Department of Biosciences, Piracicaba Dental School, University of Campinas, Piracicaba, SP, Brazil; School of Dentistry, Federal University of Alfenas (Unifal-MG), Alfenas, Minas Gerais, Brazil.
Department of Biosciences, Piracicaba Dental School, University of Campinas, Piracicaba, SP, Brazil; Graduate Program in Biological Sciences, Federal University of Alfenas (Unifal-MG), Alfenas, MG, Brazil.
Eur J Pharmacol. 2022 Aug 15;929:175127. doi: 10.1016/j.ejphar.2022.175127. Epub 2022 Jul 1.
T helper 17 (Th17) lymphocytes play a critical role in the pathogenesis of autoimmune diseases, mainly by producing the pro-inflammatory cytokine interleukin-17 (IL-17). Therefore, Th17 lymphocytes have been considered a strategic target for drug discovery and development. In this study, we investigated the activity and possible mechanisms of action of a 4-phenyl coumarin isolated from propolis, named cinnamoyloxy-mammeisin (CNM), in Th17 cell differentiation and the development of experimental Th17-dependent autoimmune encephalomyelitis (EAE). Our data showed that in vitro Th17 cell differentiation was attenuated by CNM treatment in a concentration-dependent manner (1, 3, and 10 μM). This was associated with a reduction in the release of IL-17 (35% inhibition) and interleukin-22 (IL-22, 51% inhibition). Th17-differentiated cells exposed to CNM also downregulated the expression of Th17 hallmarked cell genes, such as RAR-related orphan receptor c (Rorc, 51% inhibition), and interleukin-23 receptor (Il23r, 64% inhibition), indicating possible upstream molecular mechanisms. Mechanistically, CNM significantly reduced the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) during in vitro Th17 cell differentiation. In vivo treatment with CNM (100 μg/kg) reduced the clinical signs of EAE, which was associated with a reduction in Central Nervous System demyelination, neuroinflammation, and Th17 response in the spinal cord and inguinal lymph nodes. Consistent with this, CNM also effectively attenuated human Th17 differentiation in vitro. Collectively, our results highlight the potential of CNM as a new molecule that can modulate Th17 cells via inhibition of STAT3 signaling and, as a result, reduce autoimmune inflammation.
辅助性 T 细胞 17（Th17）淋巴细胞在自身免疫性疾病的发病机制中发挥关键作用，主要通过产生促炎细胞因子白细胞介素-17（IL-17）。因此，Th17 淋巴细胞已被视为药物发现和开发的战略目标。在这项研究中，我们研究了从蜂胶中分离出的 4-苯基香豆素，命名为肉桂酰氧基-乳香素（CNM），在 Th17 细胞分化和实验性 Th17 依赖性自身免疫性脑脊髓炎（EAE）发展中的活性和可能的作用机制。我们的数据表明，CNM 以浓度依赖的方式（1、3 和 10 μM）减弱体外 Th17 细胞分化。这与 IL-17（抑制 35%）和白细胞介素-22（IL-22，抑制 51%）释放减少有关。暴露于 CNM 的 Th17 分化细胞还下调了 Th17 标志性细胞基因的表达，如维甲酸相关孤儿受体 c（Rorc，抑制 51%）和白细胞介素-23 受体（Il23r，抑制 64%），表明可能存在上游分子机制。在机制上，CNM 在体外 Th17 细胞分化过程中显著降低信号转导和转录激活因子 3（p-STAT3）的磷酸化。体内用 CNM（100μg/kg）治疗可减轻 EAE 的临床症状，这与中枢神经系统脱髓鞘、神经炎症和脊髓和腹股沟淋巴结中 Th17 反应减少有关。与此一致，CNM 还能有效抑制体外人类 Th17 分化。总之，我们的研究结果强调了 CNM 作为一种新分子的潜力，该分子可通过抑制 STAT3 信号转导来调节 Th17 细胞，从而减少自身免疫炎症。
