Vorinostat, a histone deacetylase inhibitor, suppresses dendritic cell function and ameliorates experimental autoimmune encephalomyelitis

被引：77

作者：

Ge, Zhenzhen ^{[1
,2
,3
,4
]}

Da, Yurong ^{[1
,2
,3
,4
]}

Xue, Zhenyi ^{[1
,2
,3
,4
]}

Zhang, Kai ^{[1
,2
,3
,4
]}

Zhuang, Hao ^{[1
,2
]}

Peng, Meiyu ^{[1
,2
,3
,4
]}

Li, Yan ^{[1
,2
,3
,4
]}

Li, Wen ^{[1
,2
,3
,4
]}

Simard, Alain ^{[5
]}

Hao, Junwei ^{[6
]}

Yao, Zhi ^{[2
,3
,4
]}

Zhang, Rongxin ^{[1
,2
,3
,4
]}

机构：

[1] Tianjin Med Univ, Res Ctr Basic Med Sci, Lab Immunol & Inflammat, Tianjin 300070, Peoples R China

[2] Tianjin Med Univ, Basic Med Coll, Dept Immunol, Tianjin 300070, Peoples R China

[3] Tianjin Med Univ, Tianjin Key Lab Cellular & Mol Immunol, Tianjin 300070, Peoples R China

[4] Tianjin Med Univ, Key Lab Educ Minist China, Tianjin 300070, Peoples R China

[5] Univ Moncton, Dept Chem & Biochem, Moncton, NB E1A 3E9, Canada

[6] Tianjin Med Univ Gen Hosp, Tianjin Neurol Inst, Dept Neurol, Tianjin 300052, Peoples R China

来源：

EXPERIMENTAL NEUROLOGY | 2013年 / 241卷

基金：

中国国家自然科学基金;

关键词：

HDAC inhibitors; Vorinostat; Dendritic cells; Experimental autoimmune encephalomyelitis; Multiple sclerosis; Inflammation; SUBEROYLANILIDE HYDROXAMIC ACID; MULTIPLE-SCLEROSIS LESIONS; VERSUS-HOST-DISEASE; INFLAMMATORY CYTOKINE MILIEU; REGULATORY T-CELLS; GROWTH-FACTOR-BETA; CLASS-I; HUMAN MONOCYTES; RENAL-DISEASE; MRL/LPR MICE;

D O I：

10.1016/j.expneurol.2012.12.006

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

Vorinostat, a histone deacetylase inhibitor, has been used clinically as an anticancer drug and also has immunosuppressive properties. However, the underlying mechanisms of effects of vorinostat on central nervous system (CNS) inflammatory diseases remain incomplete. Here, this study investigates the effects of vorinostat on human CD14(+) monocyte-derived dendritic cells (DCs) and mouse immature DC in vitro. Furthermore, we explore the therapeutic effects and cellular mechanisms of vorinostat on animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) in vivo. Our findings demonstrate that vorinostat inhibited human CD14(+) monocyte-derived DCs differentiation, maturation, endocytosis, and further inhibited mDCs' stimulation of allogeneic T-cell proliferation. In addition, vorinostat inhibited DC-directed Th1- (Type 1T helper) and Th17-polarizing cytokine production. Furthermore, vorinostat ameliorated Th1- and Th17-mediated EAE by reducing CNS inflammation and demyelination. What's more, Th1 and Th17 cell functions were suppressed in vorinostat-treated EAE mice. Finally, vorinostat suppressed expression of costimulatory molecules of DC in EAE mice. These suggest therapeutic effects of vorinostat on EAE which may by suppress DCs and DCs-mediated Th1 and Th17 cell functions. Our findings warrant further investigation in the potential of vorinostat for the treatment of human multiple sclerosis. (c) 2012 Published by Elsevier Inc.

引用

页码：56 / 66

页数：11

共 55 条

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Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells [J].