CXCL10 and its receptor CXCR3 regulate synovial fibroblast invasion in rheumatoid arthritis.
CXCL10 and its receptor CXCR3 regulate synovial fibroblast invasion in rheumatoid arthritis.
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DOI：
10.1002/art.30573
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发表时间：
2011-11
影响因子：
--
通讯作者：
Gulko, Percio S.
中科院分区：
文献类型：
--
作者：
Laragione, Teresina;Brenner, Max;Sherry, Barbara;Gulko, Percio S.
在关节炎DA大鼠和类风湿关节炎(RA)的高侵袭性成纤维细胞样滑膜细胞(FLS)中，CXCL10的表达水平升高。在本研究中，我们分析了CXCL10及其受体CXCR3在FLS侵袭特性调节中的作用。FLS是从RA患者的滑膜组织、DA和关节炎保护性Cia5d大鼠的Pristane诱导的关节炎中分离出来的。我们使用了一个通过Matrigel侵袭的体外模型，该模型已被证明与RA和大鼠关节炎的关节损害相关。在有或无CXCL10、抗CXCR3抗体、CXCR3抑制剂AMG487或对照组的条件下培养FLS，研究其侵袭能力、基质金属蛋白酶-1-3的产生、细胞内钙离子内流和细胞形态。与微创Cia5d相比，da FLS产生更高水平的CXCL10。CXCL10处理使Cia5d FLS侵袭力增加2倍，这一增加可被抗CXCR3阻断。抗CXCR3和AMG487均可使DA FLS的侵袭力降低77%。AMG487可显著降低RA FLS侵袭率60%。阻断CXCR3可使大鼠和RA FLS的基质金属蛋白酶-1水平降低58%，抑制受体信号转导(细胞内钙内流减少100%-100%)，干扰肌动蛋白细胞骨架重组和片状脂膜的形成。我们描述和表征了CXCL10-CXCR3在调节大鼠和RA FLS侵袭中的新的自分泌/旁分泌作用。这些观察表明，CXCL10-CXCR3轴是一个潜在的新的治疗靶点，旨在减少类风湿关节炎的FLS侵袭及其相关的关节损伤和血管膜侵袭和破坏。
CXCL10 is expressed in increased levels in highly invasive fibroblast-like synoviocytes (FLS) from arthritic DA rats and rheumatoid arthritis (RA). In this study we analyzed the role of CXCL10 and its receptor CXCR3 on the regulation of the invasive properties of FLS. FLS were isolated from synovial tissues of RA patients, and from DA and arthritis-protected Cia5d rats with pristane-induced arthritis. We used an in vitro model of invasion through Matrigel, which has been shown to correlate with articular damage in RA and in rat arthritis. FLS were cultured in the presence or absence of CXCL10, anti-CXCR3 antibody, CXCR3 inhibitor AMG487, or controls, then studied for invasion, MMP-1-3 production, intracellular calcium influx and cell morphology. DA FLS produced higher levels of CXCL10 compared with minimally-invasive Cia5d. CXCL10 treatment increased Cia5d FLS invasion by 2-fold, and this increase was blocked by anti-CXCR3. Both anti-CXCR3 and AMG487 reduced DA FLS invasion by as much as 77%. AMG487 significantly reduced RA FLS invasion 60%. CXCR3 blockade reduced levels of MMP-1 by 58%, inhibited receptor signaling (64%-100% reduction in intracellular calcium influx) and interfered with actin cytoskeleton reorganization and lamellipodia formation in rat and RA FLS. We describe and characterize a new autocrine/paracrine role for CXCL10-CXCR3 in the regulation of rat and RA FLS invasion. These observations suggest that the CXCL10-CXCR3 axis is a potential new target for therapies aimed at reducing FLS invasion and its associated joint damage and pannus invasion and destruction in RA.
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影响因子：
--
作者：
Rutkauskaite, E;Zacharias, W;Pap, T
通讯作者：
Pap, T
影响因子：
--
作者：
García-Vicuña, R;Gómez-Gaviro, MV;Díaz-González, F
通讯作者：
Díaz-González, F
影响因子：
2.7
作者：
Johnson, Michael;Li, An-Rong;Medina, Julio
通讯作者：
Medina, Julio
DOI：
10.1111/j.1749-6632.2009.04813.x
发表时间：
2009-01-01
期刊：
CONTEMPORARY CHALLENGES IN AUTOIMMUNITY
影响因子：
--
作者：
Lacotte, Stephanie;Brun, Susana;Dumortier, Helene
通讯作者：
Dumortier, Helene
影响因子：
4.9
作者：
Ruschpler P;Lorenz P;Eichler W;Koczan D;Hänel C;Scholz R;Melzer C;Thiesen HJ;Stiehl P
通讯作者：
Stiehl P