. Etanercept reduces the serum levels of macrophage chemotactic protein-1 in patients with rheumatoid arthritis. Mod Rheumatol 19, 372–378 (2009). https://doi.org/10.1007/s10165-009-0175-z

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  • DOI: https://doi.org/10.1007/s10165-009-0175-z

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