Expression of IL-17 Homologs and Their Receptors in the Synovial Cells of Rheumatoid Arthritis Patients

  • Hwang, Sue-Yun (Graduate School of Biology and Information Technology, Institute of Genetic Engineering, Hankyong National University) ;
  • Kim, Ho-Youn (Rheumatism Research Center, The Catholic University of Korea)
  • Received : 2004.09.10
  • Accepted : 2004.11.22
  • Published : 2005.04.30

Abstract

IL-17 is a major proinflammatory cytokine secreted by activated T-lymphocytes that accumulates in the inflamed joints of rheumatoid arthritis (RA) patients. Additional IL-17-related molecules and their receptors have been discovered and may also contribute to RA pathogenesis. We examined the expression of the prototypic IL-17 (IL-17A) and its homologs, IL-17B-F, by RT-PCR analyses of synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs) from RA patients. We also tested for induction of the IL-17 receptor homologs upon stimulation of the fibroblast-like synoviocytes (FLSs) of RA patients with IL-17. The patients' SFMCs expressed IL-17C, E and F in addition to IL-17A. As in the case of IL-17, IL-15 appears to be the major inducer of these homologs in RA SFMCs. We detected transcripts of IL-17R, as well as those of IL-17RB, C and D, in the FLSs of RA patients. Whereas IL-17R expression increased upon in vitro stimulation with IL-17, expression of IL-17RB, C and D was unchanged. However the possibility of cross-interaction between other IL-17 homologs and receptor isoforms remains to be investigated. Our data suggest that these additional homologs should also be considered as targets for immune modulation in the treatment of RA joint inflammation.

Keywords

Acknowledgement

Supported by : Ministry of Health & Welfare, Korean Science and Engineering Foundation

References

  1. Aggarwal, S. and Gurney, A. (2002) IL-17: prototype member of an emerging cytokine family. J. Leukoc. Biol. 71, 1-8
  2. Bush, K., Walker, J., Lee, C., and Kirham, B. (2001) Cytokine expression and synovial pathology in the initiation and spontaneous resolution phases of adjuvant arthritis: interleukin-17 expression is upregulated in early disease. Clin. Exp. Immunol. 123, 487-495 https://doi.org/10.1046/j.1365-2249.2001.01469.x
  3. Cai, L., Yin, J., Starovasnik, M., Hogue, D., Hillan, K., et al. (2001) Pathways by which interleukin 17 induces articular cartilage breakdown in vitro and in vivo. Cytokine 16, 10-21 https://doi.org/10.1006/cyto.2001.0939
  4. Chabaud, M., Durand, J., Buchs, N., Fossiez, F., Page, G., et al. (1999) Human interleukin 17; a T cell-derived proinflammatory cytokine produced by the rheumatoid arthritis synovium. Arth. Rheum. 42, 963-970 https://doi.org/10.1002/1529-0131(199905)42:5<963::AID-ANR15>3.0.CO;2-E
  5. Chabaud, M., Lubberts, E., Joosten, L., van den Berg, W., and Miossec, P. (2001) IL-17 derived from juxta-articular bone and synovium contributes to joint degradation in rheumatoid arthritis. Arth. Res. Ther. 3, 168-177
  6. Cho, M.-L., Yoon, J.-H., Hwang, S.-Y., Park, M.-K., Min, S.-Y., et al. (2004) Effector function of type II collagen stimulated T-cells of rheumatoid arthritis patients: cross-talk between antigen stimulated T-cells and synovial fibroblasts. Arth. Rheum. 50, 776-784 https://doi.org/10.1002/art.20106
  7. Gonzales-Alvaro, I., Ortiz, A. M., Garcia-Vicuna, R., Balsa, A., Pascual-Salcedo, D., et al. (2003) Increased serum levels of interleukin-15 in rheumatoid arthritis with long-term disease. Clin. Exp. Rheumatol. 21, 639-642
  8. Hwang, S.-Y., Kim, J.-Y., Kim, K.-W., Park, M.-K., Moon, Y., et al. (2004) IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via $NF-{\kappa}B$ and PI3- kinase/Akt-dependent pathways. Arth. Res. Ther. 6, 120-128 https://doi.org/10.1186/ar1190
  9. Katz, Y., Nadiv, O., and Beer, Y. (2001) Interleukin-17 enhances tumor necrosis factor $alpha}-induced$ synthesis of interleukins 1,6, and 8 in skin and synovial fibroblasts. Arth. Rheum. 44, 2176-2184 https://doi.org/10.1002/1529-0131(200109)44:9<2176::AID-ART371>3.0.CO;2-4
  10. Lee, J., Ho, W.-H., Maruoka, M., Corpuz, R., Baldwin, D., et al. (2001) IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J. Biol. Chem. 276, 1660-1664 https://doi.org/10.1074/jbc.M008289200
  11. Li, H., Chen, J., Huang, A., Stinson, J., Heldens, S., et al. (2000) Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc. Natl. Acad. Sci. USA 97, 773-778
  12. Lubberts, E., Joosten, L., Oppers, B., van den Bersselaar, L., Coenen-de Roo, C., et al. (2001) IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J. Immunol. 167, 1004-1013
  13. Miossec, P. (2003) Interleukin-17 in rheumatoid arthritis. Arth. Rheum. 48, 594-601 https://doi.org/10.1002/art.10816
  14. Min, S.-Y., Hwang, S.-Y., Jung, Y.-O., Min, D.-J., Park, S.-H., et al. (2004) Increase of cyclooxygenase-2 expression by interleukin 15 in rheumatoid synoviocytes. J. Rheumatol. 31, 875-883
  15. Moseley, T., Haudenschild, D., Rose, L., and Reddi, A. (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 14, 155-174 https://doi.org/10.1016/S1359-6101(03)00002-9
  16. Park, S.-H., Min, D.-J., Cho, M.-L., Kim, W.-U., Youn, J., et al. (2001) Shift toward T helper 1 cytokines by type II collagenreactive T-cells in patients with rheumatoid arthritis. Arth. Rheum. 44, 561-569 https://doi.org/10.1002/1529-0131(200103)44:3<561::AID-ANR104>3.0.CO;2-Z
  17. Rho, J., Takami, M., and Choi, Y. (2004) Osteoimmunology: interactions of the immune and skeletal systems. Mol. Cells 17, 1-9
  18. Shi, Y., Ullrich, S., Zhang, J., Connolly, K., Grzegorzewski, K., et al. (2000) A novel cytokine receptor-ligand pair. J. Biol. Chem. 275, 19167-19176 https://doi.org/10.1074/jbc.M910228199
  19. Starnes, T., Robertson, M. J., Sledge, G., Kleich, S., Nakashatri, H., et al. (2001) IL-17F, a novel cytokine selectively expressed in activated T cells and monocytes, regulates angiogenesis and endothelial cell cytokine production. J. Immunol. 167, 4137-4140
  20. Starnes, T., Broxmeyer, H. E., Robertson, M. J., and Hromas, R. (2002) IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis. J. Immunol. 169, 642-646
  21. Ziolkowska, M., Koe, A., Luszczykiewicz, G., Ksiezopolska- Pietrzak, K., Klimczak, E., et al. (2000) High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporine A-sensitive mechanism. J. Immunol. 164, 2832-2838