Journal of Bone and Mineral Metabolism

, Volume 33, Issue 1, pp 40–47

A significant induction of neutrophilic chemoattractants but not RANKL in synoviocytes stimulated with interleukin 17

  • Muneo Ota
  • Maiko Yanagisawa
  • Hideyuki Tachibana
  • Kazuhiro Yokota
  • Yasuto Araki
  • Kojiro Sato
  • Toshihide Mimura
Original Article

Abstract

Interleukin 17 (IL-17) is a cytokine implicated in the promotion of osteoclastogenesis. Its effect has been believed not to be directly exerted on osteoclast precursors, but rather indirectly carried out via an induction of receptor activator of NF-κB ligand (RANKL), the osteoclast differentiation factor, on osteoclast-supporting cells, which in turn exert an effect on osteoclast precursors. The mechanistic details, however, remain unclear. In this study, we first performed a transcriptome analysis of synoviocytes derived from a patient with rheumatoid arthritis cultured in the presence or absence of IL-17. We discovered that most of the genes significantly induced by IL-17 were chemokines with a chemotactic effect on neutrophils. We confirmed these results by quantitative RT-PCR and ELISA. Unexpectedly, the stimulation with IL-17 alone did not induce the expression of RANKL either at the mRNA or the protein level. The induction of RANKL was observed when IL-17 was added in combination with 1,25-dihydroxyvitamin D3 and prostaglandin E2, well-known inducers of RANKL, although the exact mechanism of this synergistic effect remains unclear. IL-6 and monocyte chemoattractant protein-1 were also significantly induced by IL-17 at both the mRNA and protein levels. Thus, it appears that IL-17 induces the migration of neutrophils and monocytes/macrophages through the activation of synoviocytes, and enhances a positive feedback loop composed of proinflammatory cytokines IL-6 and IL-17.

Keywords

Interleukin 17 Osteoclast Synoviocytes Rheumatoid arthritis 

Abbreviations

IL

Interleukin

RANKL

Receptor activator of NF-κB ligand

RA

Rheumatoid arthritis

ODF

Osteoclast differentiation factor

M–CSF

Macrophage colony stimulating factor

IFN

Interferon

FCS

Fetal calf serum

CXCL

Chemokine (C–X–C motif) ligand

CCL

Chemokine (C–C motif) ligand

VD3

1,25-dihydroxyvitamin D3

PGE2

Prostaglandin E2

TRAP

Tartrate-resistant acid phosphatase

MCP-1

Monocyte chemoattractant protein-1

Supplementary material

774_2014_565_MOESM1_ESM.pdf (27 kb)
Supplementary material 1 (PDF 27 kb)

References

  1. 1.
    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176PubMedCrossRefGoogle Scholar
  2. 2.
    Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95:3597–3602PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L (1997) A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390:175–179PubMedCrossRefGoogle Scholar
  4. 4.
    Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS III, Frankel WN, Lee SY, Choi Y (1997) TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem 272:25190–25194PubMedCrossRefGoogle Scholar
  5. 5.
    Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A, Moseley JM, Martin TJ, Suda T (1988) Osteoblastic cells are involved in osteoclast formation. Endocrinology 123:2600–2602PubMedCrossRefGoogle Scholar
  6. 6.
    Kong YY, Feige U, Sarosi I, Bolon B, Tafuri A (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–309PubMedCrossRefGoogle Scholar
  7. 7.
    Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, Nakamura K, Taniguchi T (2000) T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-g. Nature 408:600–605PubMedCrossRefGoogle Scholar
  8. 8.
    Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, Cua DJ, Takayanagi H (2006) Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 203:2673–2682PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132PubMedCrossRefGoogle Scholar
  10. 10.
    Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT, Martin TJ, Suda T (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103:1345–1352PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Yokota K, Miyoshi F, Miyazaki T, Sato K, Yoshida Y, Asanuma Y, Akiyama Y, Mimura T (2008) High concentration simvastatin induces apoptosis in fibroblast-like synoviocytes from patients with rheumatoid arthritis. J Rheumatol 35:193–200PubMedGoogle Scholar
  13. 13.
    Onan D, Allan EH, Quinn JM, Gooi JH, Pompolo S, Sims NA, Gillespie MT, Martin TJ (2009) The chemokine Cxcl1 is a novel target gene of parathyroid hormone (PTH)/PTH-related protein in committed osteoblasts. Endocrinology 150:2244–2253PubMedCrossRefGoogle Scholar
  14. 14.
    Ha J, Choi HS, Lee Y, Kwon HJ, Song YW, Kim HH (2010) CXC chemokine ligand 2 induced by receptor activator of NF-kappa B ligand enhances osteoclastogenesis. J Immunol 184:4717–4724PubMedCrossRefGoogle Scholar
  15. 15.
    Hashizume M, Hayakawa N, Mihara M (2008) IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. Rheumatology (Oxford) 47:1635–1640CrossRefGoogle Scholar
  16. 16.
    Nishimoto N, Kishimoto T (2006) Interleukin 6: from bench to bedside. Nat Clin Pract Rheumatol 2:619–626PubMedCrossRefGoogle Scholar
  17. 17.
    Singh JA, Beg S, Lopez-Olivo MA (2011) Tocilizumab for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol 38:10–20PubMedCrossRefGoogle Scholar
  18. 18.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238PubMedCrossRefGoogle Scholar
  19. 19.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-b induces development of the TH17 lineage. Nature 441:231–234PubMedCrossRefGoogle Scholar
  20. 20.
    Ogura H, Murakami M, Okuyama Y, Tsuruoka M, Kitabayashi C, Kanamoto M, Nishihara M, Iwakura Y, Hirano T (2008) Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity 29:628–636PubMedCrossRefGoogle Scholar
  21. 21.
    Hueber AJ, Asquith DL, Miller AM, Reilly J, Kerr S, Leipe J, Melendez AJ, McInnes IB (2010) Mast cells express IL-17A in rheumatoid arthritis synovium. J Immunol 184:3336–3340PubMedCrossRefGoogle Scholar
  22. 22.
    Suurmond J, Dorjee AL, Boon MR, Knol EF, Huizinga TW, Toes RE, Schuerwegh AJ (2011) Mast cells are the main interleukin 17-positive cells in anticitrullinated protein antibody-positive and -negative rheumatoid arthritis and osteoarthritis synovium. Arthr Res Ther 13:R150CrossRefGoogle Scholar
  23. 23.
    Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, Braun D, Banerjee S (2012) Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 366:1190–1199PubMedCrossRefGoogle Scholar
  24. 24.
    Papp KA, Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G, Aras G, Li J, Russell CB, Thompson EH, Baumgartner S (2012) Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 366:1181–1189PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer Japan 2014

Authors and Affiliations

  • Muneo Ota
    • 1
  • Maiko Yanagisawa
    • 1
  • Hideyuki Tachibana
    • 1
  • Kazuhiro Yokota
    • 1
  • Yasuto Araki
    • 1
  • Kojiro Sato
    • 1
  • Toshihide Mimura
    • 1
  1. 1.Department of Rheumatology and Applied Immunology, Faculty of MedicineSaitama Medical UniversityIruma-gunJapan

Personalised recommendations