Skip to main content

Advertisement

Log in

Etanercept treatment reduces the serum levels of interleukin-15 and interferon-gamma inducible protein-10 in patients with rheumatoid arthritis

  • Orginal Article
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

Tumor necrosis factor-α (TNF-α) has an essential role in the pathogenesis of rheumatoid arthritis (RA) and has been known to induce the production of several inflammatory molecules in vivo. To analyze in vivo the active mechanism of the TNF-α blocking agent, etanercept, the serum levels of the cytokine interleukin-15 (IL-15) and the chemokines growth-regulated protein-α (Gro-α), and interferon-γ inducible protein-10 (IP-10) in RA patients were measured. Twenty-two patients with RA were administered etanercept once or twice a week for more than 6 months. The clinical and laboratory parameters were measured and serum levels of IL-15, Gro-α, and IP-10 were determined using enzyme-linked immunosorbent assay (ELISA) kits at the baseline and at 3 and 6 months after the initial treatment. Additionally, the production of IL-15 and IP-10 by cultured synovial cells stimulated with TNF-α from RA patients was determined by ELISA. A significant decrease in serum levels of IL-15 and IP-10 was observed at 3 and 6 months after initial treatment with etanercept, but not in those of Gro-α. TNF-α induced production of IP-10, but not IL-15 in cultured synovial cells from RA patients. This study demonstrated for the first time the reduction of IP-10 and IL-15 production in RA patients as active mechanisms of etanercept.

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.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Arend WP, Dayer J-M (1995) Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum 38:151–160

    Article  CAS  PubMed  Google Scholar 

  2. Maini RN, Taylor PC (2000) Anti-cytokine therapy for rheumatoid arthritis. Ann Rev Med 51:207–229

    Article  CAS  PubMed  Google Scholar 

  3. Woo CH, Kim TH, Choi JA, Ryu HC, Lee JE, You HJ et al (2006) Inhibition of receptor internalization attenuates the TNF alpha-induced ROS generation in non-phagocytic cells. Biochem Biophys Res Commun 351:972–978

    Article  CAS  PubMed  Google Scholar 

  4. Sakon S, Xue X, Takekawa M, Sasazuki T, Okazaki T, Kojima Y et al (2003) NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J 22:3898–3909

    Article  CAS  PubMed  Google Scholar 

  5. Kageyama Y, Takahashi M, Torikai E, Suzuki M, Ichikawa T, Nagafusa T et al (2007) Treatment with anti-TNF-alpha antibody infliximab reduces serum IL-15 levels in patients with rheumatoid arthritis. Clin Rheumatol 26:505–509

    Article  PubMed  Google Scholar 

  6. Torikai E, Kageyama Y, Suzuki M, Ichikawa T, Nagano A (2007) The effect of infliximab on chemokines in patients with rheumatoid arthritis. Clin Rheumatol 26:1088–1093

    Article  PubMed  Google Scholar 

  7. Kageyama Y, Torikai E, Nagano A (2007) Anti-tumor necrosis factor-alpha antibody treatment reduces serum CXCL16 levels in patients with rheumatoid arthritis. Rheumatol Int 27:467–472

    Article  CAS  PubMed  Google Scholar 

  8. Neville LF, Mathiak G, Bagasra O (1997) The immunobiology of interferon-gamma inducible protein 10 kD (IP-10): a novel, pleiotropic member of the C-X-C chemokine superfamily. Cytokine Growth Factor Rev 8:207–219

    Article  CAS  PubMed  Google Scholar 

  9. Hanaoka R, Kasama T, Muramatsu M, Yajima N, Shiozawa F, Miwa Y et al (2003) A novel mechanism for the regulation of IFN-gamma inducible protein-10 expression in rheumatoid arthritis. Arthritis Res Ther 5:74–81

