Hsu Yu-Hsiang, Chang Ming-Shi
National Cheng Kung University, Tainan, Taiwan.
Arthritis Rheum. 2010 Nov;62(11):3311-21. doi: 10.1002/art.27689.
Interleukin-20 (IL-20) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). We investigated whether anti-IL-20 antibody treatment would modulate the severity of the disease in a collagen-induced arthritis (CIA) rat model.
We generated a CIA model by immunizing rats with bovine type II collagen. Rats with CIA were treated subcutaneously with anti-IL-20 antibody 7E, with the tumor necrosis factor (TNF) blocker etanercept, or with 7E in combination with etanercept. Arthritis severity was determined according to the hind paw thickness, arthritis severity score, degree of cartilage damage, bone mineral density, and cytokine production, which were evaluated using radiologic scans, microfocal computed tomography, and enzyme-linked immunosorbent assay. To analyze gene regulation by IL-20, rat synovial fibroblasts (SFs) were isolated and analyzed for the expression of RANKL, IL-17, and TNFα. We also used real-time quantitative polymerase chain reaction analysis and flow cytometry to determine IL-20-regulated RANKL in mouse osteoblastic MC3T3-E1 cells and Th17 cells.
In vivo, treatment with 7E alone or in combination with etanercept significantly reduced the severity of arthritis by decreasing the hind paw thickness and swelling, preventing cartilage damage and bone loss, and reducing the expression of IL-20, IL-1β, IL-6, RANKL, and matrix metalloproteinases (MMPs) in synovial tissue. In vitro, IL-20 induced TNFα expression in SFs from rats with CIA. IL-20 markedly induced RANKL production in SFs, osteoblasts, and Th17 cells.
Selectively blocking IL-20 inhibited inflammation and bone loss in rats with CIA. Treatment with 7E combined with etanercept protected rats from CIA better than treatment with etanercept alone. Our findings provide evidence that IL-20 is a novel target and that 7E may be a potential therapeutic agent for RA.
白细胞介素-20（IL-20）是一种促炎细胞因子，参与类风湿关节炎（RA）的发病机制。我们研究了抗IL-20抗体治疗是否会调节胶原诱导性关节炎（CIA）大鼠模型中的疾病严重程度。
我们通过用牛II型胶原免疫大鼠建立了CIA模型。将患有CIA的大鼠皮下注射抗IL-20抗体7E、肿瘤坏死因子（TNF）阻滞剂依那西普或7E与依那西普联合使用。根据后爪厚度、关节炎严重程度评分、软骨损伤程度、骨矿物质密度和细胞因子产生情况确定关节炎严重程度，使用放射学扫描、微焦点计算机断层扫描和酶联免疫吸附测定进行评估。为了分析IL-20对基因的调控，分离大鼠滑膜成纤维细胞（SFs）并分析其RANKL、IL-17和TNFα的表达。我们还使用实时定量聚合酶链反应分析和流式细胞术来确定IL-20调节的小鼠成骨细胞MC3T3-E1细胞和Th17细胞中的RANKL。
在体内，单独使用7E或与依那西普联合使用可通过减少后爪厚度和肿胀、预防软骨损伤和骨质流失以及降低滑膜组织中IL-20、IL-1β、IL-6、RANKL和基质金属蛋白酶（MMPs）的表达来显著降低关节炎的严重程度。在体外，IL-20在患有CIA的大鼠的SFs中诱导TNFα表达。IL-20在SFs、成骨细胞和Th17细胞中显著诱导RANKL产生。
选择性阻断IL-20可抑制CIA大鼠的炎症和骨质流失。7E与依那西普联合治疗比单独使用依那西普能更好地保护大鼠免受CIA侵害。我们的研究结果提供了证据表明IL-20是一个新的靶点，并且7E可能是RA的一种潜在治疗药物。
