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首页> 外文期刊>Cytokine >Interleukin-33 acts as a transcriptional repressor and extracellular cytokine in fibroblast-like synoviocytes in patients with rheumatoid arthritis
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Interleukin-33 acts as a transcriptional repressor and extracellular cytokine in fibroblast-like synoviocytes in patients with rheumatoid arthritis

机译：白细胞介素33在类风湿关节炎患者中作为成纤维样滑膜细胞的转录抑制因子和细胞外细胞因子

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摘要

The present study aimed to assess the functions of interleukin (IL)-33 in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). Enzyme-linked immunosorbent assays (ELISAs) were used to quantify interleukin (IL)-33 in plasma obtained from patients with RA and osteoarthritis (OA). To evaluate functions of intracellular IL-33, levels of inflammatory mediators and matric metalloproteinases (MMPs) were measured in RA FLS transfected with IL-33 small- interfering RNA (siRNA) or plasmids, and changes in the expression and regulation of nuclear factor kappaB (NF-kappa B) were determined using western blotting and reporter gene assays. In addition, to examine the extracellular effects of IL-33, IP10 and receptor activator of NF-kappa B ligand (RANKL) mRNA levels were measured after treatment with IL-33 and blocking antibodies to ST2, the IL-33 receptor. To evaluate whether extracellular IL-33 regulated osteoclastogenesis, human CD14(+) monocytes cocultured with IL-33-stimulated FLS were stained with tartrate-resistant acid phosphatase (TRAP). IL-33 levels were higher in plasma obtained from patients with RA than in those obtained from patients with OA. The expression levels of IL-33 were elevated in RA FLS that had been stimulated with poly I:C, IL-1 beta, and tumor necrosis factor (TNF)-alpha. Silencing of IL-33 increased the levels of pro-inflammatory molecules and MMPs, promoted inhibitor of kappaB (1 kappa b alpha) degradation, and increased NF-kappa B activity; these effects were reversed in IL-33 plasmid-transfected FLS. Stimulation with exogenous IL-33 increased RANKL and IP-10 mRNA expression. These increases were blocked by anti-ST2 treatment. Furthermore, we confirmed that extracellular IL-33 stimulated the formation of TRAP(+) multinucleated osteoclasts through RA FLS. These results suggested that intracellular IL-33 acted as a transcriptional repressor of NF-kappa B, which may provide negative feedback against inflammatory responses, whereas, extracellular IL-33 functioned as an activator of osteoclastogenesis. Therefore, increased plasma IL-33 levels in patients with RA could be a possible biomarker to reflect the potential risks of bone erosion. (C) 2015 Elsevier Ltd. All rights reserved.
机译：本研究旨在评估类风湿关节炎（RA）患者的成纤维样滑膜细胞（FLS）中白介素（IL）-33的功能。酶联免疫吸附测定（ELISA）用于定量从RA和骨关节炎（OA）患者获得的血浆中白介素（IL）-33。为了评估细胞内IL-33的功能，在用IL-33小干扰RNA（siRNA）或质粒转染的RA FLS中测量炎症介质和基质金属蛋白酶（MMP）的水平，以及核因子κB表达和调控的变化（NF-κB）使用蛋白质印迹法和报道基因测定法测定。此外，为了检查IL-33的细胞外作用，在用IL-33和阻断针对IL-33受体ST2的抗体处理后，测量了IP10和NF-κB配体的受体激活剂（RANKL）mRNA的水平。为了评估细胞外IL-33是否调节破骨细胞形成，将与IL-33刺激的FLS共培养的人CD14（+）单核细胞用抗酒石酸的酸性磷酸酶（TRAP）染色。 RA患者血浆中的IL-33水平高于OA患者血浆中的IL-33水平。 IL-33的表达水平在多聚I：C，IL-1 beta和肿瘤坏死因子（TNF）-α刺激的RA FLS中升高。 IL-33的沉默会增加促炎分子和MMP的水平，促进kappaB（1 kappa b alpha）降解的抑制剂，并增加NF-kappa B的活性;这些作用在IL-33质粒转染的FLS中被逆转。外源IL-33刺激增加RANKL和IP-10 mRNA表达。这些增加被抗ST2治疗阻止。此外，我们证实细胞外IL-33通过RA FLS刺激了TRAP（+）多核破骨细胞的形成。这些结果表明，细胞内IL-33充当NF-κB的转录阻遏物，其可以提供针对炎症反应的负反馈，而细胞外IL-33充当破骨细胞形成的激活剂。因此，RA患者血浆IL-33水平升高可能是反映骨侵蚀潜在风险的可能生物标志物。 （C）2015 Elsevier Ltd.保留所有权利。

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