TWEAK promotes the production of Interleukin-17 in rheumatoid arthritis
Introduction
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily and functions as a secreted cytokine like TNF-α [1]. Fibroblast growth factor-inducible gene 14 (Fn14), which is a type I transmembrane receptor belonging to the TNF receptor superfamily, is a receptor for TWEAK [2]. TWEAK regulates a number of biological processes including cellular proliferation, angiogenesis, and inflammation through Fn14 [2], [3], [4]. TWEAK also has the ability to induce the expression of proinflammatory cytokines and chemokines such as interferon (IFN)-γ-inducible protein-10 (IP-10), matrix metalloproteinase-1, interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) [4], [5].
Rheumatoid arthritis (RA) is a symmetric polyarticular joint disease dominated by joint erosions and osteoporosis. RA is characterized by infiltration of inflammatory cells into the joints resulting in proliferation of synoviocytes and destruction of cartilage and bone [6], [7]. In RA, the expressions of adhesion molecules and chemokines on synovial tissues enhance the influx of immune cells including T and B cells, which induce various inflammatory cytokines [8].
Inflammatory cytokines including TNF-α, IL-1, IL-23, and IL-6 modulate a T helper cell subset termed IL-17-producing T cells (Th17). Th17 cells are involved in the pathogenesis of autoimmune disease such as experimental autoimmune encephalomyelitis, RA, and allergic responses [9], [10], [11]. In mice, Th17 development depends on the pleiotropic cytokine, transforming growth factor (TGF)-β, which is linked to regulatory T cell (Treg) development and function, as well as certain inflammatory cytokines (e.g., IL-6, TNF-α, IL-1β, IL-23) [9], [12], [13].
IL-6 is an indispensable factor that generates Th17 cells from naïve T cells through activation of the transcription factor orphan nuclear receptor (RORγt) and signal transducer and activator of transcription 3 (STAT3) [12], [14]. In an IL-6-dependent manner, RORγt+ Th17 cells upregulate the IL-23 receptor. IL-23 facilitates maintenance, expansion, and further differentiation of Th17 cells [12] as well as the number of Th17 that are amplified by TNF-α and IL-1β [13].
The role of TWEAK, which acts as a proinflammatory cytokine like TNF-α, in the modulation of IL-17 production remains unknown. We hypothesize that TWEAK induces the production of IL-17 and influences disease severity and progression.
To investigate whether TWEAK can promote IL-17 production, we evaluated the expression of Fn14 and IL-17 in mouse joint tissue and human synovium as well as the production of IL-17 in murine splenocytes and human peripheral blood mononuclear cells (PBMCs) in the presence of TWEAK. Furthermore, we examined the concentrations of TWEAK and IL-17 in both serum and synovial fluid (SF) from patients with RA and osteoarthritis (OA). The effects of Fn14-Fc on IL-17 production were performed under Th17-polarizing conditions.
Section snippets
Animals
Male DBA/1J mice (4–6 weeks old) were purchased from SLC, Inc. (Shizuoka, Japan). They were maintained under pathogen-free conditions at the Institute of Medical Science, the Catholic University of Korea, and fed standard mouse chow (Ralston Purina) and water ad libitum. All experimental procedures were examined and approved by the Animal Research Ethics Committee of the Catholic University of Korea, which conforms to all USA National Institutes of Health guidelines.
Induction of collagen-induced arthritis (CIA)
Type II collagen was
Effects of TWEAK on IL-17 production by murine splenocytes in vitro
Lipopolysaccharide (LPS), a major structural component of the outer membrane of Gram-negative bacteria, activates monocytes and macrophages to produce inflammatory cytokines such as TNF-α and IL-1 [17]. To investigate whether TWEAK induces IL-17, isolated splenocytes from normal mouse tissues were cultured with TWEAK in the presence of LPS challenge for 3 days (Fig. 1A). LPS challenge increased IL-17 mRNA expression about three-fold. However, addition of TWEAK augmented IL-17 gene expression
Discussions
This is the first study suggesting that TWEAK induces the production of IL-17 in vitro. IL-17 is overexpressed in murine knee joints and induces joint inflammation, bone erosion, and cartilage proteoglycan loss [22]. The involvement of TWEAK, a novel TNF family cytokine, in inflammation is well-known. Serum TWEAK levels are significantly elevated in a CIA mouse model and neutralizing mouse antibody against TWEAK can reduce the clinical severity of CIA. Furthermore, serum levels of arthritogenic
Acknowledgments
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (Grant Numbers 2008-2005645 and 2009-0081791).
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