Downregulation of rheumatoid arthritis-related antigen RA-A47 (HSP47/colligin-2) in chondrocytic cell lines induces apoptosis and cell-surface expression of RA-A47 in association with CD9
Downregulation of rheumatoid arthritis-related antigen RA-A47 (HSP47/colligin-2) in chondrocytic cell lines induces apoptosis and cell-surface expression of RA-A47 in association with CD9
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DOI：
10.1002/jcp.20112
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发表时间：
2005-01-01
影响因子：
5.6
通讯作者：
Takigawa, M
中科院分区：
文献类型：
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作者：
Hattori, T;von der Mark, K;Takigawa, M
先前，我们发现类风湿关节炎相关抗原RA-A47（与人热休克蛋白（HSP）47相同）的基因表达在软骨细胞中被炎性细胞因子（如TNF α）下调。与此现象相关，RA-A47出现在细胞表面上，伴随着与软骨破坏相关的代谢因子的上调。用ra-a47特异性反义寡核苷酸调控RA-A47的表达，可以实现代谢因子的上调。在这里，我们表明，RA-A47在软骨细胞系HCS-2/8上的增强的表面表达也是RA-A47反义颗粒下调RA-A47的直接结果，与细胞因子效应无关。此外，在ra-a47反义寡核苷酸处理的细胞中，CD9（一种参与细胞粘附和细胞运动事件的整合素相关跨膜蛋白）的细胞表面表达增强。CD9与RA-A47共定位在细胞表面上，在那里它可能影响了整联蛋白信号传导。此外，在ra-a47反义颗粒处理后，与细胞表面结合的Annexin-V和包括caspase-9在内的许多凋亡相关基因的水平增加，表明RA-A47和CD9的表面表达增强可能启动凋亡。使用cDNA基因阵列的差异筛选显示，通过反义处理诱导金属硫蛋白-III和趋化因子受体CXCR 4以及Notch信号传导途径的因子，但不诱导TNF α。因此，在这里，我们第一次展示了通过下调分子伴侣诱导细胞凋亡的替代机制，而不依赖于TNF α的作用。表面暴露的RA-A47可能在自身免疫性疾病情况下诱导自身抗体和炎症反应，例如类风湿性关节炎。J.细胞。202：191 - 204，2005。(C)2004 Wiley-Liss，Inc.
Previously, we showed that gene expression of the rheurnatoid arthritis-related antigen RA-A47, which is identical to human heat shock protein (HSP)47, was downregulated in chondrocytes by inflammatory cytokines such as TNFalpha. Associated with this phenomenon, RA-A47 appeared on the cell surface concomitant with upregulation of metabolic factors related to cartilage destruction. The upregulation of the metabolic factors could be achieved by clownregulation of RA-A47 expression with ra-a47-specific anti-senseoligonucleotide. Here, we show that the enhanced surface expression of RA-A47 on a chondrocytic cell line, HCS-2/ 8 was also a direct result of RA-A47 downregulation by ra-a47 anti-sense oligonucleoticle, independent of the cytokine effects. Moreover, cell-surface expression of CD9, a l integrin-associated transmembrane protein that is involved in cell adhesion and cell motility events, was enhanced in the ra-a47 anti-sense oligonucleoticle-treated cells. The CD9 was colocalized with RA-A47 on the cell surface, where it may have affected integrin signaling. Furthermore, Annexin-V binding to the cell surface and the level of a number of apoptosis-related genes including caspase-9 were increased after ra-a47 anti-sense oligonucleoticle treatment, suggesting that enhanced surface expression of RA-A47 and CD9 may be initiating apoptosis. Differential screening using a cDNA gene array showed induction of metal lothionein-III and chemokine receptor CXCR4 and of factors of the Notch signaling pathway by the anti-sense treatment, but not by TNFalpha.. Thus, here we show for the first time an alternative mechanism of inducing apoptosis by downregulating molecular chaperones, independent of the action of TNFalpha. The surface-exposed RA-A47 may induce autoantibodies and inflammatory reactions in autoimmune disease situations such as rheurnatoid arthritis. J. Cell. Physiol. 202: 191 -204, 2005. (C) 2004 Wiley-Liss, Inc.