School of Life Sciences and Health Engineering, Jiangnan University, No. 1800, Lihu Avenue, Wuxi, 214122, China.
In Vitro Cell Dev Biol Anim. 2024 Jun;60(6):667-677. doi: 10.1007/s11626-024-00919-x. Epub 2024 May 22.
BP001 is a promising small molecule compound that has been specifically designed to target and degrade Bruton's tyrosine kinases (BTK), which is known to play a crucial role in lymphoma development. Macrophages are important immune cells in inflammation regulation and immune response. In this study, we aimed to investigate the effect of BP001 on RAW264.7 macrophage activation stimulated by a high glucose environment. Our findings revealed that treatment with BP001 significantly inhibited the production of nitric oxide (NO), reactive oxygen species (ROS), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) in RAW264.7 macrophages exposed to high glucose conditions. Furthermore, we observed that BP001 treatment also down-regulated the expression of BTK in these activated macrophages. To elucidate the underlying mechanism behind these observations, we investigated the phosphorylation level of NF-κB. Our results demonstrated that BP001 treatment led to decreased phosphorylation levels of NF-κB, thereby inhibiting the level of inflammation. In addition, we also found that BP001 could restore RAW264.7 macrophages from the pro-inflammatory state to the normal phenotype and reduce the occurrence of inflammation. The regulatory function of BP001 in autoimmunity is mediated through the degradation of BTK protein, thereby attenuating macrophage activation. Additionally, BTK plays a pivotal role in transcriptional regulation by inducing NF-κB activity. Consequently, it is not difficult to understand that BP001 effectively inhibits inflammation. In conclusion, the present study provides evidence that BP001, a BTK degrader, can serve as a novel immunomodulator of inflammation induced by high glucose, making it an attractive candidate for further investigation.
BP001 是一种有前景的小分子化合物，专门设计用于靶向和降解布鲁顿酪氨酸激酶（BTK），BTK 已知在淋巴瘤发展中发挥关键作用。巨噬细胞是炎症调节和免疫反应中的重要免疫细胞。在这项研究中，我们旨在研究 BP001 对高糖环境刺激的 RAW264.7 巨噬细胞活化的影响。我们的研究结果表明，BP001 处理显著抑制了在高糖条件下暴露的 RAW264.7 巨噬细胞中一氧化氮（NO）、活性氧（ROS）、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）的产生。此外，我们还观察到 BP001 处理还下调了这些活化巨噬细胞中 BTK 的表达。为了阐明这些观察结果的潜在机制，我们研究了 NF-κB 的磷酸化水平。我们的结果表明，BP001 处理导致 NF-κB 的磷酸化水平降低，从而抑制了炎症水平。此外，我们还发现 BP001 可以使 RAW264.7 巨噬细胞从促炎状态恢复到正常表型并减少炎症的发生。BP001 在自身免疫中的调节功能是通过 BTK 蛋白的降解介导的，从而减弱巨噬细胞的活化。此外，BTK 通过诱导 NF-κB 活性在转录调节中发挥关键作用。因此，不难理解 BP001 可以有效抑制炎症。总之，本研究提供了证据表明，BTK 降解剂 BP001 可作为高糖诱导的炎症的新型免疫调节剂，是进一步研究的有吸引力的候选药物。
