Skip to main content

Advertisement

SpringerLink
Log in

The production of CXCR3-agonistic chemokines by synovial fibroblasts from patients with rheumatoid arthritis

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

Abstract

The inflamed synovial tissue of rheumatoid arthritis (RA) is characterized by an infiltration with Th1 cells that predominantly express the chemokine receptors CXCR3 and CCR5. In this study, we investigated the production of the CXCR3-agonistic chemokines CXCL9, CXCL10, and CXCL11 by synovial tissue cells and synovial fibroblast-cell lines (fourth or fifth passage) from RA patients. Concentrations of all CXCR3 ligands in synovial fluids were markedly higher in RA patients than in osteoarthritis (OA) patients. Synovial tissue cells from RA patients more strongly expressed mRNAs for CXCR3 ligands and spontaneously secreted larger amounts of these chemokine proteins than the cells from OA patients. The mRNA expression of all CXCR3 ligands was induced in synovial fibroblasts from RA patients after stimulation with interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), or interleukin-1 beta (IL-1β). However, synovial fibroblasts significantly secreted CXCL9 and CXCL10 proteins, but not CXCL11 protein, after IFN-γ stimulation and secreted only CXCL10 protein after TNF-α or IL-1β stimulation. When stimulated with a combination of IFN-γ and TNF-α, these cells were able to secrete large amounts of all three chemokines. These results indicate that synovial fibroblasts may be involved in perpetuating the Th1 immune response by producing the Th1-associated CXCR3 ligands, and the synergistic effect of IFN-γ and TNF-α may be important for their chemokine production in RA joints.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14:397–440

    PubMed  Google Scholar 

  2. Feldmann M, Maini RN (2001) Anti-TNFα therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 19:163-196

    CAS  PubMed  Google Scholar 

  3. Miossec P, van den Berg W (1997) Th1/Th2 cytokine balance in arthritis. Arthritis Rheum 40:2105-2115

    Google Scholar 

  4. Morita Y, Yamamura M, Kawashima M, Harada S, Tsuji K, Shibuya K, Maruyama K, Makino H (1998) Flow cytometric single-cell analysis of cytokine production byCD4+ T cells in synovial tissue and peripheral blood from patients with rheumatoid arthritis. Arthritis Rheum 41:1669-1676

    PubMed  Google Scholar 

  5. Yamamura M, Kawashima M, Taniai M, Yamauchi H, Tanimoto T, Kurimoto M, Morita Y, Ohmoto Y, Makino H (2001) Interferon-γ-inducing activity of interleukin-18 in the joint with rheumatoid arthritis. Arthritis Rheum 44:275-285

    CAS  PubMed  Google Scholar 

  6. Morita Y, Yamamura M, Nishida K, Harada S, Okamoto H, Inoue H, Ohmoto Y, Modlin RL, Makino H (1998) Expression of interleukin-12 in synovial tissue from patients with rheumatoid arthritis. Arthritis Rheum 41:306-314

    Article  CAS  PubMed  Google Scholar 

  7. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer JM (1998) CCR5 is characteristic of Th1 lymphocytes. Nature 391:344-345

    CAS  PubMed  Google Scholar 

  8. Kim CH, Rott L, Kunkel EJ, Genovese MC, Andrew DP, Wu L, Butcher EC (2001) Rules of chemokine receptor association with T cell polarization in vivo. J Clin Invest 108:1331-1339

    Article  CAS  PubMed  Google Scholar 

  9. 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 44:2750-2760

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Sallusto F, Mackay CR, Lanzavecchia A. (2000) The role of chemokine receptors in primary, effector, and memory immune responses. Annu Rev Immunol 18:593–620

    CAS  PubMed  Google Scholar 

  12. Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383:787–793

    CAS  PubMed  Google Scholar 

  13. Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F (1998) Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1 s) and Th2 s. J Exp Med 187:129–134

    CAS  PubMed  Google Scholar 

  14. Sallusto F, Lenig D, Mackay CR, Lanzavecchia A (1998) Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med 187:875–883

    CAS  PubMed  Google Scholar 

  15. Sauty A, Dziejman M, Taha RA, Iarossi AS, Neote K, Garcia-Zepeda EA, Hamid Q, Luster AD (1999) The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells. J Immunol162:3549–3558

    Google Scholar 

  16. Sorensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, Qin S, Rottman J, Sellebjerg F, Strieter RM, Frederiksen JL, Ransohoff RM (1999) Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest103:807–815

    Google Scholar 

  17. Agostini C, Cassatella M, Zambello R, Trentin L, Gasperini S, Perin A, Piazza F, Siviero M, Facco M, Dziejman M, Chilosi M, Qin S, Luster AD, Semenzato G (1998) Involvement of the IP-10 chemokine in sarcoid granulomatous reactions. J Immunol 161:6413–6420