    Article  Google Scholar 

  10. Berthier-Vergnes O, Bermond F, Flacher V, Massacrier C, Schmitt D, Péguet-Navarro J (2005) TNF-alpha enhances phenotypic and functional maturation of human epidermal Langerhans cells and induces IL-12 p40 and IP-10/CXCL-10 production. FEBS Lett 579:60–68

    Google Scholar 

  11. Thorburn E, Kolesar L, Brabcova E, Petrickova K, Petricek M, Jaresova M et al (2009) CXC and CC chemokines induced in human renal epithelial cells by inflammatory cytokines. APMIS 117:477–487

    Article  CAS  PubMed  Google Scholar 

  12. Boorsma DM, de Haan P, Willemze R, Stoof TJ (1994) Human growth factor (huGRO), interleukin-8 (IL-8) and interferon-gamma-inducible protein (gamma-IP-10) gene expression in cultured normal human keratinocytes. Arch Dermatol Res 286:471–475

    Article  CAS  PubMed  Google Scholar 

  13. Ogata Y, Kukita A, Kukita T, Komine M, Miyahara A, Miyazaki S et al (1999) A novel role of IL-15 in the development of osteoclasts: inability to replace its activity with IL-2. J Immunol 162:2754–2760

    CAS  PubMed  Google Scholar 

  14. König A, Krenn V, Toksoy A, Gerhard N, Gillitzer R (2000) Mig, GRO alpha and RANTES messenger RNA expression in lining layer, infiltrates and different leucocyte populations of synovial tissue from patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Virchows Arch 436:449–458

    Article  PubMed  Google Scholar 

  15. 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 57:117–120

    Article  CAS  PubMed  Google Scholar 

  16. Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J (2004) Effect of repeated infliximab therapy on serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with rheumatoid arthritis. J Rheumatol 31:238–242

    CAS  PubMed  Google Scholar 

  17. Zhang HG, Hyde K, Page GP, Brand JP, Zhou J, Yu S et al (2004) Novel tumor necrosis factor alpha-regulated genes in rheumatoid arthritis. Arthritis Rheum 50:420–431

    Article  CAS  PubMed  Google Scholar 

  18. Zoja C, Wang JM, Bettoni S, Sironi M, Renzi D, Chiaffarino F et al (1991) 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 138:991–1003

    CAS  PubMed  Google Scholar 

  19. Visser CE, Tekstra J, Brouwer-Steenbergen JJ, Tuk CW, Boorsma DM, Sampat-Sardjoepersad SC et al (1998) Chemokines produced by mesothelial cells: huGRO-alpha, IP-10, MCP-1 and RANTES. Clin Exp Immunol 112:270–275

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Arend WP, Dayer JM (1990) Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum 33:305–315

    Article  CAS  PubMed  Google Scholar 

  22. Harada S, Yamamura M, Okamoto H, Morita Y, Kawashima M, Aita T, Makino H (1999) Production of interleukin-7 and interleukin-15 by fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum 42:1508–1516

    Article  CAS  PubMed  Google Scholar 

  23. Miranda-Carus ME, Balsa A, Benito-Miguel M, Perez de Ayala C, Martin-Mola E (2004) IL-15 and the initiation of cell contact-dependent synovial fibroblast-T lymphocyte cross-talk in rheumatoid arthritis: effect of methotrexate. J Immunol 173:1463–1476

    CAS  PubMed  Google Scholar 

  24. Raza K, Falciani F, Curnow SJ, Ross EJ, Lee CY, Akbar AN et al (2005) Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther 7:784–795

    Article  Google Scholar 

  25. Ruchatz H, Leung BP, Wei XQ, McInnes IB, Liew FY (1998) Soluble IL-15 receptor alpha-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J Immunol 160:5654–5660

    CAS  PubMed  Google Scholar 

  26. Ferrari-Lacraz S, Zanelli E, Neuberg M, Donskoy E, Kim YS, Zheng XX et al (2004) Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis. J Immunol 173:5818–5826

