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,
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