    CAS  PubMed  Google Scholar 

  18. 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 

  19. Mohan K, Ding Z, Hanly J, Issekutz TB (2002) IFN-γ-inducible T cell α chemoattractant is a potent stimulator of normal human blood T lymphocyte transendothelial migration: differential regulation by IFN-γ and TNF-α. J Immunol168:6420–6428

    Google Scholar 

  20. 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 

  21. Hosaka S, Akahoshi T, Wada C, Kondo H (1994) Expression of the chemokine superfamily in rheumatoid arthritis. Clin Exp Immunol 97:451–457

    CAS  Google Scholar 

  22. Rathanaswami P, Hachicha M, Sadick M, Schall 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 268:5834–5839

    CAS  PubMed  Google Scholar 

  23. Arnett FC, Edworthy SM, Bloch A, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, Medsger TA Jr, Mitchell DM, Neustadt DH, Pinals RS, Schaller JG, Sharp JT, Wilder RL, Hunder GG (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    CAS  PubMed  Google Scholar 

  24. Okamoto H, Yamamura M, Morita Y, Harada S, Makino H, Ota Z. (1997) The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis. Arthritis Rheum 40:1096–1105

    Google Scholar 

  25. Yamamura M, Uyemura K, Deans RJ, Weinberg K, Rea TH, Bloom BR, Modlin RL (1991) Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science 254:277–279

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Liao F, Rabin RL, Yannelli JR, Koniaris LG, Vanguri P, Farber JM (1995) Human Mig chemokine: biochemical and functional characterization. J Exp Med 182:1301–1314

    CAS  PubMed  Google Scholar 

  28. Cole KE, Strick CA, Paradis TJ, Ogborne KT, Loetscher M, Gladue RP, Lin W, Boyd JG, Moser B, Wood DE, Sahagan BG, Neote K (1998) Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J Exp Med 187:2009–2021

    PubMed  Google Scholar 

  29. Mach F, Sauty A, Iarossi AS, Sukhova GK, Neote K, Libby P, Luster AD (1999) Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells. J Clin Invest. 104:1041–1050

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  31. 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 165:6590–6598

    CAS  PubMed  Google Scholar 

  32. Zimmermann T, Kunisch E, Pfeiffer R, Hirth A, Stahl HD, Sack U, Laube A, Liesaus E, Roth A, Palombo-Kinne E, Emmrich F, Kinne RW (2001) Isolation and characterization of rheumatoid arthritis synovial fibroblasts from primary culture—primary culture cells markedly differ from fourth-passage cells. Arthritis Res 3:72–76

    Article  CAS  PubMed  Google Scholar 

  33. Hirth A, Skapenko A, Kinne RW, Emmrich F, Schulze-Koops H, Sack U (2002) Cytokine mRNA and protein expression in primary-culture and repeated-passage synovial fibroblasts from patients with rheumatoid arthritis. Arthritis Res 4:117–125

    Article  CAS  PubMed  Google Scholar 

  34. Aaronson DS, Horvath CM (2002) A road map for those who know JAK-STAT. Science 296:1653–1655

    Article  CAS  PubMed  Google Scholar 

  35. Ghosh S, May MJ, Kopp EB (1998) NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260

    CAS  PubMed  Google Scholar 

  36. Ohmori Y, Hamilton TA (1993) Cooperative interaction between interferon (IFN) stimulus response element and κB sequence motifs controls IFNγ- and lipopolysaccharide-stimulated transcription from the murine IP-10 promoter. J Biol Chem 268:6677–6688

    CAS  PubMed  Google Scholar 

  37. Farber JM (1997) Mig and IP-10: CXC chemokines that target lymphocytes. J Leukoc Biol 61:246–257

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. H. Inoue, Dr. K. Nishida, and Ms A. Yoshida (Okayama University) for providing clinical samples and technical assistance. This work was supported in part by grants-in-aid (10670411/1270426) from the Ministry of Education, Science, and Culture of Japan.

Author information

Authors and Affiliations

  1. Department of Medicine and Clinical Science, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan

    Akiko Ueno, Masahiro Yamamura, Mitsuhiro Iwahashi, Akira Okamoto, Tetsushi Aita & Hirofumi Makino

  2. Department of Brain Science, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan

    Norio Ogawa

Authors
  1. Akiko Ueno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masahiro Yamamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mitsuhiro Iwahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akira Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tetsushi Aita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Norio Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hirofumi Makino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masahiro Yamamura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ueno, A., Yamamura, M., Iwahashi, M. et al. The production of CXCR3-agonistic chemokines by synovial fibroblasts from patients with rheumatoid arthritis. Rheumatol Int 25, 361–367 (2005). https://doi.org/10.1007/s00296-004-0449-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-004-0449-x

Keywords

Search

Navigation