text: Introduction
  Rheumatoid arthritis (RA) is characterized by infiltrations of macrophages and T cells into the joint, and synovial hyperplasia. Proinflammatory cytokines released from these cells are known to be important in the destruction of joints in RA [1]. The favorable clinical benefits obtained with inhibitors of tumor necrosis factor (TNF)-alpha) and interleukin (IL)-1 suggest that the blockade of key inflammatory cytokines has been the important issue in the development of new therapeutic applications [2]. A little over a decade ago, the primacy of T cells in the pathogenesis of autoimmune disease such as RA was undisputed because they are the largest cell population infiltrating the synovium. However, a series of studies demonstrated paucity of T cell-derived cytokines such as IL-2 and interferon-gamma in the joints of RA, whereas macrophage and fibroblast cytokines including IL-1, IL-6, IL-15, IL-18 and TNF-alpha were abundant in rheumatoid synovium. This paradox has questioned the role of T cells in the pathogenesis of RA [3]. Because we have already demonstrated the enhanced proliferation of antigen specific T cells, especially to type II collagen, and the skewing of T helper type 1 (Th1) cytokines in RA [4], the role of T cells needs to be elucidated in different aspects. 
  IL-17 is one of the inflammatory cytokines secreted mainly by activated T cells, which can induce IL-6 and IL-8 by fibroblasts [5]. This cytokine is of interest for two major reasons: first, similarly to TNF-alpha and IL-1, IL-17 has proinflammatory properties; second, it is produced by T cells [6]. Recent observations demonstrated that IL-17 can also activate osteoclastic bone resorption by the induction of RANKL (receptor activator of nuclear factor kappaB [NF-kappaB] ligand), which is involved in bony erosion in RA [7]. It also stimulates the production of IL-6 and leukemia inhibitory factor by synoviocytes, and of prostaglandin E2 and nitric oxide by chondrocytes, and has the ability to differentiate and activate the dendritic cells [8-10]. Levels of IL-17 in synovial fluids were significantly higher in patients with RA than in patients with osteoarthritis (OA), and it was produced by CD4+ T cells in the synovium [11,12]. 
  IL-15, secreted from activated macrophages, has been reported to be an important trigger of IL-17 production in RA peripheral blood mononuclear cells (PBMC) by cyclosporine and steroid sensitive pathways [13]. Recently, Happel and colleagues also showed that IL-23 could be an efficient trigger of IL-17 production from both CD4+ and CD8+ T cells [14]. 
  Although the contribution of IL-17 in joint inflammation in RA has been documented in earlier studies [12,15,16], the intracellular signal transduction pathway for IL-17 production remains uncertain. In the present study we used various stimuli to investigate IL-17 production in PBMC of patients with RA and its signaling transduction pathway. 
  We found that the intracellular signaling pathway involving phosphoinositide 3-kinase (PI3K)/Akt and NF-kappaB might be involved in the overproduction of the key inflammatory cytokine IL-17 in RA. These results might provide new insights into the pathogenesis of RA and future directions for new therapeutic strategies in RA. 
  