Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic.
Department of Experimental Biology, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic.
Int J Mol Sci. 2021 Feb 16;22(4):1938. doi: 10.3390/ijms22041938.
Pseurotins, a family of secondary metabolites of different fungi characterized by an unusual spirocyclic furanone-lactam core, are suggested to have different biological activities including the modulation of immune response.
Complex characterization of the effects of pseurotin D on human lymphocyte activation in order to understand the potential of pseurotin to modulate immune response in humans.
CD4+ and CD8+ T cells and CD19+ B cells isolated from human blood were activated by various activators simultaneously with pseurotin D treatment. The effects of pseurotin were tested on the basis of changes in cell viability, apoptosis, activation of signal transducers and activators of transcription (STAT) signaling pathways, production of tumor necrosis factor (TNF)-α by T cells, expression of activation markers CD69 and CD25 on T cells and Human Leukocyte Antigen-DR isotype (HLA-DR) on B cells, and the differentiation markers CD20, CD27, CD38, and immunoglobulin (Ig) D on B cells.
Pseurotin D significantly inhibited the activation of both CD4+ and CD8+ human T cells complemented by the inhibition of TNF-α production without significant acute toxic effects. The Pseurotin D-mediated inhibition of T-cell activation was accompanied by the induction of the apoptosis of T cells. This corresponded with the inhibited phosphorylation of STAT3 and STAT5. In human B cells, pseurotin D did not significantly inhibit their activation; however, it affected their differentiation.
Our results advance the current mechanistic understanding of the pseurotin-induced inhibition of lymphocytes and suggest pseurotins as new attractive chemotypes for future research in the context of immune-modulatory drugs.
倍半萜类化合物 pseurotins 是一组不同真菌的次生代谢产物，其特征为具有不寻常的螺环呋喃酮-内酰胺核心，被认为具有不同的生物学活性，包括调节免疫反应。
对 pseurotin D 对人淋巴细胞激活的影响进行综合分析，以了解 pseurotin 调节人类免疫反应的潜力。
从人血中分离出 CD4+和 CD8+T 细胞和 CD19+B 细胞，并用各种激活剂同时激活这些细胞，并与 pseurotin D 处理。根据细胞活力、凋亡、转录信号转导和激活因子（STAT）信号通路的激活、T 细胞产生肿瘤坏死因子（TNF）-α、T 细胞上激活标志物 CD69 和 CD25 以及 B 细胞上人类白细胞抗原-DR 同种型（HLA-DR）的表达、B 细胞上的分化标志物 CD20、CD27、CD38 和免疫球蛋白（Ig）D 的变化来测试 pseurotin 的作用。
Pseurotin D 显著抑制了 CD4+和 CD8+人类 T 细胞的激活，同时抑制了 TNF-α的产生，而没有明显的急性毒性作用。Pseurotin D 介导的 T 细胞激活抑制伴随着 T 细胞凋亡的诱导。这与 STAT3 和 STAT5 的磷酸化抑制相对应。在人类 B 细胞中，pseurotin D 并没有显著抑制其激活，但它影响了它们的分化。
我们的结果推进了当前对 pseurotin 诱导的淋巴细胞抑制的机制理解，并表明 pseurotins 是未来免疫调节药物研究的新有吸引力的化学型。
