Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
J Pharmacol Exp Ther. 2021 Apr;377(1):75-85. doi: 10.1124/jpet.120.000395. Epub 2021 Jan 27.
Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the gastrointestinal tract arising from abnormal responses of the innate and adaptative immune systems. Interleukin (IL)-10-producing CD4CD25 regulatory T (T) cells play a protective role in the recovery phase of IBD. In the present study, the effects of the administration of the selective Ca-activated K channel K3.1 inhibitor TRAM-34 on disease activities were examined in chemically induced IBD model mice. IBD disease severity, as assessed by diarrhea, visible fecal blood, inflammation, and crypt damage in the colon, was significantly lower in mice administered 1 mg/kg TRAM-34 than in vehicle-administered mice. Quantitative real-time polymerase chain reaction examinations showed that IL-10 expression levels in the recovery phase were markedly increased by the inhibition of K3.1 in mesenteric lymph node (mLN) T cells of IBD model mice compared with vehicle-administered mice. Among several positive and negative transcriptional regulators (TRs) for IL-10, three positive TRs-E4BP4, KLF4, and Blimp1-were upregulated by the inhibition of K3.1 in the mLN T cells of IBD model mice. In mouse peripheral CD4CD25 T cells induced by lectin stimulation, IL-10 expression and secretion were enhanced by the treatment with TRAM-34, together with the upregulation of E4BP4, KLF4, and Blimp1. Collectively, the present results demonstrated that the pharmacological inhibition of K3.1 decreased IBD symptoms in the IBD model by increasing IL-10 production in peripheral T cells and that IL-10 T cells produced by the treatment with K3.1 inhibitor may contribute to efficient T therapy for chronic inflammatory disorders, including IBD. SIGNIFICANCE STATEMENT: Pharmacological inhibition of Ca-activated K channel K3.1 increased IL-10 expression in peripheral T cells, together with the upregulation of the transcriptional regulators of IL-10: Krüppel-like factor 4, E4 promoter-binding protein 4, and/or B lymphocyte-induced maturation protein 1. The manipulation of IL-10-producing T cells by the pharmacological inhibition of K3.1 may be beneficial in the treatment of chronic inflammatory diseases such as inflammatory bowel disease.
炎症性肠病（IBD）是一种起源于先天和适应性免疫系统异常反应的胃肠道慢性炎症性疾病。产生白细胞介素（IL）-10 的 CD4+CD25+调节性 T（T）细胞在 IBD 的恢复阶段发挥保护作用。在本研究中，研究了选择性钙激活钾通道 K3.1 抑制剂 TRAM-34 对化学诱导的 IBD 模型小鼠疾病活动的影响。与给予载体的小鼠相比，给予 1mg/kg TRAM-34 的小鼠的疾病严重程度（通过腹泻、肉眼可见的粪便血、炎症和结肠隐窝损伤评估）明显降低。定量实时聚合酶链反应检查显示，与给予载体的小鼠相比，IBD 模型小鼠肠系膜淋巴结（mLN）T 细胞中 K3.1 的抑制显著增加了恢复阶段的 IL-10 表达水平。在几种 IL-10 的阳性和阴性转录调节剂（TR）中，在 IBD 模型小鼠的 mLN T 细胞中，三种阳性 TR-E4BP4、KLF4 和 Blimp1 被 K3.1 的抑制上调。在由凝集素刺激诱导的小鼠外周 CD4+CD25+T 细胞中，TRAM-34 的处理增强了 IL-10 的表达和分泌，同时上调了 E4BP4、KLF4 和 Blimp1。总之，本研究结果表明，通过增加外周 T 细胞中 IL-10 的产生，药理学抑制 K3.1 可降低 IBD 模型中的 IBD 症状，并且 K3.1 抑制剂治疗产生的 IL-10 产生的 T 细胞可能有助于慢性炎症性疾病（包括 IBD）的有效 T 细胞治疗。
钙激活钾通道 K3.1 的药理学抑制增加了外周 T 细胞中 IL-10 的表达，同时上调了 IL-10 的转录调节剂：Krüppel 样因子 4、E4 启动子结合蛋白 4 和/或 B 淋巴细胞诱导成熟蛋白 1。通过 K3.1 的药理学抑制来操纵产生 IL-10 的 T 细胞可能有益于治疗炎症性肠病等慢性炎症性疾病。
