Skip to main content

Advertisement

SpringerLink
Log in

Th-17 associated cytokines in patients with reactive arthritis/undifferentiated spondyloarthropathy

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

Abstract

We and others have previously shown that IL-17 is elevated in the synovial fluid of patients with reactive arthritis (ReA)/undifferentiated spondyloarthropathy (uSpA) having acute synovitis. Major source for IL-17 is Th17 cells, which differentiate from Th0 cells under the influence of TGF-β and IL-6, IL1-β and are maintained by IL-21 and 23. There is a paucity of data on these cytokines in ReA/uSpA. Thus, we measured the levels of Th-17 differentiating and maintaining cytokines in synovial fluid of patients with ReA and uSpA. Fifty patients with ReA/uSpA (ReA 24, uSpA 26), 19 patients with rheumatoid arthritis (RA) and 11 patients with osteoarthritis (OA) were included in the study. Synovial fluid (SF) were collected from knee joint and stored at −80°C until analysis. Cytokines were assayed using ELISA in SF specimens. The median IL-17A levels were significantly elevated in ReA (48.3 pg/ml) and uSpA (32.5 pg/ml) as compared to non-inflammatory OA controls (<7.8 pg/ml; p < 0.0001), while comparable to RA (57.9 pg/ml). Further, IL-6 median values were higher in ReA (25.2 ng/ml) and uSpA (13.6 ng/ml) as compared to OA (0.76 ng/ml; p < 0.0001), and comparable to RA (15.8 ng/ml). The median levels of IL-1β, IL-21 levels were elevated in ReA, uSpA and RA as compared to OA but were not statistically significant. TGF-β levels in ReA and uSpA were similar to OA but lower than in RA (4340 pg/ml; p < 0.05). IL-23 was not detectable in any synovial fluid sample. However, levels of these cytokines did not correlate with disease activity parameters. Significant positive correlation was observed between IL-17 and IL-1β (r = 0.38, p < 0.005), IL-17 and IL-6 (r = 0.659, p < 0.0001), and IL-1β and IL-6 (r = 0.391, p < 0.0001) in ReA and uSpA group. Inflammatory synovitis in ReA/uSpA is mediated by pro-inflammatory cytokines like IL-17, IL-6, IL-1β, and IL-21. However, IL-23 was not detectable in SF. Good correlation between IL-17, IL-6, and IL 1β suggest that either they are co-regulated or they regulate each other.

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

Similar content being viewed by others

References

  1. Braun J, Sieper J (1996) The sacroiliac joint in the spondyloarthropathies. Curr Opin Rheumatol 8:275–287

    Article  PubMed  CAS  Google Scholar 

  2. Yu D, Kuipers JG (2003) Role of bacteria and HLA-B27 in the pathogenesis of reactive arthritis. Rheum Dis Clin North Am 29:21–36

    Article  PubMed  Google Scholar 

  3. Sieper J (2001) Pathogenesis of reactive arthritis. Curr Rheumatol Rep 3:412–418

    Article  PubMed  CAS  Google Scholar 

  4. Sallusto F, Lanzavecchia A (2009) Human Th17 cells in infection and autoimmunity. Microbes Infect 11:620–624

    Article  PubMed  CAS  Google Scholar 

  5. Chabaud M, Durand JM, Buchs N, Fossiez F, Page G, Frappart L et al (1999) Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 42:963–970

    Article  PubMed  CAS  Google Scholar 

  6. RL Van bezooijen, Farih-Sips HC, Papapoulos SE, Lowik CW (1999) Interleukin-17: A new bone acting cytokine in vitro. J Bone Miner Res 14:1513–1521

    Article  Google Scholar 

  7. Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y et al (2006) Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 203:2673–2682

    Article  PubMed  CAS  Google Scholar 

  8. Burchill MA, Nardelli DT, England DM, DeCoster DJ, Christopherson JA, Callister SM et al (2003) Inhibition of interleukin-17 prevents the development of arthritis in vaccinated mice challenged with Borrelia burgdorferi. Infect Immun 71:3437–3442

    Article  PubMed  CAS  Google Scholar 

  9. Singh R, Aggarwal A, Misra R (2007) Th1/Th17 cytokine profiles in patients with reactive arthritis/undifferentiated spondyloarthropathy. J Rheumatol 34:2285–2290

    PubMed  CAS  Google Scholar 

  10. Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD et al (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453:236–240

    Article  PubMed  CAS  Google Scholar 

  11. Thomas Korn EB, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517

    Article  PubMed  Google Scholar 

  12. Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M et al (2008) IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454(7202):350–352

    Article  PubMed  CAS  Google Scholar 

  13. McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM et al (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10:314–324

    Article  PubMed  CAS  Google Scholar 

  14. Dougados M, van der Linden S, Juhlin R et al (1991) The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 34:1218–1227

