TOB1 Blocks Intestinal Mucosal Inflammation Through Inducing ID2-Mediated Suppression of Th1/Th17 Cell Immune Responses in IBD.
TOB1 Blocks Intestinal Mucosal Inflammation Through Inducing ID2-Mediated Suppression of Th1/Th17 Cell Immune Responses in IBD.
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TOB1 通过诱导 ID2 介导的 IBD Th1/Th17 细胞免疫反应抑制来阻断肠粘膜炎症
DOI：
10.1016/j.jcmgh.2021.12.007
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发表时间：
2022
影响因子：
7.2
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Lin R;Ma C;Fang L;Xu C;Zhang C;Wu X;Wu W;Zhu R;Cong Y;Liu Z
TOB 1是Tob/BTG家族的一种抗增殖蛋白，与肿瘤发生和T细胞活化密切相关。虽然TOB 1与T辅助细胞17相关的自身免疫有关，但其在IBD中调节T细胞介导的免疫应答的作用仍然知之甚少。在这里，我们探讨了它的表达和炎症性肠病（IBD）的发病机制。采用真实的实时定量聚合酶链反应和免疫组化方法检测IBD患者血清中TOB 1和ID 2的表达。IBD CD 4 + T细胞分别用表达TOB 1、ID 2、TOB 1短发夹RNA和ID 2短发夹RNA的慢病毒转染，Tob 1-/-CD 4 + T细胞用表达Id 2的慢病毒转染。采用三硝基苯磺酸灌肠法建立Tob 1-/-小鼠实验性结肠炎模型，并采用Tob 1-/-CD 45 RBhighCD 4 + T细胞重建Rag 1-/-小鼠模型，进一步探讨Tob 1在肠黏膜炎症中的作用。分选Tob 1-/-小鼠的脾脏CD 4 + T细胞，以通过RNA测序确定转录组差异。与健康受试者相比，IBD患者炎症粘膜和外周血CD 4 + T细胞中TOB 1表达降低。与对照组相比，TOB 1过表达下调IBD CD 4 + T细胞分化为Th 1/Th 17细胞。与对照动物相比，通过三硝基苯磺酸灌肠在Tob 1-/-小鼠中或用Tob 1-/-CD 45 RB高CD 4 + T细胞重建的Rag 1-/-小鼠中观察到严重的结肠炎。RNA测序分析显示ID 2是TOB 1抑制IBD CD 4 + T细胞分化为Th 1/Th 17细胞的功能靶标。TOB 1与Smad 4/5协同诱导ID 2表达，抑制Th 1/Th 17细胞分化。TOB 1通过Smad 4/5-ID 2途径抑制Th 1/Th 17细胞介导的免疫应答来抑制肠粘膜炎症。它可能作为一种新的治疗靶点，用于治疗人类IBD。
TOB1 is an anti-proliferative protein of Tob/BTG family and typically involved in the tumorigenesis and T cell activation. Although TOB1 is associated with T helper 17 cell–related autoimmunity, its role in modulating T cell–mediated immune responses in IBD remains poorly understood. Here, we explored its expression and the underlying mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD). TOB1 and ID2 expression in IBD patients was examined by quantitative real time polymerase chain reaction and immunohistochemistry. IBD CD4+ T cells were transfected with lentivirus expressing TOB1, ID2, TOB1 short hairpin RNA and ID2 short hairpin RNA, respectively, and Tob1–/–CD4+ T cells were transfected with lentivirus expressing Id2. Experimental colitis was established in Tob1–/– mice by trinitrobenzene sulfonic acid enema and in Rag1–/– mice reconstituted with Tob1–/–CD45RBhighCD4+ T cells to further explore the role of Tob1 in intestinal mucosal inflammation. Splenic CD4+ T cells of Tob1–/– mice were sorted to determine transcriptome differences by RNA sequencing. TOB1 expression was decreased in inflamed mucosa and peripheral blood CD4+ T cells of IBD patients compared with healthy subjects. Overexpression of TOB1 downregulated IBD CD4+ T cells to differentiate into Th1/Th17 cells compared with control subjects. Severe colitis was observed in Tob1–/– mice through trinitrobenzene sulfonic acid enema or in Rag1–/– mice reconstituted with Tob1–/–CD45RBhighCD4+ T cells, compared with control animals. RNA sequencing analysis revealed ID2 as functional target of TOB1 to inhibit IBD CD4+ T cell differentiation into Th1/Th17 cells. Mechanistically, TOB1 was associated with Smad4/5 to induce ID2 expression and restrain Th1/Th17 cell differentiation. TOB1 restrains intestinal mucosal inflammation through suppressing Th1/Th17 cell–mediated immune responses via the Smad4/5-ID2 pathway. It may serve as a novel therapeutic target for treatment of human IBD.
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影响因子：
9.7
作者：
Ito, Y;Suzuki, T;Miyauchi, A
通讯作者：
Miyauchi, A
影响因子：
9.7
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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