中文摘要
類風濕性關節炎（rheumatoid arthritis; RA）屬於一種慢性發炎疾病，罹患率佔全球總人口數的百分之一。RA會引起關節液增多，白血球浸潤及關節變形等發炎反應。細胞激素於發炎過程中扮演極重要的角色，可促使發炎反應更加嚴重並造成關節的損傷。文獻指出介白素-20（interleukin-20; IL-20）可促進角質細胞（keratinocytes）表現促發炎細胞激素 (pro-inflammatory cytokine)，因此我們想探討IL-20是否也參與RA的致病過程。研究利用酵素連結免疫吸附分析法（enzyme-linked immunosorbent assay），偵測RA、骨關節炎（osteoarthritis）及痛風（gout）患者之關節液中IL-20含量，結果發現RA患者之關節液中，可偵測到高含量的IL-20。利用免疫組織化學染色法（immunohistochemical staining）則可偵測到RA患者關節膜（synovial membrane）以及關節纖維母細胞 (synovial fibroblast）中，皆會表現IL-20與其接受器，因此我們推測關節纖維母細胞對於IL-20參與RA致病過程應扮演一個重要的角色。此外，IL-20也會作用在RA患者之關節纖維母細胞上，促使其表現大量的IL-6、IL-8及MCP-1等細胞激素。利用增生試驗與細胞移行實驗（migration assay）可進一步得知，IL-20促使內皮細胞增生，同時伴隨會趨化嗜中性白血球至關節組織，並趨使關節纖維母細胞的移行。利用第二型膠原蛋白來建立大鼠關節炎之動物模式，經由反轉錄-聚合酶連鎖反應（RT-PCR），可偵測到關節炎大鼠的關節組織以及關節纖維母細胞中會表現IL-20與其接受器，但正常大鼠並不表現IL-20與IL-20R1。此外，TNF-��n也會作用在關節炎大鼠的關節纖維母細胞上，促使關節炎大鼠的關節纖維母細胞表現大量的IL-20。最後利用基因療法將構築在載體上的可溶性接受器（sIL-20R1或sIL-20R2），以電擊（electroporation）的方式送入關節炎大鼠之大腿肌肉內，結果可有效地預防大鼠關節炎的發生。綜合以上的研究結果顯示，在RA患者的關節液中表現高含量的IL-20，同時IL-20也是一種化學趨化物質（chemokine），其可趨化嗜中性白血球與關節纖維母細胞的移行，並促使內皮細胞的增生。最後利用關節炎動物模式更進一步證實，可溶性IL-20接受器，可顯著改善關節炎的嚴重程度。因此，IL-20在RA病程中調控著一些重要的分子，並在其致病機轉中扮演著非常重要的角色。

ABSTRACT
The pathogenesis of rheumatoid arthritis (RA) reflects an ongoing imbalance between pro- and anti-inflammatory cytokines. Interleukin-20 (IL-20) has pro-inflammatory properties for keratinocytes. We wanted to determine whether IL-20 was involved in RA. Using ELISA, we demonstrated that RA patients expressed significantly higher levels of IL-20 in synovial fluid than did gout or osteoarthritis patients. IL-20 and its receptors were consistently expressed in the synovial membranes and synovial fibroblasts of RA patients (RASFs) and it acted on RASFs through the ERK 1/2 signal transduction pathway. The effect of IL-20 on endothelial cells, RASFs, and neutrophils was investigated using MTT and the migration assay. The result showed that IL-20 induced RASFs to secrete monocyte chemoattractant protein-1 (MCP-1), IL-6, and IL-8, and it promoted neutrophil chemotaxis and the proliferation of endothelial cells in vitro. The expression of rat IL-20 and its receptors in healthy and collagen-induced arthritis (CIA) rats was analyzed and compared. Both IL-20 and IL-20R1 were upregulated in the rat CIA model. Rat IL-20 was upregulated by TNF-�-stimulated in SFs derived from CIA was demonstrated using RT-PCR. We used intramuscular electroporation to deliver soluble (s)IL-20R1 or sIL-20R2 into CIA rats and monitored the severity of arthritis in vivo. Electroporated sIL-20R1 plasmid DNA significantly decreased the severity of arthritis in CIA rats. These data indicated that IL-20 is upregulated in the synovial fluid of RA patients and acts as a chemokine that attracts migration of neutrophils, SFs, and promotes proliferation of endothelial cells. The rat CIA model further demonstrated that IL-20 is involved in the pathogenesis of arthritis because sIL-20R1 effectively reduced arthritis in CIA rats. Thus, IL-20 regulated several crucial molecules in RA and might play multiple roles in the pathogenesis of RA.

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