Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice.
Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice.
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DOI：
10.1186/ar3339
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发表时间：
2011-05-18
影响因子：
4.9
通讯作者：
Kumagai S
中科院分区：
文献类型：
--
作者：
Misaki K;Morinobu A;Saegusa J;Kasagi S;Fujita M;Miyamoto Y;Matsuki F;Kumagai S
本研究的目的是阐明组蛋白去乙酰化酶抑制剂对树突状细胞表型和功能以及对SKG小鼠关节炎的影响。通过注射酵母聚糖A在SKG小鼠中诱导关节炎。给予组蛋白去乙酰化酶抑制剂曲古抑菌素A，通过关节肿胀和组织学评价其对关节炎的影响。通过酶联免疫吸附试验（ELISA）测定淋巴结细胞中的白细胞介素-17产生。荧光激活细胞分选（FACS）检测淋巴结细胞Foxp 3表达和脾树突状细胞表型。骨髓来源的树突状细胞（BM-DC）与粒细胞巨噬细胞集落刺激因子。分别采用流式细胞仪、ELISA、实时定量PCR和Western blot以及同种混合淋巴细胞反应等方法，检测不同浓度的阿曲他汀A对细胞表面分子、细胞因子产生、吲哚胺2，3-双加氧酶（IDO）表达和T细胞刺激能力的影响。曲古抑菌素A，当在关节炎发作之前给药时，防止SKG小鼠患关节炎。曲古抑菌素A治疗也显示出对SKG小鼠关节炎的治疗效果，当它在关节炎发作后给药时。曲古抑菌素A处理减少Th 17细胞和诱导的调节性T细胞在淋巴结中，并且还减少共刺激分子在体内脾树突状细胞上的表达。体外实验表明，曲马斯他汀A显著抑制酵母多糖A诱导的BM-DC产生白细胞介素-12和白细胞介素-6，并在mRNA和蛋白水平上调IDO表达。曲古抑菌素A处理的BM-DC也显示出较低的T细胞刺激能力。组蛋白去乙酰化酶抑制剂改变树突状细胞的耐受性表型，并改善关节炎在SKG小鼠。
The purpose of this study was to elucidate the effects of histone deacetylase inhibition on the phenotype and function of dendritic cells and on arthritis in SKG mice. Arthritis was induced in SKG mice by zymosan A injection. Trichostatin A, a histone deacetylase inhibitor, was administered and its effects on arthritis were evaluated by joint swelling and histological evaluation. Interleukin-17 production in lymph node cells was determined by an enzyme-linked immunosorbent assay (ELISA). Foxp3 expression in lymph node cells and the phenotypes of splenic dendritic cells were examined by fluorescence-activated cell sorting (FACS). Bone marrow-derived dendritic cells (BM-DC) were generated with granulocyte macrophage colony-stimulating factor. The effects of trichostatin A on cell surface molecules, cytokine production, indoleamine 2,3-dioxygenase (IDO) expression and T cell stimulatory capacity were examined by FACS, ELISA, quantitative real-time polymerase chain reaction and Western blot, and the allo-mixed lymphocyte reaction, respectively. Trichostatin A, when administered before the onset of arthritis, prevented SKG mice from getting arthritis. Trichostatin A treatment also showed therapeutic effects on arthritis in SKG mice, when it was administered after the onset of arthritis. Trichostatin A treatment reduced Th17 cells and induced regulatory T cells in lymph node, and also decreased co-stimulatory molecule expression on splenic dendritic cells in vivo. In vitro, trichostatin A markedly suppressed zymosan A-induced interleukin-12 and interleukin-6 production by BM-DC and up-regulated IDO expression at mRNA and protein levels. Trichostatin A-treated BM-DC also showed less T cell stimulatory capacity. Histone deacetylase inhibition changes dendritic cells to a tolerogenic phenotype and ameliorates arthritis in SKG mice.
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