The deubiquitinating enzyme UCHL1 negatively regulates the immunosuppressive capacity and survival of multipotent mesenchymal stromal cells.
The deubiquitinating enzyme UCHL1 negatively regulates the immunosuppressive capacity and survival of multipotent mesenchymal stromal cells.
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去泛素化酶 UCHL1 负向调节多能间充质基质细胞的免疫抑制能力和存活
DOI：
10.1038/s41419-018-0532-y
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Gu Y;Ding X;Huang J;Xue M;Zhang J;Wang Q;Yu H;Wang Y;Zhao F;Wang H;Jin M;Wu Y;Zhang Y
已知促炎细胞因子赋予多能间充质基质细胞（MSC）治疗各种炎性疾病的免疫抑制能力。然而，促炎细胞因子如何调节MSC的免疫抑制能力知之甚少。在本研究中，我们发现去泛素化酶泛素C末端水解酶1（UCHL 1）在促炎细胞因子IFN-γ和TNF-α刺激后在MSC中上调。有趣的是，通过干扰UCHL 1的shRNA敲除或其抑制剂LDN 57444或过表达，我们发现UCHL 1在抑制细胞因子诱导的诱导型一氧化氮合酶在小鼠MSC和吲哚胺2，3-双加氧酶在人MSC的表达中发挥了关键作用，从而抑制了它们的免疫抑制能力。UCHL 1的这种作用归因于在调节NF-κB和STAT 1信号传导中的负作用，如通过在抑制UCHL 1时促进NF-κB和STAT 1活化所展示的。此外，UCHL 1的抑制通过上调Bcl-2抑制细胞因子诱导的MSC凋亡。因此，UCHL 1抑制的MSC有效地减轻了刀豆球蛋白A诱导的炎性肝损伤。因此，我们的研究证明了UCHL 1在调节MSC的免疫抑制能力和存活方面的新作用，这进一步影响了它们对炎症性疾病的免疫治疗。
It is known that proinflammatory cytokines empower multipotent mesenchymal stromal cells (MSCs) the immunosuppressive capacity to treat various inflammatory diseases. Nevertheless, how the proinflammatory cytokines modulate the immunosuppressive capacity of MSCs is poorly understood. In the present study, we identified that the deubiquitinating enzyme ubiquitin C-terminal hydrolase 1 (UCHL1) was upregulated in MSCs upon stimulation of proinflammatory cytokines IFN-γ plus TNF-α. Interestingly, through intervening UCHL1 by shRNA knockdown or its inhibitor LDN57444 or overexpression, we found that UCHL1 played a critical role in suppressing cytokines-induced inducible nitric oxide synthase expression in murine MSCs and indoleamine 2,3-dioxygenase expression in human MSCs, thereby restrained their immunosuppressive capacity. This effect of UCHL1 was attributed to the negative role in regulating NF-κB and STAT1 signaling, as exhibited by promoting NF-κB and STAT1 activation upon inhibition of UCHL1. Besides, inhibition of UCHL1 suppressed cytokines-induced MSC apoptosis via upregulation of Bcl-2. As a consequence, UCHL1-inhibited MSCs effectively alleviated concanavalin A-induced inflammatory liver injury. Therefore, our study demonstrates a novel role of UCHL1 in regulating the immunosuppressive capacity and survival of MSCs, which further affects their immunotherapy for inflammatory diseases.
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影响因子：
3.9
作者：
Jin C;Yu W;Lou X;Zhou F;Han X;Zhao N;Lin B
通讯作者：
Lin B
自噬促进炎症微环境下间充质干细胞凋亡。
影响因子：
7.5
作者：
Dang S;Yu ZM;Zhang CY;Zheng J;Li KL;Wu Y;Qian LL;Yang ZY;Li XR;Zhang Y;Wang RX
通讯作者：
Wang RX
影响因子：
8.8
作者：
Brinkmann, Kerstin;Zigrino, Paola;Kashkar, Hamid
通讯作者：
Kashkar, Hamid
DOI：
10.1161/atvbaha.107.142505
发表时间：
2007-10-01
影响因子：
8.7
作者：
Takami, Yoichi;Nakagami, Hironori;Kaneda, Yasufumi
通讯作者：
Kaneda, Yasufumi
DOI：
10.1073/pnas.1300532110
发表时间：
2013-06-04
影响因子：
11.1
作者：
Chang, Jia;Liu, Fei;Wang, Cun-Yu
通讯作者：
Wang, Cun-Yu