Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression.
Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression.
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DOI：
10.1136/annrheumdis-2014-205635
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发表时间：
2016-02
影响因子：
27.4
通讯作者：
Reedquist KA
中科院分区：
文献类型：
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作者：
Angiolilli C;Grabiec AM;Ferguson BS;Ospelt C;Malvar Fernandez B;van Es IE;van Baarsen LG;Gay S;McKinsey TA;Tak PP;Baeten DL;Reedquist KA
表观遗传修饰在基因转录和细胞功能调控中起着重要作用。在这里，我们研究了类风湿性关节炎（RA）患者发炎关节中存在的促炎因子是否可以调节成纤维细胞样滑膜细胞（FLS）中组蛋白脱乙酰酶（HDAC）的表达和功能。通过免疫组织化学评估滑膜组织中的蛋白质乙酰化。定量PCR检测滑膜组织中HDAC家族成员和炎症介质的mRNA水平以及RA FLS中HDAC表达的变化。用HDAC 5 siRNA转染FLS或用编码野生型HDAC 5的腺病毒载体转导FLS，并通过qPCR阵列、ELISA和基于ELISA的测定来检查HDAC 5操作的影响。滑膜I类HDAC表达与肿瘤坏死因子（TNF）和基质金属蛋白酶-1的局部表达相关，而IIa类HDAC 5表达与疾病活动性参数（红细胞沉降率、C反应蛋白、28个关节的疾病活动性评分）呈负相关。白细胞介素（IL）-1β或TNF刺激选择性抑制RA FLS中的HDAC 5表达，这是IL-1β诱导最佳IFNB、CXCL 9、CXCL 10和CXCL 11所必需的，与转录因子干扰素调节因子1（IRF 1）的核积累增加相关。炎性细胞因子抑制RA FLS HDAC 5表达，促进IRF 1的核定位和I型干扰素应答基因的子集的转录。我们的结果确定HDAC 5是RA中的一种新型炎症介质，并表明挽救体内HDAC 5表达的策略或开发不影响HDAC 5活性的HDAC抑制剂可能在RA治疗中具有治疗应用。
Epigenetic modifications play an important role in the regulation of gene transcription and cellular function. Here, we examined if pro-inflammatory factors present in the inflamed joint of patients with rheumatoid arthritis (RA) could regulate histone deacetylase (HDAC) expression and function in fibroblast-like synoviocytes (FLS). Protein acetylation in synovial tissue was assessed by immunohistochemistry. The mRNA levels of HDAC family members and inflammatory mediators in the synovial tissue and the changes in HDAC expression in RA FLS were measured by quantitative (q) PCR. FLS were either transfected with HDAC5 siRNA or transduced with adenoviral vector encoding wild-type HDAC5 and the effects of HDAC5 manipulation were examined by qPCR arrays, ELISA and ELISA-based assays. Synovial class I HDAC expression was associated with local expression of tumour necrosis factor (TNF) and matrix metalloproteinase-1, while class IIa HDAC5 expression was inversely associated with parameters of disease activity (erythrocyte sedimentation rate, C-reactive protein, Disease Activity Score in 28 Joints). Interleukin (IL)-1β or TNF stimulation selectively suppressed HDAC5 expression in RA FLS, which was sufficient and required for optimal IFNB, CXCL9, CXCL10 and CXCL11 induction by IL-1β, associated with increased nuclear accumulation of the transcription factor, interferon regulatory factor 1(IRF1). Inflammatory cytokines suppress RA FLS HDAC5 expression, promoting nuclear localisation of IRF1 and transcription of a subset of type I interferon response genes. Our results identify HDAC5 as a novel inflammatory mediator in RA, and suggest that strategies rescuing HDAC5 expression in vivo, or the development of HDAC inhibitors not affecting HDAC5 activity, may have therapeutic applications in RA treatment.