Reddy Pavan, Sun Yaping, Toubai Tomomi, Duran-Struuck Raimon, Clouthier Shawn G, Weisiger Elizabeth, Maeda Yoshinobu, Tawara Isao, Krijanovski Oleg, Gatza Erin, Liu Chen, Malter Chelsea, Mascagni Paolo, Dinarello Charles A, Ferrara James L M
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0942, USA.
J Clin Invest. 2008 Jul;118(7):2562-73. doi: 10.1172/JCI34712.
Histone deacetylase (HDAC) inhibitors are antitumor agents that also have antiinflammatory properties. However, the mechanisms of their immunomodulatory functions are not known. We investigated the mechanisms of action of 2 HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and ITF 2357, on mouse DC responses. Pretreatment of DCs with HDAC inhibitors significantly reduced TLR-induced secretion of proinflammatory cytokines, suppressed the expression of CD40 and CD80, and reduced the in vitro and in vivo allostimulatory responses induced by the DCs. In addition, injection of DCs treated ex vivo with HDAC inhibitors reduced experimental graft-versus-host disease (GVHD) in a murine allogeneic BM transplantation model. Exposure of DCs to HDAC inhibitors increased expression of indoleamine 2,3-dioxygenase (IDO), a suppressor of DC function. Blockade of IDO in WT DCs with siRNA and with DCs from IDO-deficient animals caused substantial reversal of HDAC inhibition-induced in vitro suppression of DC-stimulated responses. Direct injection of HDAC inhibitors early after allogeneic BM transplantation to chimeric animals whose BM-derived cells lacked IDO failed to protect from GVHD, demonstrating an in vivo functional role for IDO. Together, these data show that HDAC inhibitors regulate multiple DC functions through the induction of IDO and suggest that they may represent a novel class of agents to treat immune-mediated diseases.
组蛋白去乙酰化酶（HDAC）抑制剂是具有抗炎特性的抗肿瘤药物。然而，其免疫调节功能的机制尚不清楚。我们研究了两种HDAC抑制剂，辛二酰苯胺异羟肟酸（SAHA）和ITF 2357，对小鼠树突状细胞（DC）反应的作用机制。用HDAC抑制剂预处理DC可显著降低TLR诱导的促炎细胞因子分泌，抑制CD40和CD80的表达，并降低DC诱导的体外和体内同种异体刺激反应。此外，注射经HDAC抑制剂离体处理的DC可减轻小鼠同种异体骨髓移植模型中的实验性移植物抗宿主病（GVHD）。DC暴露于HDAC抑制剂可增加吲哚胺2,3-双加氧酶（IDO）的表达，IDO是DC功能的抑制剂。用小干扰RNA（siRNA）阻断野生型DC中的IDO以及使用来自IDO缺陷动物的DC可导致HDAC抑制诱导的DC刺激反应体外抑制的显著逆转。在同种异体骨髓移植后早期将HDAC抑制剂直接注射到骨髓来源细胞缺乏IDO的嵌合动物中不能预防GVHD，这证明了IDO在体内的功能作用。总之，这些数据表明HDAC抑制剂通过诱导IDO调节多种DC功能，并表明它们可能代表一类治疗免疫介导疾病的新型药物。
