Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease in which many cytokines have been implicated. In particular, IL-15 is a cytokine involved in the inflammatory processes and bone loss. The aim of this study was to investigate the existence in synovial fluid of soluble IL-15Rα, a private receptor subunit for IL-15 which may act as an enhancer of IL-15-induced proinflammatory cytokines. Soluble IL-15Rα was quantified by a newly developed enzyme-linked immunosorbent assay (ELISA) in samples of synovial fluid from patients with RA and osteoarthritis (OA). The levels of IL-15Rα were significantly increased in RA patients compared to OA patients. Also, we studied the presence of membrane-bound IL-15 in cells from synovial fluids, another element necessary to induce pro-inflammatory cytokines through reverse signaling. Interestingly, we found high levels of IL-6 related to high levels of IL-15Rα in RA but not in OA. Thus, our results evidenced presence of IL-15Rα in synovial fluids and suggested that its pro-inflammatory effect could be related to induction of IL-6. 1. Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease in which imbalances in pro- and anti-inflammatory cytokines promote induction of autoimmunity, inflammation and joint destruction [1]. IL-15 is a proinflammatory cytokine associated with several autoimmune diseases, particularly rheumatoid arthritis. [2, 3]. Three different functional forms of IL-15 have been identified: the soluble cytokine [4], IL-15R-independent membrane-bound IL-15 [5, 6] and membrane-IL-15 anchored through IL-15Rα [7]. IL-15Rα is a unique high affinity private α chain that together with the IL-2 receptor, IL-2Rβ chain and the IL-2Rγ chain subunits constitute a trimeric receptor for IL-15 on cell membranes. Also, IL-15Rα may be secreted as a functional soluble molecule (s-IL-15Rα) and could behave as an agonist by forming a complex with IL-15 which is 100-fold more efficient than the noncomplexed soluble cytokine or as an antagonist for IL-15 [8–10]. In addition, s-IL-15Rα may activate a reverse signaling through interaction with IL-15R-independent membrane-bound IL-15, activating MAPKs (mitogen-activated protein kinases) and increasing production of several proinflammatory cytokines such as IL-6, IL-8, and tumor necrosis factor α [5, 6, 11]. This bidirectional signaling has also been described for most members of TNF ligand family contributing to multiple stages of immune regulation [12]. Soluble IL-15 has been detected in synovia of patients with RA mainly expressed by macrophages,
References
[1]
I. B. McInnes and G. Schett, “Cytokines in the pathogenesis of rheumatoid arthritis,” Nature Reviews Immunology, vol. 7, no. 6, pp. 429–442, 2007.
[2]
I. B. Mcinnes, J. Al-Mughales, M. Field et al., “The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis,” Nature Medicine, vol. 2, no. 2, pp. 175–182, 1996.
[3]
H. P. Carroll, V. Paunovi？, and M. Gadina, “Signalling, inflammation and arthritis: crossed signals: the role of interleukin-15 and -18 in autoimmunity,” Rheumatology, vol. 47, no. 9, pp. 1269–1277, 2008.
[4]
J. D. Burton, R. N. Bamford, C. Peters et al., “A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 11, pp. 4935–4939, 1994.
[5]
V. Budagian, E. Bulanova, Z. Orinska et al., “Reverse signaling through membrane-bound interleukin-15,” The Journal of Biological Chemistry, vol. 279, no. 40, pp. 42192–42201, 2004.
[6]
G. G. Neely, S. Epelman, L. L. Ma et al., “Monocyte surface-bound IL-15 can function as an activating receptor and participate in reverse signaling,” Journal of Immunology, vol. 172, no. 7, pp. 4225–4234, 2004.
[7]
S. Dubois, J. Mariner, T. A. Waldmann, and Y. Tagaya, “IL-15Rα recycles and presents IL-15 in trans to neighboring cells,” Immunity, vol. 17, no. 5, pp. 537–547, 2002.
[8]
E. Mortier, A. Quéméner, P. Vusio et al., “Soluble interleukin-15 receptor α (IL-15Rα)-sushi as a selective and potent agonist of IL-15 action through IL-15Rβ/γ: hyperagonist IL-15·IL-15Rα fusion proteins,” The Journal of Biological Chemistry, vol. 281, no. 3, pp. 1612–1619, 2006.
[9]
E. Mortier, J. Bernard, A. Plet, and Y. Jacques, “Natural, proteolytic release of a soluble form of human IL-15 receptor α-chain that behaves as a specific, high affinity IL-15 antagonist,” Journal of Immunology, vol. 173, no. 3, pp. 1681–1688, 2004.
[10]
M. P. Rubinstein, M. Kovar, J. F. Purton et al., “Converting IL-15 to a superagonist by binding to soluble IL-15Rα,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 24, pp. 9166–9171, 2006.
