Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell
Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell
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DOI：
10.4049/jimmunol.178.12.7730
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发表时间：
2007-06-15
影响因子：
4.4
通讯作者：
Munshi, Nikhil C.
中科院分区：
文献类型：
--
作者：
Bae, Jooeun;Mitsiades, Constantine;Munshi, Nikhil C.
90 kDa 热休克蛋白 (Hsp90) 在细胞蛋白的构象调节以及细胞信号传导和功能中发挥着重要作用。由于Hsp90被认为是免疫功能的关键组成部分，其抑制已成为癌症治疗的重要靶点，我们在这里评估了Hsp90在人树突状细胞（DQ表型和功能）中的作用。Hsp90抑制显着降低了细胞表面共刺激（CD40、CD80、CD86）、成熟（CD83）和MHC（HLA-A、B、C和 未成熟 DC 和成熟 DC 中的 HLA-DP、DQ、DR）标记物与 RNA 和细胞内蛋白表达的下调相关。重要的是，Hsp90 抑制显着抑制 DC 功能。它减少了未成熟 DC 的 Ag 摄取、加工和呈递，导致作为召回 Ag 的破伤风类毒素响应的 T 细胞增殖减少。它还降低了成熟DC的能力 向 T 细胞呈递 Ag 并分泌 IL-12，并诱导同种异体 T 细胞分泌 IFN-γ。因此，这些数据表明 Hsp90 介导的蛋白质折叠是 DC 功能所必需的，相反，Hsp90 抑制会破坏 DC 功能，这在评估新型 Hsp90 抑制剂治疗癌症的临床试验中具有重要意义。
The 90-kDa heat shock protein (Hsp90) plays an important role in conformational regulation of cellular proteins and thereby cellular signaling and function. As Hsp90 is considered a key component of immune function and its inhibition has become an important target for cancer therapy, we here evaluated the role of Hsp90 in human dendritic cell (DQ phenotype and function. Hsp90 inhibition significantly decreased cell surface expression of costimulatory (CD40, CD80, CD86), maturation (CD83), and MHC (HLA-A, B, C and HLA-DP, DQ, DR) markers in immature DC and mature DC and was associated with down-regulation of both RNA and intracellular protein expression. Importantly, Hsp90 inhibition significantly inhibited DC function. It decreased Ag uptake, processing, and presentation by immature DC, leading to reduced T cell proliferation in response to tetanus toxoid as a recall Ag. It also decreased the ability of mature DC to present Ag to T cells and secrete IL-12 as well as induce IFN-gamma secretion by allogeneic T cells. These data therefore demonstrate that Hsp90-mediated protein folding is required for DC function and, conversely, Hsp90 inhibition disrupts the DC function of significant relevance in the setting of clinical trials evaluating novel Hsp90 inhibitor therapy in cancer.