Arbez Jessy, Lamarthée Baptiste, Gaugler Béatrice, Saas Philippe
INSERM UMR1098, Besançon F25020, France; Université de Franche-Comté, Besançon F25000, France; EFS Bourgogne Franche-Comté, F25020 Besançon Cedex, France.
INSERM UMR1098, Besançon F25020, France; Université de Franche-Comté, Besançon F25000, France; EFS Bourgogne Franche-Comté, F25020 Besançon Cedex, France.
Immunobiology. 2014 Aug;219(8):637-43. doi: 10.1016/j.imbio.2014.03.013. Epub 2014 Mar 29.
Plasmacytoid dendritic cells (PDC) represent a rare subset of dendritic cells specialized in the production of type I IFN in response to microbial pathogens. Recent data suggested that histone deacetylase (HDAC) inhibitors possess potent immunomodulatory properties both in vitro and in vivo. In this study, we assayed the ability of the HDAC inhibitor, valproic acid (VPA), to influence the phenotype and functional properties of human PDC isolated from peripheral blood.
We showed that VPA inhibited the production of IFN-α and the proinflammatory cytokines TNF-α and IL-6 by CpG-activated PDC. VPA also affected the phenotype of PDC by reducing the expression of costimulatory molecules induced by CpG activation. Moreover, VPA reduced the capacity of CpG-stimulated PDC to promote CD4(+) T cell proliferation and IFN-γ production, while enhancing the proportion of IL-10 positive T cells.
These results suggest that HDAC inhibition by VPA alters essential human PDC functions, highlighting the need for monitoring immune functions in cancer patients receiving HDAC inhibitors, but also making these drugs attractive therapies in inflammatory, and autoimmune diseases implicating PDC.
浆细胞样树突状细胞（pDC）是树突状细胞中的一个稀有亚群，专门负责在响应微生物病原体时产生I型干扰素。最近的数据表明，组蛋白脱乙酰酶（HDAC）抑制剂在体外和体内均具有强大的免疫调节特性。在本研究中，我们检测了HDAC抑制剂丙戊酸（VPA）对从外周血中分离出的人pDC的表型和功能特性的影响。
我们发现VPA可抑制CpG激活的pDC产生IFN-α以及促炎细胞因子TNF-α和IL-6。VPA还通过降低CpG激活诱导的共刺激分子的表达来影响pDC的表型。此外，VPA降低了CpG刺激的pDC促进CD4(+) T细胞增殖和IFN-γ产生的能力，同时增加了IL-10阳性T细胞的比例。
这些结果表明，VPA抑制HDAC会改变人pDC的基本功能，这突出表明需要对接受HDAC抑制剂治疗的癌症患者的免疫功能进行监测，但同时也使这些药物成为涉及pDC的炎症性和自身免疫性疾病的有吸引力的治疗方法。
