Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
Int J Mol Sci. 2024 Sep 26;25(19):10381. doi: 10.3390/ijms251910381.
Atherosclerosis is characterized by the deposition and accumulation of extracellular cholesterol and inflammatory cells in the arterial blood vessel walls, and 27-hydroxycholesterol (27OHChol) is the most abundant cholesterol metabolite. 27OHChol is an oxysterol that induces immune responses, including immune cell activation and chemokine secretion, although the underlying mechanisms are not fully understood. In this study, we investigated the roles of the mechanistic target of rapamycin (mTOR) in 27HChol-induced inflammation using rapamycin. Treating monocytic cells with rapamycin effectively reduced the expression of CCL2 and CD14, which was involved with the increased immune response by 27OHChol. Rapamycin also suppressed the phosphorylation of S6 and 4EBP1, which are downstream of mTORC1. Additionally, it also alleviates the increase in differentiation markers into macrophage. These results suggest that 27OHChol induces inflammation by activating the mTORC1 signaling pathway, and rapamycin may be useful for the treatment of atherosclerosis-related inflammation involving 27OHchol.
动脉粥样硬化的特征是细胞外胆固醇和炎性细胞在动脉血管壁中的沉积和积累，而 27-羟胆固醇（27OHChol）是最丰富的胆固醇代谢物。27OHChol 是一种氧化固醇，可诱导免疫反应，包括免疫细胞激活和趋化因子分泌，尽管其潜在机制尚不完全清楚。在这项研究中，我们使用雷帕霉素研究了机械性靶标雷帕霉素（mTOR）在 27HChol 诱导的炎症中的作用。用雷帕霉素处理单核细胞可有效降低 CCL2 和 CD14 的表达，这涉及到 27OHChol 引起的免疫反应增强。雷帕霉素还抑制了 mTORC1 下游的 S6 和 4EBP1 的磷酸化。此外，它还减轻了向巨噬细胞分化标记物的增加。这些结果表明，27OHChol 通过激活 mTORC1 信号通路引起炎症，雷帕霉素可能对治疗涉及 27OHchol 的动脉粥样硬化相关炎症有用。