    CAS  PubMed  Google Scholar 

  27. Ernestam S, af Klint E, Catrina AI, Sundberg E, Engström M, Klareskog L, Ulfgren AK (2006) Synovial expression of IL-15 in rheumatoid arthritis is not influenced by blockade of tumour necrosis factor. Arthritis Res Ther 8:R18

    Article  PubMed  Google Scholar 

  28. Bédard PA, Golds EE (1993) Cytokine-induced expression of mRNAs for chemotactic factors in human synovial cells and fibroblasts. Cell Physiol 154:433–441

    Article  Google Scholar 

  29. Boorsma DM, Flier J, Sampat S, Ottevanger C, de Haan P, Hooft L et al (1998) Chemokine IP-10 expression in cultured human keratinocytes. Arch Dermatol Res 290:335–341

    Article  CAS  PubMed  Google Scholar 

  30. Cassatella MA, Gasperini S, Calzetti F, Bertagnin A, Luster AD, McDonald PP (1997) Regulated production of the interferon-gamma-inducible protein-10 (IP-10) chemokine by human neutrophils. Eur J Immunol 27:111–115

    Article  CAS  PubMed  Google Scholar 

  31. Ebnet K, Simon MM, Shaw S (1996) Regulation of chemokine gene expression in human endothelial cells by proinflammatory cytokines and Borrelia burgdorferi. Ann N Y Acad Sci 797:107–117

    Article  CAS  PubMed  Google Scholar 

  32. Luster AD, Unkeless JC, Ravetch JV (1985) Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature 315:672–676

    Article  CAS  PubMed  Google Scholar 

  33. Luster AD (1998) Chemokines-chemotactic cytokines that mediate inflammation. N Engl J Med 338:436–445

    Article  CAS  PubMed  Google Scholar 

  34. Luster AD, Ravetch JV (1987) Biochemical characterization of a gamma interferon-inducible cytokine (IP-10). J Exp Med 166:1084–1097

    Article  CAS  PubMed  Google Scholar 

  35. Neville LF, Mathiak G, Bagasra O (1997) The immunobiology of interferon-gamma inducible protein 10 kD (IP-10): a novel, pleiotropic member of the C-X-C chemokine superfamily. Cytokine Growth Factor Rev 8:207–219

    Article  CAS  PubMed  Google Scholar 

  36. Kwak HB, Ha H, Kim HN, Lee JH, Kim HS, Lee S et al (1997) Reciprocal cross-talk between RANKL and interferon-gamma-inducible protein 10 is responsible for bone-erosive experimental arthritis. Arthritis Rheum 58:1332–1342

    Article  Google Scholar 

  37. Hanaoka R, Kasama T, Muramatsu M, Yajima N, Shiozawa F, Miwa Y et al (2003) A novel mechanism for the regulation of IFN-gamma inducible protein-10 expression in rheumatoid arthritis. Arthritis Res Ther 5:74–81

    Article  Google Scholar 

  38. Patel DD, Zachariah JP, Whichard LP (2001) CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. Clin Immunol 98:39–45

    Article  CAS  PubMed  Google Scholar 

  39. Rigby WF (2007) Drug insight: different mechanisms of action of tumor necrosis factor antagonists-passive-aggressive behavior? Nat Clin Pract Rheumatol 3:227–233

    Article  CAS  PubMed  Google Scholar 

  40. Mitoma H, Horiuchi T, Hatta N, Tsukamoto H, Harashima S, Kikuchi Y et al (2005) Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-alpha. Gastroenterology 128:376–392

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

In this study, I appreciate the cooperation of the division of host defense at the department of infectious disease in Hamamatsu University School of Medicine for the measurement of the levels of a cytokine and chemokines.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yasunori Kageyama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ichikawa, T., Kageyama, Y., Kobayashi, H. et al. Etanercept treatment reduces the serum levels of interleukin-15 and interferon-gamma inducible protein-10 in patients with rheumatoid arthritis. Rheumatol Int 30, 725–730 (2010). https://doi.org/10.1007/s00296-009-1356-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-009-1356-y

Keywords

Navigation