    Article  PubMed  CAS  Google Scholar 

  15. Shahrara S, Huang Q, Mandelin AM 2nd, Pope RM (2008) TH-17 cells in rheumatoid arthritis. Arthritis Res Ther 10:R93

    Article  PubMed  Google Scholar 

  16. Agarwal S, Misra R, Aggarwal A (2008) Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases. J Rheumatol 35:515–519

    PubMed  CAS  Google Scholar 

  17. Nardelli DT, Kevin Luk KH, Kotloski NJ, Warner TF, Torrealba JR, Callister SM et al (2008) Role of IL-17, transforming growth factor-beta, and IL-6 in the development of arthritis and production of anti-outer surface protein a borreliacidal antibodies in Borrelia-vaccinated and -challenged mice. FEMS Immunol Med Microbiol 53:265–274

    Article  PubMed  CAS  Google Scholar 

  18. Schlaak J, Pfers I, Meyer zum Büschenfelde K, Märker-Hermann E (1996) Different cytokine profiles in the synovial fluid of patients with osteoarthritis, rheumatoid arthritis and seronegative spondylarthropathies. Clin Exp Rheumatol 14:155–162

    PubMed  CAS  Google Scholar 

  19. Kahle P, Saal J, Schaudt K, Zacher J, Fritz P, Pawelec G (1992) Determination of cytokines in synovial fluids: correlation with diagnosis and histomorphological characteristics of synovial tissue. Ann Rheum Dis 51:731–734

    Article  PubMed  CAS  Google Scholar 

  20. Langrish C, Chen Y, Blumenschein W, Mattson J, Basham B, Sedgwick J et al (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240

    Article  PubMed  CAS  Google Scholar 

  21. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24:677–688

    Article  PubMed  CAS  Google Scholar 

  22. Veldhoen M, Hocking R, Atkins C, Locksley R, Stockinger B (2006) TGF in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189

    Article  PubMed  CAS  Google Scholar 

  23. Chen Z, Tato C, Muul L, Laurence A, O'Shea J (2007) Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum 56:2936–2946

    Article  PubMed  CAS  Google Scholar 

  24. Wilson N, Boniface K, Chan J, McKenzie B, Blumenschein W, Mattson J et al (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8:950–957

    Article  PubMed  CAS  Google Scholar 

  25. Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS et al (2009) Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30:576–587

    Article  PubMed  CAS  Google Scholar 

  26. Kimura A, Naka T, Kishimoto T (2007) IL-6-dependent and-independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci USA 104:12099–12104

    Article  PubMed  CAS  Google Scholar 

  27. Nurieva R, Yang X, Martinez G, Zhang Y, Panopoulos A, Ma L et al (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448:480–483

    Article  PubMed  CAS  Google Scholar 

  28. Jüngel A, Distler J, Kurowska-Stolarska M, Seemayer C, Seibl R, Forster A et al (2004) Expression of interleukin-21 receptor, but not interleukin-21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis. Arthritis Rheum 50:1468–1476

    Article  PubMed  Google Scholar 

  29. Mahendra A, Misra R, Aggarwal A (2009) Th1 and Th17 predominance in the enthesitis-related arthritis form of juvenile idiopathic arthritis. J Rheumatol 36:1730–1736

    Article  PubMed  CAS  Google Scholar 

  30. Wendling D, Cedoz JP et al (2009) Serum and synovial fluid levels of p40 IL12/23 in spondyloarthropathy patients. Clin Rheumatol 28:187–190

    Article  PubMed  Google Scholar 

  31. Bas S, Kvien T, Buchs N, Fulpius T, Gabay C (2003) Lower level of synovial fluid interferon-{gamma} in HLA-B27-positive than in HLA-B27-negative patients with Chlamydia trachomatis reactive arthritis. Rheumatology 42:461–467

    Article  PubMed  CAS  Google Scholar 

  32. Wendling D, Cedoz J, Racadot E, Dumoulin G (2007) Serum IL-17, BMP-7, and bone turnover markers in patients with ankylosing spondylitis. Joint Bone Spine 74:304–305

    Article  PubMed  CAS  Google Scholar 

  33. Melis L, Vandooren B, Kruithof E, Jacques P, De Vos M, Mielants H et al (2010) Systemic levels of IL-23 are strongly associated with disease activity in rheumatoid arthritis but not spondyloarthritis. Ann Rheum Dis 69:618–623

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

AKS is a recipient of a Senior Research Fellowship of the University Grants Commission of India.

Disclosures

None

Author information

Authors and Affiliations

  1. Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, 226014

    Amit Kumar Singh, Ramnath Misra & Amita Aggarwal

Authors
  1. Amit Kumar Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ramnath Misra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amita Aggarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amita Aggarwal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Singh, A.K., Misra, R. & Aggarwal, A. Th-17 associated cytokines in patients with reactive arthritis/undifferentiated spondyloarthropathy. Clin Rheumatol 30, 771–776 (2011). https://doi.org/10.1007/s10067-010-1646-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-010-1646-5

Keywords

Search

Navigation