The Bromodomain and Extra-Terminal Protein Inhibitor OTX015 Suppresses T Helper Cell Proliferation and Differentiation
The Bromodomain and Extra-Terminal Protein Inhibitor OTX015 Suppresses T Helper Cell Proliferation and Differentiation
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Bromodomain 和末端外蛋白抑制剂 OTX015 抑制 T 辅助细胞增殖和分化
DOI：
10.2174/1566524019666190126112238
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发表时间：
2018-01-01
影响因子：
2.5
通讯作者：
Wei, Lai
中科院分区：
文献类型：
--
作者：
Hu, Xiao;Schewitz-Bowers, Lauren P.;Wei, Lai
背景：伴随CD 4（+）T辅助细胞分化的动态表观遗传学改变与多种自身免疫性疾病有关。布罗莫结构域和额外末端（BET）蛋白是识别并结合染色质中的乙酰化组蛋白的表观遗传调节剂，并且是药理学抑制的靶标。在这项研究中，我们测试了一种正在临床开发的新BET抑制剂OTX 015，以询问其对与自身免疫相关的关键CD 4（+）T细胞亚群的影响。分离出初始和记忆性鼠和人CD 4（+）T细胞，并分化成以表达干扰素（IFN）-γ和白细胞介素（IL）-γ为特征的群体。17.然后将培养的细胞在体外暴露于不同浓度的OTX 015，并通过流式细胞术定量其对细胞因子表达的影响。同时，通过PCR定量转录因子TBX 21和RORC的表达。结果：OTX 015抑制小鼠和人CD 4（+）T细胞增殖。其对细胞因子表达的影响在小鼠和人幼稚和记忆亚组中不同。OTX 015在抑制细胞因子和T辅助细胞增殖方面与JQ 1类似有效。较高浓度的OTX 015对鼠细胞相对于人细胞的活力也具有更大的影响。IL-17和IFN-γ的表达在鼠记忆性CD 4（+）T细胞中没有改变，而在人记忆性CD 4（+）T细胞中，OTX 015抑制IL-17，但不抑制IFN-γ。在所有的人类T细胞亚群中，OTX 015比IFN-γ更有效地抑制IL-17。结论：我们的研究表明，OTX 015通过抑制小鼠和人类CD 4（+）T细胞增殖和亚群依赖性促炎细胞因子表达，包括选择性抑制人类记忆性CD 4（+）T细胞中的IL-17，具有抗炎作用。
Background: Dynamic epigenetic alterations accompanying CD4(+) T helper cell differentiation have been implicated in multiple autoimmune diseases. The bromodomain and extra-terminal (BET) proteins are epigenetic regulators that recognize and bind to acetylated histones in chromatin and are targets for pharmacological inhibition. In this study we tested a new BET inhibitor under clinical development, OTX015, to interrogate its effects on key CD4(+) T cell subsets associated with autoimmunity.Methods: Naive and memory murine and human CD4(+) T cells were isolated and differentiated into populations characterized by the expression of interferon (IFN)-gamma and interleukin (IL)-17.Cultured cells were then exposed to varying concentrations of OTX015 in vitro, and its impact on cytokine expression was quantified by flow cytometry. In parallel, the expression of the transcription factors TBX21 and RORC was quantified by PCR. A previously studied BET inhibitor JQ1 was used as a pharmacological control.Results: OTX015 suppressed both murine and human CD4(+) T cell proliferation. Its impact on cytokine expression varied in murine and human naive and memory subsets. OTX015 was similarly effective as JQ1 in the suppression of cytokines and T helper cell proliferation. Higher concentrations of OTX015 also had a greater impact on the viability of murine versus human cells. IL-17 and IFN-gamma expression was not altered in murine memory CD4(+) T cells, whereas in human memory CD4(+) T cells, OTX015 inhibited IL-17, but not IFN-gamma. Across all human T cell subsets OTX015 suppressed IL-17 more effectively than IFN-gamma.Conclusion: Our studies demonstrate that OTX015 has anti-inflammatory effects by suppressing murine and human CD4(+) T cell proliferation and subset-dependent proinflammatory cytokine expression, including the selective suppression of IL-17 in human memory CD4(+) T cells.