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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >Instantaneous depolarization of T cells via dopamine receptors, and inhibition of activated T cells of Psoriasis patients and inflamed human skin, by D1-like receptor agonist: Fenoldopam
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Instantaneous depolarization of T cells via dopamine receptors, and inhibition of activated T cells of Psoriasis patients and inflamed human skin, by D1-like receptor agonist: Fenoldopam

机译：通过多巴胺受体瞬时去极化T细胞，以及牛皮癣患者活化T细胞的抑制，D1样受体激动剂：FeNoldopam

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Activated T cells are pathological in various autoimmune and inflammatory diseases including Psoriasis, and also in graft rejection and graft-versus-host-disease. In these pathological conditions, selective silencing of activated T cells through physiological receptors they express remains a clinical challenge. In our previous studies we found that activation of dopamine receptors (DRs) in resting human T cells activates these cells, and induces by itself many beneficial T cell functions. In this study, we found that normal human T cells express all types of DRs, and that expression of D1R, D4R and D5R increases profoundly after T cell receptor (TCR) activation. Interestingly, DR agonists shift the membrane potential (V-m) of both resting and activated human T cells, and induces instantaneous T cell depolarization within 15 seconds only. Thus, activation of DRs in T cells depolarize these immune cells, alike activation of DRs in neural cells. The skin of Psoriasis patients contains 20-fold more D1R(+) T cells than healthy human skin. In line with that, 25-fold more D1R(+) T cells are present in Psoriasis humanized mouse model. Highly selective D1-like receptor agonists, primarily Fenoldopam (Corlopam) - a D1-like receptor agonist and a drug used in hypertension, induced the following suppressive effects on activated T cells of Psoriasis patients: reduced chemotactic migration towards the chemokine SDF-1/CXCL12; reduced dramatically the secretion of eight cytokines: tumor necrosis factor-alpha, interferon-gamma, interleukin-1 beta (IL-1 beta), IL-2, IL-4, IL-6, IL-8 and IL-10; and reduced three T cell activation proteins/markers: CD69, CD28 and IL-2. Next, we invented a novel topical/dermal Fenoldopam formulation, allowing it to be spread on, and providing prolonged and regulated release in, diseased skin. Our novel topical/dermal Fenoldopam: reduced secretion of the eight cytokines by activated human T cells; reduced IL-1 beta and IL-6 secretion by human lipopolysaccharide-inflamed skin; eliminated preferentially >90% of live and large/proliferating human T cells. Together, our findings show for the first time that both resting and activated T cells are depolarized instantaneously via DRs, and that targeting D1-like receptors in activated T cells and inflamed human skin by Fenoldopam, in Psoriasis, and potentially in other T cell-mediated diseases, could be therapeutic. Validation in vivo is required.
机译：活化的T细胞在各种自身免疫和炎性疾病中是病态的，包括牛皮癣，以及移植物排斥和移植物与宿主病。在这些病理条件下，通过它们表达的生理受体选择性沉默活化的T细胞仍然是临床挑战。在我们之前的研究中，我们发现在静息人T细胞中激活多巴胺受体（DRS）激活这些细胞，并通过本身诱导许多有益的T细胞功能。在这项研究中，我们发现正常的人T细胞表达所有类型的DRS，并且D1R，D4R和D5R的表达在T细胞受体（TCR）活化后增加了深刻的增加。有趣的是，博士激动剂的激动剂移位休息和活化的人T细胞的膜电位（V-M），并在15秒内诱导瞬时T细胞去极化。因此，将T细胞中的DRS活化去极化了这些免疫细胞，类似于神经细胞中的DRS的活化。牛皮癣患者的皮肤含有比健康人体皮肤更多的D1R（+）T细胞20倍。符合该，牛皮癣的小鼠模型中存在25倍以下的D1R（+）T细胞。高度选择性D1样受体激动剂，主要是FENOLDOPAM（CORLOPAM） - 一种类似于高血压的D1样受体激动剂和药物，诱导对牛皮癣患者的活化T细胞的以下抑制作用：降低趋化因子SDF-1 / cxcl12;大幅减少了八种细胞因子的分泌：肿瘤坏死因子-α，干扰素-γ，白细胞介素-1β（IL-1β），IL-2，IL-4，IL-6，IL-8和IL-10;并减少了三个T细胞活化蛋白/标记：CD69，CD28和IL-2。接下来，我们发明了一种新型局部/皮肤卵泡配方，使其散布并提供延长和调节的释放，患病皮肤。我们的小说局部/皮肤Fenoldopam：通过活化的人T细胞减少了八个细胞因子的分泌;通过人脂多糖发炎的皮肤减少IL-1β和IL-6分泌;优先淘汰> 90％的活体和大/增殖人T细胞。我们的研究结果一起显示休息和活化的T细胞首次通过DRS瞬间去偏振，并且靶向活化的T细胞中的D1样受体并通过FENoldopam，在牛皮癣中发炎人体皮肤，并且可能在其他T细胞中介导的疾病，可能是治疗性的。需要在体内验证。

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