Department of Pharmacology, School of Pharmacy, Shahid Sadoughi University of Medical Sciences and Health Services, Yazd, Iran.
Department of Biochemistry, School of medicine, Shahid Sadoughi University of medical sciences and Health Services, Yazd, Iran.
Basic Clin Pharmacol Toxicol. 2021 May;128(5):669-676. doi: 10.1111/bcpt.13565. Epub 2021 Feb 15.
Numerous documents have been stated that tropisetron, an antagonist of the 5-HT3 receptor and α7nAChR agonist, modulates immune responses. However, the mechanistic basis for this aspect of tropisetron action is largely unknown. Here, the immuno-modulatory effects of tropisetron are investigated, focusing on the possible molecular targets and the mechanisms. Aside from the well-characterized role in immune signalling, JAK2/STAT3, TLR2 and TLR4 are signal transducers linked to both immuno-modulatory actions of acetylcholine and serotonin. Therefore, we evaluated their involvement in the immunoregulatory effects of tropisetron. To test the hypothesis, we assessed the expression of pro-/anti-inflammatory cytokines including TNF-α, IL-1β, IL-17 and IL-10 following tropisetron treatment in lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) derived from healthy subjects. Tropisetron up-regulates the transcription of TLR2, TLR4, JAK2 and STAT3 genes. Tropisetron also increases the expression of target pro-inflammatory cytokines, although considerably suppresses the pro-inflammatory cytokines (IL-1β, IL-17 and TNF-α) levels in media. Tropisetron notably promotes both IL-10 gene expression and secretion. These findings confirm the antiphlogistic properties of tropisetron. The present data also shed light on a new aspect of tropisetron immune-modulatory action that engaged TLR2, TLR4 and JAK2/STAT3 signalling cascades.
有大量文献表明，5-HT3 受体拮抗剂和 α7nAChR 激动剂托烷司琼可调节免疫反应。然而，托烷司琼作用于这一方面的机制基础在很大程度上尚不清楚。本研究旨在探讨托烷司琼的免疫调节作用，重点研究其可能的分子靶点和作用机制。除了在免疫信号中具有特征性作用外，JAK2/STAT3、TLR2 和 TLR4 还是与乙酰胆碱和 5-羟色胺的免疫调节作用相关的信号转导物。因此，我们评估了它们在托烷司琼免疫调节作用中的参与情况。为了验证这一假设，我们评估了托烷司琼治疗对健康受试者外周血单个核细胞（PBMC）中 LPS 刺激后促炎/抗炎细胞因子（包括 TNF-α、IL-1β、IL-17 和 IL-10）表达的影响。托烷司琼上调 TLR2、TLR4、JAK2 和 STAT3 基因的转录。托烷司琼还增加了靶标促炎细胞因子的表达，尽管可显著抑制细胞因子（IL-1β、IL-17 和 TNF-α）在培养基中的水平。托烷司琼明显促进了 IL-10 基因表达和分泌。这些发现证实了托烷司琼的抗炎特性。本研究数据还揭示了托烷司琼免疫调节作用的一个新方面，即参与 TLR2、TLR4 和 JAK2/STAT3 信号级联反应。
