A New Role for Conivaptan in Ulcerative Colitis in Mice: Inhibiting Differentiation of CD4+T Cells into Th1 Cells
A New Role for Conivaptan in Ulcerative Colitis in Mice: Inhibiting Differentiation of CD4+T Cells into Th1 Cells
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Conivaptan 在抑制 CD4 T 细胞分化为 Th1 细胞的小鼠溃疡性结肠炎中的新作用
DOI：
10.1007/s10620-021-07300-y
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发表时间：
2021-11-09
影响因子：
3.1
通讯作者：
Jing, Haiyan
中科院分区：
文献类型：
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作者：
Dou, Dandan;Ji, Yuge;Jing, Haiyan
Conivaptan是一种非选择性的血管加压素受体V1 a和V2拮抗剂，是第一个用于治疗正常血容量和高血容量性低钠血症的药物。最近，越来越多的证据支持加压素参与免疫反应。目的：本研究旨在探讨康伐普坦对CD 4（+）T细胞稳态调节和实验性结肠炎进展的影响。方法采用免疫荧光法和western blot法检测CD 4 + T细胞V1 a受体的表达。在精氨酸加压素（AVP）孵育后检查分离的CD 4（+）T细胞亚群。通过尾静脉将CD 4（+）T细胞注射到DNBS诱导的小鼠中。根据体重、疾病活动指数（DAI）和形态学损伤评估结肠炎的严重程度。使用Fluo-3 AM负载法测量CD 4（+）T细胞中的细胞内Ca 2+（[Ca 2 +]（i））信号。通过实时聚合酶链反应（qPCR）检测结肠中的T-bet和IFN-γ mRNA。结果CD 4 + T细胞表达V1 a受体。V1 a受体的激活显著促进了CD 4（+）T细胞向辅助性T细胞1（Th 1）的分化。该过程被Conivaptan处理阻断。然而，V1 a受体的激活并没有引起CD 4（+）T细胞中[Ca 2 +]（i）的增加。值得注意的是，conivaptan显着减轻体重减轻，病理损伤，并在DNBS处理的小鼠的结肠中的T-bet和IFN-γ的表达。结论首次报道了考尼伐坦通过抑制CD 4（+）T细胞向Th 1细胞分化而减轻结肠炎。从机制上讲，conivaptan的抗炎作用不依赖于[Ca 2 +]（i）。
Background Conivaptan, a nonselective antagonist of vasopressin receptors V1a and V2, is the first drug of this class to be used for treating euvolemic and hypervolemic hyponatremia. Recently, increasing evidence supports the involvement of vasopressin in immune responses. Aims In this study, we investigated the effect of conivaptan on the modulation of CD4(+) T cell homeostasis and the progression of experimental colitis. Methods The expression of the V1a receptor on CD4(+) T cells was detected by immunofluorescence and western blot. The subset of isolated CD4(+) T cells were examined after arginine vasopressin (AVP) incubation. CD4(+) T cells were injected into DNBS-induced mice through the tail vein. The severity of colitis was evaluated according to weight, disease activity index (DAI), and morphological injury. Intracellular Ca2+ ([Ca2+](i)) signaling in CD4(+) T cells was measured using the Fluo-3 AM loading method. T-bet and IFN-gamma mRNAs in the colon were detected by real-time polymerase chain reaction (qPCR). Results We found that CD4(+) T cells expressed the V1a receptor. Activation of the V1a receptor significantly promoted the differentiation of CD4(+) T cells into T helper 1 (Th1) cells. This process was blocked by conivaptan treatment. However, the activation of the V1a receptor did not evoke an increase in [Ca2+](i) in CD4(+) T cells. Notably, conivaptan markedly alleviated body weight loss, pathological damage, and expression of T-bet and IFN-gamma in the colon of DNBS-treated mice. Conclusions For the first time, we report that conivaptan attenuated colitis by inhibiting the differentiation of CD4(+) T cells into Th1 cells. Mechanistically, the anti-inflammatory role of conivaptan is independent of [Ca2+](i).