左旋咪唑通过诱导 p53 依赖性 DNA 损伤反应来抑制人类 T 细胞的活化和增殖,European Journal of Immunology

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左旋咪唑通过诱导 p53 依赖性 DNA 损伤反应来抑制人类 T 细胞的活化和增殖
European Journal of Immunology ( IF 4.5 ) Pub Date : 2023-08-19 , DOI: 10.1002/eji.202350562
Gerarda H Khan ₁ , Floor Veltkamp _{1,

2} , Mirte Scheper ₁ , Ron A Hoebe ₃ , Nike Claessen ₁ , Loes Butter ₁ , Antonia H M Bouts ₂ , Sandrine Florquin ₁ , Jeroen E J Guikema ₁ ,

Affiliation

左旋咪唑 (LMS) 是一种用于治疗特发性肾病综合征 (INS) 的小分子。INS 的发病机制仍不清楚，但有证据表明该疾病具有免疫学基础。最近，LMS 已被证明可以提高 INS 患者的无复发生存率。虽然 LMS 被假设具有免疫调节作用，但其作用机制仍不清楚。在这里，我们发现 LMS 降低了人类 T 细胞的活化和增殖。LMS 治疗后，T 细胞活化相关细胞因子（例如 IL-2、TNF-α 和 IFN-γ）减少，而 IL-4 和 IL-13 增加。基因表达谱证实，LMS 作为参与细胞周期进程的基因的抑制作用被下调。此外，LMS 上调了与 p53 激活相关的基因。一致地，LMS 处理导致 p53 磷酸化并增加 p53 靶基因FAS的表达。因此，LMS 使活化的 T 细胞对 Fas 介导的细胞凋亡敏感。LMS 处理导致细胞周期中期 S 期停滞，并伴有 γH2AX 灶形成和 CHK1 磷酸化。我们的研究结果表明，LMS 作为一种免疫抑制药物，通过诱导 DNA 损伤和激活 p53 依赖性 DNA 损伤反应，直接影响人类 T 细胞的激活和增殖。

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Levamisole suppresses activation and proliferation of human T cells by the induction of a p53-dependent DNA damage response

Levamisole (LMS) is a small molecule used in the treatment of idiopathic nephrotic syndrome (INS). The pathogenesis of INS remains unknown, but evidence points toward an immunological basis of the disease. Recently, LMS has been shown to increase the relapse-free survival in INS patients. While LMS has been hypothesized to exert an immunomodulatory effect, its mechanism of action remains unknown. Here, we show that LMS decreased activation and proliferation of human T cells. T-cell activation-associated cytokines such as IL-2, TNF-α, and IFN-γ were reduced upon LMS treatment, whereas IL-4 and IL-13 were increased. Gene expression profiling confirmed that the suppressive effects of LMS as genes involved in cell cycle progression were downregulated. Furthermore, genes associated with p53 activation were upregulated by LMS. In agreement, LMS treatment resulted in p53 phosphorylation and increased expression of the p53 target gene FAS. Accordingly, LMS sensitized activated T cells for Fas-mediated apoptosis. LMS treatment resulted in a mid-S phase cell cycle arrest accompanied by γH2AX-foci formation and phosphorylation of CHK1. Our findings indicate that LMS acts as an immunosuppressive drug that directly affects the activation and proliferation of human T cells by induction of DNA damage and the activation of a p53-dependent DNA damage response.

更新日期：2023-08-19

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