Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA.
Department of Specialty Medicine, Ohio University, Athens, OH, 45701, USA.
Eur J Pharmacol. 2020 Sep 15;883:173340. doi: 10.1016/j.ejphar.2020.173340. Epub 2020 Jul 4.
Sepsis is a serious condition that can lead to long-term organ damage and death. At the molecular level, the hallmark of sepsis is the elevated expression of a multitude of potent cytokines, i.e. a cytokine storm. For sepsis involving gram-negative bacteria, macrophages recognize lipopolysaccharide (LPS) shed from the bacteria, activating Toll-like-receptor 4 (TLR4), and triggering a cytokine storm. Glycogen synthase kinase-3 (GSK-3) is a highly active kinase that has been implicated in LPS-induced cytokine production. Thus, compounds that inhibit GSK-3 could be potential therapeutics for sepsis. Our group has recently described a novel and highly selective inhibitor of GSK-3 termed COB-187. In the present study, using THP-1 macrophages, we evaluated the ability of COB-187 to attenuate LPS-induced cytokine production. We found that COB-187 significantly reduced, at the protein and mRNA levels, cytokines induced by LPS (e.g. IL-6, TNF-α, IL-1β, CXCL10, and IFN-β). Further, the data suggest that the inhibition could be due, at least in part, to COB-187 reducing NF-κB (p65/p50) DNA binding activity as well as reducing IRF-3 phosphorylation at Serine 396. Thus, COB-187 appears to be a potent inhibitor of the cytokine storm induced by LPS.
败血症是一种严重的病症，可能导致长期的器官损伤和死亡。在分子水平上，败血症的标志是多种强效细胞因子的表达升高，即细胞因子风暴。对于涉及革兰氏阴性菌的败血症，巨噬细胞识别从细菌脱落的脂多糖（LPS），激活 Toll 样受体 4（TLR4），并引发细胞因子风暴。糖原合成酶激酶-3（GSK-3）是一种高度活跃的激酶，已被牵连到 LPS 诱导的细胞因子产生中。因此，抑制 GSK-3 的化合物可能是败血症的潜在治疗方法。我们的小组最近描述了一种称为 COB-187 的新型高度选择性 GSK-3 抑制剂。在本研究中，我们使用 THP-1 巨噬细胞评估了 COB-187 减弱 LPS 诱导的细胞因子产生的能力。我们发现 COB-187 显著降低了 LPS 诱导的细胞因子（例如 IL-6、TNF-α、IL-1β、CXCL10 和 IFN-β）的蛋白和 mRNA 水平。此外，数据表明抑制作用至少部分归因于 COB-187 降低了 NF-κB（p65/p50）DNA 结合活性以及降低了 IRF-3 在丝氨酸 396 上的磷酸化。因此，COB-187 似乎是 LPS 诱导的细胞因子风暴的有效抑制剂。
