IL-15 and the initiation of cell contact-dependent synovial fibroblast-T lymphocyte cross-talk in rheumatoid arthritis:: Effect of methotrexate
IL-15 and the initiation of cell contact-dependent synovial fibroblast-T lymphocyte cross-talk in rheumatoid arthritis:: Effect of methotrexate
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DOI：
10.4049/jimmunol.173.2.1463
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发表时间：
2004-07-15
影响因子：
4.4
通讯作者：
Martín-Mola, E
中科院分区：
文献类型：
--
作者：
Miranda-Carús, ME;Balsa, A;Martín-Mola, E
为了表征类风湿性关节炎（RA）中负责滑膜成纤维细胞-T淋巴细胞（TL）串扰的分子，将来自已建立的RA患者的滑膜成纤维细胞（RASFib）与来自早期RA患者的外周血的TL（RAPBTL）共培养。健康对照外周血和RA关节液的TL作为对照。通过流式细胞术、ELISA和实时PCR测定粘附分子和细胞因子。RAPBTL（n = 20）诱导ICAM-1、细胞内IL-8、IL-6、IL-15和表面IL-15的上调。RASFibs反过来，RAPBTL显示TNF-α、IFN-γ、IL-17、CD 25和CD 69表达上调。从健康对照组（n = 20）外周血中观察到的TL反应显著较低，而从RA滑液中观察到的TL反应（n = 20）最大。IL-15和CD 54的阻断性Ab，而不是同种型对照Ab，下调了增加的TL细胞因子和活化标志物表达。针对CD 69、CD 11 a、IL-17、TNF-alpha和IFN-γ的抗体显着降低了RASFib细胞因子和CD 54表达的上调。共培养使用0.4妈妈插入没有导致上调表面分子或。细胞因子甲氨蝶呤显著抑制RASFib/TL串扰信号，并降低TL与RASFib的粘附。总之，IL-15的RASFib产生通过细胞接触依赖性机制在共培养的TL中诱导促炎细胞因子TNF-α、IFN-γ和IL-17。反过来，这些细胞因子刺激RASFib中IL-15、IL-8和IL-6的表达，从而产生有利于持续性滑膜炎症的反馈回路。甲氨蝶呤似乎通过减少细胞粘附来破坏该环。
To characterize the molecules responsible for synovial fibroblast-T lymphocyte (TL) cross-talk in rheumatoid arthritis (RA), synovial fibroblasts from patients with established RA (RASFibs) were cocultured with TLs from peripheral blood of early RA patients (RAPBTL). TLs from peripheral blood of healthy controls and from synovial fluid of RA served as controls. Adhesion molecules and cytokines were determined by flow cytometry, ELISA, and real-time PCR. RAPBTL (n = 20) induced an upregulation of ICAM-1, intracellular IL-8, IL-6, IL-15, and surface IL-15 in cocultured. RASFibs. In turn, RAPBTL showed an up-regulation of TNF-alpha, IFN-gamma, IL-17, CD25, and CD69 expression. Responses seen with TLs from peripheral blood of healthy controls (n = 20) were significantly lower, whereas responses with TLs from synovial fluid of RA (n = 20) were maximal. Blocking Abs to IL-15 and CD54, but not an isotype-control Ab, down-regulated the increased TL cytokine and activation marker expression. Abs to CD69, CD11a, IL-17, TNF-alpha, and-IFN-gamma significantly decreased the up-regulation of RASFib cytokine and CD54 expression. Cocultures using 0.4-mum inserts did not result in up-regulation of surface molecules or. cytokines. Methotrexate significantly inhibited RASFib/TL cross-talk signals and decreased adhesion of TL to RASFibs. In summary, RASFib production of IL-15 induces the proinflammatory cytokines TNF-alpha, IFN-gamma, and IL-17 in cocultured TLs through a cell contact-dependent mechanism. In turn, these cytokines stimulate the expression of IL-15, IL-8, and IL-6 in RASFibs, thereby creating a feedback loop that favors persistent synovial inflammation. Methotrexate seems to disrupt this loop by decreasing cell adhesion.