Chou Shao-Ting, Jung Fang, Yang Shih-Hsing, Chou Hwei-Ling, Jow Guey-Mei, Lin Jau-Chen
Division of Chest Medicine, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan.
Department of Respiratory Therapy, Fu-Jen Catholic University, New Taipei City, Taiwan.
Pharmacol Res Perspect. 2017 Aug;5(4). doi: 10.1002/prp2.337.
The inhibition of activated macrophages has been used to develop anti-inflammatory agents for therapeutic intervention to human diseases that cause excessive inflammatory responses. Antofine, a phenanthroindolizidine alkaloid, has a potent anti-inflammatory effect. However, the molecular mechanisms of its anti-inflammatory activity have not yet been fully detailed. In this study, we comprehensively explored the anti-inflammatory effects of antofine on endotoxin-induced inflammation in macrophages using cDNA microarray analysis, thereby elucidating the potential mechanism by which antofine suppresses inflammation. Antofine significantly suppressed the secretion of proinflammatory cytokines such as TNFα and IL-1β and the production of iNOS in LPS-activated Raw264.7 macrophage cells. In addition, antofine can suppress the expressions of several inflammation-related genes (such as ARG-1, IL1F9, IL-10, and IL-33) and extracellular matrix genes (such as TNC and HYAL1), as well as a vasopressor gene (EDN1) in activated macrophage cells, that are induced by LPS stimulation. The gene expression profiles analyzed by GeneMANIA software showed that antofine not only contributed anti-inflammatory activity but also modulated the cellular metabolism via AMPK. Furthermore, antofine also modulated the activation of AMPK and caspase-1, the key regulator in inflammasome-mediated IL-1β maturation, in activated macrophage cells. In conclusion, these data indicated that antofine potentially can not only contribute an anti-inflammatory effect but can also attenuate the metabolic disorders induced by inflammation via AMPK.
抑制活化巨噬细胞已被用于开发抗炎药物，用于对引起过度炎症反应的人类疾病进行治疗干预。安托芬是一种菲并吲哚里西啶生物碱，具有强大的抗炎作用。然而，其抗炎活性的分子机制尚未完全阐明。在本研究中，我们使用cDNA微阵列分析全面探讨了安托芬对内毒素诱导的巨噬细胞炎症的抗炎作用，从而阐明了安托芬抑制炎症的潜在机制。安托芬显著抑制LPS激活的Raw264.7巨噬细胞中促炎细胞因子如TNFα和IL-1β的分泌以及iNOS的产生。此外，安托芬可以抑制活化巨噬细胞中几种炎症相关基因（如ARG-1、IL1F9、IL-10和IL-33）和细胞外基质基因（如TNC和HYAL1）以及血管加压素基因（EDN1）的表达，这些基因是由LPS刺激诱导的。通过GeneMANIA软件分析的基因表达谱表明，安托芬不仅具有抗炎活性，还通过AMPK调节细胞代谢。此外，安托芬还调节活化巨噬细胞中AMPK和caspase-1的激活，caspase-1是炎性小体介导的IL-1β成熟的关键调节因子。总之，这些数据表明，安托芬不仅可能具有抗炎作用，还可以通过AMPK减轻炎症诱导的代谢紊乱。
