Inhibition of HDAC9 increases T regulatory cell function and prevents colitis in mice.
Inhibition of HDAC9 increases T regulatory cell function and prevents colitis in mice.
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DOI：
10.1053/j.gastro.2009.10.037
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发表时间：
2010-02
期刊：
影响因子：
29.4
通讯作者：
Hancock WW
中科院分区：
文献类型：
--
作者：
de Zoeten EF;Wang L;Sai H;Dillmann WH;Hancock WW
Foxp 3+调节性T细胞（TCFs）有助于预防自身免疫，其功能数量的增加可以减少炎症性肠病的发展。与其他细胞一样，Foxp 3 + TcB表达组蛋白/蛋白脱乙酰酶（HDAC），其调节染色质重塑和基因表达。我们研究了Tclase中特定的IIa类HDAC，HDAC 9活性的破坏是否会影响小鼠结肠炎的发病机制。我们使用野生型小鼠测试了各种HDAC抑制剂（HDACi）在结肠炎模型中的作用。我们还从HDAC 9 −/−或野生型小鼠中转移了TcR和非Treg细胞到免疫缺陷小鼠中。在结肠炎的发展和进展过程中确定HDAC 9对TdR功能的贡献。Pan-HDACi，而不是I类特异性HDACi，增加Foxp 3 + T细胞的功能，预防结肠炎，并减少小鼠中已建立的结肠炎，表明II类HDACs在控制Treg功能中的作用。泛HDACi预防/减少结肠炎的能力与Foxp 3 + TcR数量增加及其抑制功能相关。结肠炎与HDAC 9的局部表达增加有关; HDAC 9 −/−小鼠对结肠炎的发展有抵抗力。与对照组相比，HDAC 9 −/− TdR表达的热休克蛋白（HSP）70水平增加。免疫沉淀实验表明HSP 70和Foxp 3之间存在相互作用。HSP 70的抑制降低了HDAC 9 −/− TcR的抑制功能;过表达HSP 70的TcR具有增强的抑制功能。降低THP中HDAC 9表达或功能或增加HSP 70表达的策略可用于治疗结肠炎和其他自身免疫性疾病。
Foxp3+ T regulatory cells (Tregs) help prevent autoimmunity, and increases in their numbers of functions could decrease the development of inflammatory bowel disease. Like other cells, Foxp3+ Tregs express histone/protein deacetylases (HDACs), which regulate chromatin remodeling and gene expression. We investigated whether disruption of a specific class IIa HDAC, HDAC9, activity in Tregs affects the pathogenesis of colitis in mice. We tested the effects of various HDAC inhibitors (HDACi) in models of colitis using wild-type mice. We also transferred Tregs and non-Treg cells from HDAC9−/− or wild-type mice to immunodeficient mice. HDAC9 contributions to the functions of Tregs were determined during development and progression of colitis. Pan-HDACi, but not class I-specific HDACi, increased the functions of Foxp3+ Tregs, prevented colitis, and reduced established colitis in mice, indicating the role of class II HDACs in controlling Treg function. The abilities of pan-HDACi to prevent/reduce colitis were associated with increased numbers of Foxp3+ Tregs and their suppressive functions. Colitis was associated with increased local expression of HDAC9; HDAC9−/− mice resistant to development of colitis. HDAC9−/− Tregs expressed increased levels of the heat shock protein (HSP) 70, compared with controls. Immunoprecipitation experiments indicated an interaction between HSP70 and Foxp3. Inhibition of HSP70 reduced the suppressive functions of HDAC9−/− Tregs; Tregs that overexpressed HSP70 had increased suppressive functions. Strategies to decrease HDAC9 expression or function in Tregs or to increase expression of HSP70 might be used to treat colitis and other autoimmune disorders.
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DOI：
10.1073/pnas.0700298104
发表时间：
2007-03-13
影响因子：
11.1
作者：
Li, Bin;Samanta, Arabinda;Greene, Mark I.
通讯作者：
Greene, Mark I.
影响因子：
4.4
作者：
Glauben, Rainer;Batra, Arvind;Siegmund, Britta
通讯作者：
Siegmund, Britta
影响因子：
6.7
作者：
Axelsson, LG;Landstrom, E;BylundFellenius, AC
通讯作者：
BylundFellenius, AC
影响因子：
7.3
作者：
Mai, A;Massa, S;Brosch, G
通讯作者：
Brosch, G
DOI：
10.1073/pnas.0400380101
发表时间：
2004-03-16
影响因子：
11.1
作者：
Reddy, P;Maeda, Y;Ferrara, JLM
通讯作者：
Ferrara, JLM