Bone marrow-derived and synovium-derived mesenchymal cells promote Th17 cell expansion and activation through caspase 1 activation: Contribution to the chronicity of rheumatoid arthritis
Bone marrow-derived and synovium-derived mesenchymal cells promote Th17 cell expansion and activation through caspase 1 activation: Contribution to the chronicity of rheumatoid arthritis
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DOI：
10.1002/art.34391
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发表时间：
2012-07-01
影响因子：
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通讯作者：
Miossec, Pierre
中科院分区：
文献类型：
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作者：
Eljaafari, Assia;Tartelin, Marie-Laure;Miossec, Pierre
目的 Th17 细胞与类风湿性关节炎 (RA) 有关。我们假设，T 细胞与骨髓间充质干细胞 (BM-MSC) 或与成纤维细胞样滑膜细胞 (FLS) 的相互作用可能在 T 细胞分泌的炎症细胞因子（即白介素-17A [IL-17A]、肿瘤坏死因子 a [TNFa] 和/或干扰素-? [IFN?]）的帮助下促进 Th17 细胞扩增和活化。方法将来自健康献血者的外周血单核细胞（PBMC）与来自RA患者或骨关节炎（OA）患者的BM-MSC或FLS共培养。将共培养物暴露于含有或不含IL-17A、TNFa或IFNα的植物血凝素。使用定量逆转录聚合酶链反应分析、酶联免疫吸附测定和细胞荧光测定法来测量 IL-17A 的产生。结果 PBMC 与 BM-MSC 的相互作用抑制 Th1 和 Th2 反应，但早在 24 小时就促进 Th17 细胞扩增，如视黄酸受体相关孤儿核受体 ? 的增加所证明的那样。或 IL-17A 信使 RNA (mRNA) 水平、IL-17A 分泌水平和 IL-17A 分泌细胞频率，以及 MSC 刺激 2 轮后 T 细胞切换到 Th17 途径。在用抗 CD3 加抗 CD28 刺激的 PBMC 或分离的 CD3+ 或 CD45RO+ T 细胞中，IL-17A 的产生也有所增加，从而证明了 T 细胞激活的作用。当添加 T 细胞分泌的炎症细胞因子时，IL-6、IL-8 和 IL-1 beta 的 mRNA 水平进一步放大。有趣的是，OA FLS 或 RA FLS 也增强了 IL-17A 和 IL-6 的产生，但只有 RA FLS 增强了 IFN？和IL-1β的产生。我们通过使用抑制肽并测量其活性进一步证明 MSC 介导的 Th17 促进需要 caspase 1 激活。结论我们发现MSCs或FLS与T细胞的相互作用通过caspase 1激活促进Th17细胞的激活和扩增。由于促炎细胞因子和 T 细胞分泌的炎性细胞因子也被放大，因此这种机制可能参与了 RA 的慢性化。
Objective Th17 cells have been implicated in rheumatoid arthritis (RA). We hypothesized that the interaction of T cells with bone marrowderived mesenchymal stem cells (BM-MSCs) or with fibroblast- like synoviocytes (FLS) might, with the help of T cellsecreted inflammatory cytokines (i.e., interleukin-17A [IL-17A], tumor necrosis factor a [TNFa], and/or interferon-? [IFN?]), promote Th17 cell expansion and activation. Methods Peripheral blood mononuclear cells (PBMCs) from healthy blood donors were cocultured with BM-MSCs or FLS from RA patients or osteoarthritis (OA) patients. Cocultures were exposed to phytohemagglutinin with or without IL-17A, TNFa, or IFN?. Quantitative reverse transcriptionpolymerase chain reaction analysis, enzyme-linked immunosorbent assay, and cytofluorometry were used to measure IL-17A production. Results Interaction of PBMCs with BM-MSCs inhibited Th1 and Th2 responses, but promoted Th17 cell expansion, as early as 24 hours, as demonstrated by increases in retinoic acid receptorrelated orphan nuclear receptor ? or IL-17A messenger RNA (mRNA) levels, IL-17A secretion levels, and IL-17Asecreting cell frequency, as well as by T cell switching to the Th17 pathway after 2 rounds of stimulation with MSCs. IL-17A production was also increased in PBMCs stimulated with anti-CD3 plus anti-CD28 or in isolated CD3+ or CD45RO+ T cells, thus demonstrating the role of T cell activation. Levels of mRNA for IL-6, IL-8, and IL-1 beta were further amplified when T cellsecreted inflammatory cytokines were added. Interestingly, OA FLS or RA FLS also enhanced IL-17A and IL-6 production, but only RA FLS enhanced IFN? and IL-1 beta production. We further demonstrated that MSC-mediated Th17 promotion requires caspase 1 activation by using an inhibitory peptide and measuring its activity. Conclusion We found that the interaction of MSCs or FLS with T cells promotes the activation and expansion of Th17 cells through caspase 1 activation. Since proinflammatory and T cellsecreted inflammatory cytokines are also amplified, this mechanism may participate in the chronicity of RA.