Volume 4 Issue 10 - June 20, 2008
Interleukin-20 antagonist is a potential drug for rheumatoid arthritis
Ming-Shi Chang*1,2, and Yu-Hsiang Hsu2

1Department of Biochemistry and Molecular Biology, 2 Institute of Biopharmaceutical Sciences, Medical college, National Cheng Kung University, Tainan, Taiwan, R.O.C
Email: mschang@mail.ncku.edu.tw

Arthritis Rheum. 2006 Sep; 54(9):2722-33.

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Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis. Intense inflammation occurs in synovial joints, infiltrating the normally delicate synovial membranes with mononuclear phagocytes, lymphocytes, and neutrophils. The inflamed synovium usually exudes an inflammatory fluid. Cytokines promote severe inflammation in the synovial membrane and caused cartilage damage and bone destruction.

The effectiveness of therapies that are directed against tumor-necrosis factor (TNF) has identified macrophages as a crucial target for therapeutic intervention (Figure 1). However, not all patients respond to these therapies, and the benefits of this form of treatment lasts for short time.
Figure 1. Mechanism of Enbrel
Inhibition of TNF (Enbrel and Remicade), which is produced primarily by synovial macrophages, effectively ameliorates the symptoms and joint destruction of RA. TNF-α is a mediator of the innate immune system, and it enhances inflammation and destruction in various ways, mostly through effects on endothelial cells, synovial fibroblasts (SFs), osteoclasts and cartilage. However, therapy that is directed against TNF is clinically effective in only 40% to 70% of patients, and when it is stopped, the disease recurs, which indicates that this form of therapy is disease suppressive, but not curative. Therefore, TNF-α is not the only key factor in the pathogenesis of RA. It is necessary to develop new drugs for treatment of RA.

In addition, SFs, which secretes mediators of inflammation and joint destruction, would not be affected directly by the current anti-cytokine therapies. These observations suggest synovial macrophages, and potentially SFs, as crucial targets for new strategies of therapeutic intervention in RA.

Figure 2. IL-20 levels in synovial fluid were significantly higher in RA patients.
Figure 3. Expression of IL-20 and its receptors in the synovial membranes and synovial fibroblasts of RA patients.

IL-20 belongs to the IL-10 family and plays a role in skin inflammation and the development of hematopoietic cells.
Figure 4. IL-20 up-regulated the production of MCP-1, IL-6, and IL-8 by synovial fibroblasts of RA patients.
Little is known about its other biological functions and clinical implications. Recently, our studies of IL-20 show that it plays some important roles in the pathogenesis of RA. IL-20 was overexpressed in the synovial fluid of RA patients compared with that of patients with gout and OA (Figure 2). In addition, IL-20 and its receptors were consistently expressed in the synovial membranes and synovial fibroblasts of RA patients (Figure 3), indicating that IL-20 is involved in RA, especially in local inflammation site. Recent studies have revealed key roles of inflammatory cytokines and chemokines, such as TNFα, IL-1β, IL-6, IL-8, and MCP-1 in tissue from the inflamed joints of patients with RA. We investigated the association of IL-20 with these cytokines and chemokines. IL-20 up-regulated the production of MCP-1, IL-6, and IL-8 by RASFs (Figure 4). These properties support our claim that IL-20 exerts distinctly proinflammatory effects on RASFs and plays multiple roles in the pathogenesis of RA.

Figure 5. IL-20 induced proliferation of HUVEC.
Angiogenesis is the process of new blood-vessel formation and is highly active in RA, particularly in early-onset disease. Our data demonstrated that IL-20 also induces the proliferation of endothelial cells (Figure 5). Thus, we speculated that IL-20 is also involved in the pathogenesis of RA through angiogenesis. In rat collagen-induced arthritis (CIA) model, electroporation of soluble IL-20 receptor1 (sIL-20R1) significantly reduced the severity of CIA and local swelling in the hind paws of CIA rat (Figure 6). Moreover, IL-20 up-regulated TNF-α expression and existed a bi-directional interaction with TNF-αFigure 7. Thus, IL-20 and TNF-αmight produce synergistic effects and caused severe inflammation. Therefore, blocking the activity of IL-20 might also inhibit the biological functions of TNF-α. Currently, we have developed a monoclonal antibody against IL-20 which also significantly inhibited the IL-20 activity in vivo. Therefore, the soluble receptor or antibody which could neutralize the bioactivity of IL-20 would be a potential therapeutic agent for treatment of RA.
Figure 7. Upregulation of TNF-α by IL-20 in synovial fibroblasts derived from healthy rat.
Figure 6. Soluble IL-20 receptor 1 (sIL-20R1) inhibited collagen-induced arthritis (CIA) in rats.

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