Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes.
Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes.
复制标题
组蛋白脱乙酰基酶3调节类风湿关节炎成纤维细胞样的滑膜细胞的炎症基因表达程序。
DOI：
10.1136/annrheumdis-2015-209064
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发表时间：
2017-01
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;Kabala PA;Grabiec AM;Van Baarsen IM;Ferguson BS;García S;Malvar Fernandez B;McKinsey TA;Tak PP;Fossati G;Mascagni P;Baeten DL;Reedquist KA
非选择性组蛋白去乙酰化酶（HDAC）抑制剂（HDACi）在类风湿性关节炎（RA）的体外和体内模型中都表现出抗炎特性。在这里，我们研究了特定的I类和IIb类HDAC对RA成纤维细胞样滑膜细胞（FLS）中炎症基因表达的潜在贡献。将RA FLS与泛HDACi（ITF 2357，givinostat）或选择性HDAC 1/2 i、HDAC 3/6 i、HDAC 6 i和HDAC 8i孵育。或者，用HDAC 3、HDAC 6或干扰素（IFN）-α/β受体α链（IFNAR 1）siRNA转染FLS。通过定量PCR（qPCR）阵列和免疫印迹和DNA结合试验测定白细胞介素（IL）-1β诱导基因的mRNA表达和信号通路激活。HDAC 3/6 i，而不是HDAC 1/2 i和HDAC 8i，显著抑制RA FLS中pan-HDACi靶向的大多数IL-1β诱导型基因。HDAC 3表达的沉默再现了HDAC 3/6 i对基因调控的影响，与HDAC 6特异性抑制和HDAC 6沉默相反。对候选信号转导和转录激活因子（STAT）1转录因子的筛选显示，HDAC 3/6 i废除了STAT 1 Tyr 701磷酸化和DNA结合，但不影响STAT 1乙酰化。HDAC 3活性是FLS中I型IFN产生和随后的STAT 1活化所必需的。HDAC 3/6 i抑制I型IFN释放导致IFN依赖性基因亚组的表达减少，包括趋化因子CXCL 9和CXCL 11。RA FLS中HDAC 3的抑制在很大程度上概括了泛HDACi在抑制炎性基因表达中的作用，包括RA FLS中I型IFN的产生。我们的研究结果确定HDAC 3作为治疗RA和I型IFN驱动的自身免疫性疾病的潜在治疗靶点。
Non-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both in vitro and in vivo models of rheumatoid arthritis (RA). Here, we investigated the potential contribution of specific class I and class IIb HDACs to inflammatory gene expression in RA fibroblast-like synoviocytes (FLS). RA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i and HDAC8i. Alternatively, FLS were transfected with HDAC3, HDAC6 or interferon (IFN)-α/β receptor alpha chain (IFNAR1) siRNA. mRNA expression of interleukin (IL)-1β-inducible genes was measured by quantitative PCR (qPCR) array and signalling pathway activation by immunoblotting and DNA-binding assays. HDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppressed the majority of IL-1β-inducible genes targeted by pan-HDACi in RA FLS. Silencing of HDAC3 expression reproduced the effects of HDAC3/6i on gene regulation, contrary to HDAC6-specific inhibition and HDAC6 silencing. Screening of the candidate signal transducers and activators of transcription (STAT)1 transcription factor revealed that HDAC3/6i abrogated STAT1 Tyr701 phosphorylation and DNA binding, but did not affect STAT1 acetylation. HDAC3 activity was required for type I IFN production and subsequent STAT1 activation in FLS. Suppression of type I IFN release by HDAC3/6i resulted in reduced expression of a subset of IFN-dependent genes, including the chemokines CXCL9 and CXCL11. Inhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN production in RA FLS. Our results identify HDAC3 as a potential therapeutic target in the treatment of RA and type I IFN-driven autoimmune diseases.