Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute of Molecular Life Science (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute of Molecular Life Science (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
Ann Rheum Dis. 2016 Apr;75(4):755-62. doi: 10.1136/annrheumdis-2014-206564. Epub 2015 Feb 3.
The study of the proinflammatory role of uric acid has focused on the effects of its crystals of monosodium urate (MSU). However, little is known whether uric acid itself can directly have proinflammatory effects. In this study, we investigate the priming effects of uric acid exposure on the cytokine production of primary human cells upon stimulation with gout-related stimuli.
Peripheral blood mononuclear cells (PBMCs) were harvested from patients with gout and healthy volunteers. Cells were pretreated with or without uric acid in soluble form for 24 h and then stimulated for 24 h with toll-like receptor (TLR)2 or TLR4 ligands in the presence or absence of MSU crystals. Cytokine production was measured by ELISA; mRNA levels were assessed using qPCR.
The production of interleukin (IL)-1β and IL-6 was higher in patients compared with controls and this correlated with serum urate levels. Proinflammatory cytokine production was significantly potentiated when cells from healthy subjects were pretreated with uric acid. Surprisingly, this was associated with a significant downregulation of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra). This effect was specific to stimulation by uric acid and was exerted at the level of gene transcription. Epigenetic reprogramming at the level of histone methylation by uric acid was involved in this effect.
In this study we demonstrate a mechanism through which high concentrations of uric acid (up to 50 mg/dL) influence inflammatory responses by facilitating IL-1β production in PBMCs. We show that a mechanism for the amplification of IL-1β consists in the downregulation of IL-1Ra and that this effect could be exerted via epigenetic mechanisms such as histone methylation. Hyperuricaemia causes a shift in the IL-1β/IL-1Ra balance produced by PBMCs after exposure to MSU crystals and TLR-mediated stimuli, and this phenomenon is likely to reinforce the enhanced state of chronic inflammation.
尿酸的促炎作用研究主要集中在其单钠尿酸盐（MSU）晶体的影响上。然而，目前尚不清楚尿酸本身是否能直接产生促炎作用。在这项研究中，我们研究了尿酸暴露对原发性人细胞细胞因子产生的预刺激作用，这些细胞在受到痛风相关刺激物刺激时会产生细胞因子。
从痛风患者和健康志愿者中采集外周血单核细胞（PBMCs）。细胞用或不用可溶性尿酸预处理 24 小时，然后在 MSU 晶体存在或不存在的情况下用 Toll 样受体（TLR）2 或 TLR4 配体刺激 24 小时。通过 ELISA 测量细胞因子的产生；使用 qPCR 评估 mRNA 水平。
与对照组相比，患者的白细胞介素（IL）-1β和 IL-6 产生更高，这与血清尿酸水平相关。当健康受试者的细胞用尿酸预处理时，促炎细胞因子的产生显著增强。令人惊讶的是，这与抗炎细胞因子白细胞介素 1 受体拮抗剂（IL-1Ra）的显著下调有关。这种效应是尿酸刺激的特异性，发生在基因转录水平。尿酸引起的组蛋白甲基化的表观遗传重编程参与了这种效应。
在这项研究中，我们证明了一种机制，即高浓度的尿酸（高达 50mg/dL）通过促进 PBMCs 中 IL-1β的产生来影响炎症反应。我们表明，IL-1β放大的机制包括 IL-1Ra 的下调，这种效应可以通过表观遗传机制如组蛋白甲基化来发挥作用。高尿酸血症导致 PBMC 暴露于 MSU 晶体和 TLR 介导的刺激物后产生的 IL-1β/IL-1Ra 平衡发生转移，这种现象很可能加强慢性炎症的增强状态。
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