ENHANCED EXPRESSION OF TUMOR-NECROSIS-FACTOR RECEPTOR MESSENGER-RNA AND PROTEIN IN MONONUCLEAR-CELLS ISOLATED FROM RHEUMATOID-ARTHRITIS SYNOVIAL JOINTS
ENHANCED EXPRESSION OF TUMOR-NECROSIS-FACTOR RECEPTOR MESSENGER-RNA AND PROTEIN IN MONONUCLEAR-CELLS ISOLATED FROM RHEUMATOID-ARTHRITIS SYNOVIAL JOINTS
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DOI：
10.1002/eji.1830220734
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发表时间：
1992-07-01
影响因子：
5.4
通讯作者：
FELDMANN, M
中科院分区：
文献类型：
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作者：
BRENNAN, FM;GIBBONS, DL;FELDMANN, M
我们之前提出的假设，促炎细胞因子肿瘤坏死因子- α (tnf - α)在类风湿关节炎（RA）的发病机制中起关键作用，基于我们观察到它是培养的RA滑膜关节单核（MNC）细胞中白细胞介素-1 （IL-1）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）产生的主要诱导剂。由于TNF- α通过两种膜受体起作用，我们扩展了这些研究，以研究p55和p75 TNF受体（TNF- r）在RA组织中的分布。使用p55 （HTR-9）和p75 (UTR-1) TNF-R特异性单克隆抗体，流式细胞术定量检测表面受体的表达。与正常或RA外周血MNC相比，从RA患者滑膜分离的MNC中这两种受体显著增加。有趣的是，p75 TNF-R在大型单核/巨噬细胞和CD3+淋巴细胞上均升高。此外，与匹配的外周血MNC相比，RA滑液中表达p75 TNF-R的CD3+细胞比例显著增加。与RA滑膜MNC相比，p75或p55 TNF-R表达在骨关节炎滑膜MNC中未显着增加。此外，Northern blot分析显示RA滑膜关节MNC中p55和p75 mRNA均有丰富表达。这与正常外周血MNC细胞形成对比，正常外周血MNC细胞含有很少或不含组成型TNF-R mRNA；在植物血凝素和IL-2刺激下，诱导两种受体mRNA的快速和短暂表达。因此，这些结果表明，在RA滑膜关节组织中，p55和p75 TNF-R mRNA和表面蛋白的表达均上调，并且在RA组织中存在tnf - α，这些结果支持了我们关于tnf - α在RA发病机制中起关键作用的假设。
We previously proposed the hypothesis that the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA) based on our observations that it is the dominant inducer of interleukin-1 (IL-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in RA synovial joint mononuclear (MNC) cells in culture. Since TNF-alpha acts via two membrane receptors, we have extended those studies to investigate the distribution of the p55 and p75 TNF receptors (TNF-R) in RA tissue. Surface receptor expression was quantitated by flow cytometry using monoclonal antibodies specific to the p55 (HTR-9) and the p75 (UTR-1) TNF-R. Both receptors were significantly increased on MNC isolated from the synovial membrane of RA patients compared to normal or RA peripheral blood MNC. Interestingly, the p75 TNF-R was increased both on large monocytic/macrophage-type cells and CD3+ lymphocytes. Furthermore, there was a significant increase in the proportion of CD3+ cells in RA synovial fluid expressing the p75 TNF-R, compared to matched peripheral blood MNC. In contrast to RA synovial MNC, p75 or p55 TNF-R expression was not significantly increased in osteoarthritis synovial MNC. In addition, Northern blot analysis indicated abundant expression of both p55 and p75 mRNA in RA synovial joint MNC. This was in contrast to normal peripheral blood MNC cells which contained little or no constitutive TNF-R mRNA; following stimulation with phytohemagglutinin and IL-2, a rapid and transient expression of both receptor mRNA was induced.These results, therefore, indicate that in RA synovial joint tissue there is up-regulation of both p55 and p75 TNF-R mRNA and surface protein expression, and with the presence of TNF-alpha in RA tissues, these results provide support to our hypothesis that TNF-alpha is of critical importance in the pathogenesis of RA.