[11]
T. Thalhamer, M. A. McGrath, and M. M. Harnett, “MAPKs and their relevance to arthritis and inflammation,” Rheumatology, vol. 47, no. 4, pp. 409–414, 2008.
[12]
N. J. Chen, M. W. Huang, and S. L. Hsieh, “Enhanced secretion of IFN-γ by activated Th1 cells occurs via reverse signaling through TNF-related activation-induced cytokine,” Journal of Immunology, vol. 166, no. 1, pp. 270–276, 2001.
[13]
I. B. McInnes, J. A. Gracie, M. Harnett, W. Harnett, and F. Y. Liew, “New strategies to control inflammatory synovitis: interleukin 15 and beyond,” Annals of the Rheumatic Diseases, vol. 62, no. 2, pp. 51–54, 2003.
[14]
N. Oppenheimer-Marks, R. I. Brezinschek, M. Mohamadzadeh, R. Vita, and P. E. Lipsky, “Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells in vitro and in the SCID mouse-human rheumatoid arthritis model in vivo,” Journal of Clinical Investigation, vol. 101, no. 6, pp. 1261–1272, 1998.
[15]
I. B. Mcinnes, B. P. Leung, R. D. Sturrock, M. Field, and F. Y. Liew, “Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-α production in rheumatoid arthritis,” Nature Medicine, vol. 3, no. 2, pp. 189–195, 1997.
[16]
S. Ferretti, O. Bonneau, G. R. Dubois, C. E. Jones, and A. Trifilieff, “Il-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger,” Journal of Immunology, vol. 170, no. 4, pp. 2106–2112, 2003.
[17]
W. A. Verri, T. M. Cunha, S. H. Ferreira et al., “IL-15 mediates antigen-induced neutrophil migration by triggering IL-18 production,” European Journal of Immunology, vol. 37, no. 12, pp. 3373–3380, 2007.
[18]
M. E. Miranda-Carús, M. Benito-Miguel, A. Balsa et al., “Peripheral blood T lymphocytes from patients with early rheumatoid arthritis express RANKL and interleukin-15 on the cell surface and promote osteoclastogenesis in autologous monocytes,” Arthritis and Rheumatism, vol. 54, no. 4, pp. 1151–1164, 2006.
[19]
Y. Ogata, A. Kukita, T. Kukita et al., “A novel role of IL-15 in the development of osteoclasts: inability to replace its activity with IL-2,” Journal of Immunology, vol. 162, no. 5, pp. 2754–2760, 1999.
[20]
S. Djaafar, D. D. Pierroz, R. Chicheportiche, X. X. Zheng, S. L. Ferrari, and S. Ferrari-Lacraz, “Inhibition of T cell-dependent and RANKL-dependent osteoclastogenic processes associated with high levels of bone mass in interleukin-15 receptor-deficient mice,” Arthritis and Rheumatism, vol. 62, no. 11, pp. 3300–3310, 2010.
[21]
A. Santos, A. Cabrales, O. Reyes et al., “Identification of an interleukin-15 antagonist peptide that binds to IL-15Rα,” Biotecnología Aplicada, vol. 25, no. 4, pp. 320–324, 2008.
[22]
T. Thalhamer, M. A. McGrath, and M. M. Harnett, “MAPKs and their relevance to arthritis and inflammation,” Rheumatology, vol. 47, no. 4, pp. 409–414, 2008.
[23]
P. Emery, E. Keystone, H. P. Tony et al., “IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial,” Annals of the Rheumatic Diseases, vol. 67, no. 11, pp. 1516–1523, 2008.
[24]
E. W. Thurkow, I. M. Van Der Heijden, F. C. Breedveld et al., “Increased expression of IL-15 in the synovium of patients with rheumatoid arthritis compared with patients with Yersinia-induced arthritis and osteoarthritis,” Journal of Pathology, vol. 181, no. 4, pp. 444–450, 1997.
[25]
T. Musso, L. Calosso, M. Zucca et al., “Human monocytes constitutively express membrane-bound, biologically active, and interferon-γ-upregulated interleukin-15,” Blood, vol. 93, no. 10, pp. 3531–3539, 1999.
[26]
H. Kobayashi, S. Dubois, N. Sato et al., “Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance,” Blood, vol. 105, no. 2, pp. 721–727, 2005.
[27]
N. J. Zvaifler, “The immunopathology of joint inflammation in rheumatoid arthritis,” Advances in Immunology, vol. 16, pp. 265–336, 1973.
[28]
T. Matsumoto, T. Tsurumoto, and H. Shindo, “Interleukin-6 levels in synovial fluids of patients with rheumatoid arthritis correlated with the infiltration of inflammatory cells in synovial membrane,” Rheumatology International, vol. 26, no. 12, pp. 1096–1100, 2006.
