Qu Xueqi, Pröll Maren, Neuhoff Christiane, Zhang Rui, Cinar Mehmet Ulas, Hossain Md Munir, Tesfaye Dawit, Große-Brinkhaus Christine, Salilew-Wondim Dessie, Tholen Ernst, Looft Christian, Hölker Michael, Schellander Karl, Uddin Muhammad Jasim
Institute of Animal Science, University of Bonn, Endenicher Allee 15, 53115 Bonn, Germany.
Institute of Animal Science, University of Bonn, Endenicher Allee 15, 53115 Bonn, Germany; Department of Animal Science, Faculty of Agriculture, Erciyes University, 38039 Kayseri, Turkey.
PLoS One. 2015 Mar 20;10(3):e0121574. doi: 10.1371/journal.pone.0121574. eCollection 2015.
Histone acetylation, regulated by histone deacetylases (HDACs) is a key epigenetic mechanism controlling gene expressions. Although dendritic cells (DCs) are playing pivotal roles in host immune responses, the effect of epigenetic modulation of DCs immune responses remains unknown. Sulforaphane (SFN) as a HDAC inhibitor has anti-inflammatory properties, which is used to investigate the epigenetic regulation of LPS-induced immune gene and HDAC family gene expressions in porcine monocyte-derived dendritic cells (moDCs). SFN was found to inhibit the lipopolysaccharide LPS induced HDAC6, HDAC10 and DNA methyltransferase (DNMT3a) gene expression, whereas up-regulated the expression of DNMT1 gene. Additionally, SFN was observed to inhibit the global HDAC activity, and suppressed moDCs differentiation from immature to mature DCs through down-regulating the CD40, CD80 and CD86 expression and led further to enhanced phagocytosis of moDCs. The SFN pre-treated of moDCs directly altered the LPS-induced TLR4 and MD2 gene expression and dynamically regulated the TLR4-induced activity of transcription factor NF-κB and TBP. SFN showed a protective role in LPS induced cell apoptosis through suppressing the IRF6 and TGF-ß1 production. SFN impaired the pro-inflammatory cytokine TNF-α and IL-1ß secretion into the cell culture supernatants that were induced in moDCs by LPS stimulation, whereas SFN increased the cellular-resident TNF-α accumulation. This study demonstrates that through the epigenetic mechanism the HDAC inhibitor SFN could modulate the LPS induced innate immune responses of porcine moDCs.
由组蛋白去乙酰化酶（HDACs）调控的组蛋白乙酰化是控制基因表达的关键表观遗传机制。尽管树突状细胞（DCs）在宿主免疫反应中发挥着关键作用，但DCs免疫反应的表观遗传调控作用仍不清楚。萝卜硫素（SFN）作为一种HDAC抑制剂具有抗炎特性，用于研究其对猪单核细胞衍生树突状细胞（moDCs）中脂多糖（LPS）诱导的免疫基因和HDAC家族基因表达的表观遗传调控。研究发现，SFN可抑制脂多糖（LPS）诱导的HDAC6、HDAC10和DNA甲基转移酶（DNMT3a）基因表达，而上调DNMT1基因的表达。此外，观察到SFN可抑制整体HDAC活性，并通过下调CD40、CD80和CD86的表达抑制moDCs从不成熟向成熟DCs的分化，进而增强moDCs的吞噬作用。对moDCs进行SFN预处理可直接改变LPS诱导的TLR4和MD2基因表达，并动态调节TLR4诱导的转录因子NF-κB和TBP的活性。SFN通过抑制IRF6和TGF-β1的产生，在LPS诱导的细胞凋亡中发挥保护作用。SFN可减少LPS刺激诱导的moDCs向细胞培养上清液中分泌促炎细胞因子TNF-α和IL-1β，而SFN增加了细胞内TNF-α的积累。本研究表明，HDAC抑制剂SFN可通过表观遗传机制调节LPS诱导的猪moDCs的固有免疫反应。
