Inhibiting STAT5 by the BET bromodomain inhibitor JQ1 disrupts human dendritic cell maturation.
Inhibiting STAT5 by the BET bromodomain inhibitor JQ1 disrupts human dendritic cell maturation.
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DOI：
10.4049/jimmunol.1401635
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发表时间：
2015-04-01
期刊：
影响因子：
--
通讯作者：
Frank DA
中科院分区：
文献类型：
--
作者：
Toniolo PA;Liu S;Yeh JE;Moraes-Vieira PM;Walker SR;Vafaizadeh V;Barbuto JA;Frank DA
树突状细胞（DC）的成熟是诱导T细胞免疫所必需的，而未成熟的DC可以诱导免疫耐受。虽然转录因子STAT 5被认为参与了DC的成熟，但其在这一过程中的作用仍不清楚。在这里，我们研究了STAT 5抑制对LPS诱导的人单核细胞来源的DC（Mo-DC）成熟的影响。我们通过用JQ 1处理Mo-DCs来抑制STAT 5，JQ 1是BET表观遗传阅读器的选择性抑制剂，其可以抑制STAT 5功能。我们发现JQ 1抑制LPS诱导的STAT 5磷酸化和核积累，从而减弱其在Mo-DCs中的转录活性。STAT 5活性的降低导致Mo-DCs成熟受损，如共刺激分子和CD 83的上调缺陷和IL 12 p70分泌减少所示。在JQ 1处理的Mo-DCs中组成型活化的STAT 5的表达克服了JQ 1的作用并增强了CD 86、CD 83和IL-12的表达。Mo-DCs中STAT 5的活化由LPS刺激后产生的GM-CSF介导。活化的STAT 5然后导致GM-CSF和GM-CSFR的表达增加，触发进一步增强STAT 5信号传导的自分泌环，使Mo-DCs能够获得更成熟的表型。JQ 1降低Mo-DCs诱导同种异体CD 4+和CD 8 + T细胞增殖和促炎细胞因子产生的能力。此外，JQ 1导致炎性CD 8 + T细胞的产生减少和Th 1分化减少。因此，JQ 1通过抑制STAT 5活性损害LPS诱导的Mo-DC成熟，从而产生只能微弱刺激适应性免疫应答的细胞。因此，JQ 1可能在治疗T细胞介导的炎症性疾病中具有有益作用。
Maturation of dendritic cells (DCs) is required to induce T-cell immunity while immature DCs can induce immune tolerance. Although the transcription factor STAT5 is suggested to participate in DC maturation, its role in this process remains unclear. Here, we investigated the effect of STAT5 inhibition on LPS-induced maturation of human monocyte-derived DCs (Mo-DCs). We inhibited STAT5 by treating Mo-DCs with JQ1, a selective inhibitor of BET epigenetic readers, which can suppress STAT5 function. We found that JQ1 inhibits LPS-induced STAT5 phosphorylation and nuclear accumulation, thereby attenuating its transcriptional activity in Mo-DCs. The diminished STAT5 activity results in impaired maturation of Mo-DCs as indicated by defective upregulation of costimulatory molecules and CD83, and reduced secretion of IL12p70. Expression of constitutively activated STAT5 in JQ1-treated Mo-DCs overcomes the effects of JQ1 and enhances the expression of CD86, CD83 and IL-12. The activation of STAT5 in Mo-DCs is mediated by GM-CSF produced following LPS stimulation. Activated STAT5 then leads to increased expression of both GM-CSF and GM-CSFR, triggering an autocrine loop that further enhances STAT5 signaling, enabling Mo-DCs to acquire a more mature phenotype. JQ1 decreases the ability of Mo-DCs to induce allogeneic CD4+ and CD8+ T-cell proliferation and production of pro-inflammatory cytokines. Furthermore, JQ1 leads to a reduced generation of inflammatory CD8+ T-cells and decreased Th1 differentiation. Thus, JQ1 impairs LPS-induced Mo-DC maturation by inhibiting STAT5 activity, thereby generating cells that can only weakly stimulate an adaptive immune response. Therefore, JQ1 could have beneficial effects in treating T-cell mediated inflammatory diseases.
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影响因子：
4.4
作者：
Sallusto, Federica;Lanzavecchia, Antonio
通讯作者：
Lanzavecchia, Antonio
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.4
作者：
Miah, Mohammad Alam;Yoon, Cheol-Hee;Bae, Yong-Soo
通讯作者：
Bae, Yong-Soo
影响因子：
5.5
作者：
Hansen, Morten;Hjorto, Gertrud Malene;Svane, Inge Marie
通讯作者：
Svane, Inge Marie
影响因子：
8.7
作者：
Podojil JR;Miller SD
通讯作者：
Miller SD