Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China.
Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China.
Int Immunopharmacol. 2019 Sep;74:105736. doi: 10.1016/j.intimp.2019.105736. Epub 2019 Jul 11.
C646 is a newly discovered competitive p300/CREB-binding protein-specific inhibitor. Previous studies have shown its potential antitumor activity, but the immunomodulatory function of C646 remains largely unknown. In this study, we investigated the effects of C646 in cytokine expression and antibacterial activity in mouse macrophages. Results showed that C646 significantly reduced LPS-induced pro-inflammatory cytokines, which relied on suppression of JNK, ERK1/2, and NF-κB p65 signaling pathways. In addition, the inhibitory effects were not associated with modulating the expression of CD14/TLR4/MD2 complex or antagonizing its binding ability to LPS. Furthermore, C646 also down-regulated the levels of FcγR III/II and CR3 on macrophage, impaired the phagocytic ability against E. coli, and blocked phagosome-lysosome fusion. Consistent with this, C646 inhibited macrophage-associated bactericidal ability. Collectively, these data indicated that C646 exhibited potent immunomodulatory effects on macrophage both in the production of pro-inflammatory cytokines and bacterial phagocytosis.
C646 是一种新发现的竞争性 p300/CREB 结合蛋白特异性抑制剂。先前的研究表明它具有潜在的抗肿瘤活性，但 C646 的免疫调节功能在很大程度上尚不清楚。在这项研究中，我们研究了 C646 在细胞因子表达和小鼠巨噬细胞抗菌活性中的作用。结果表明，C646 可显著降低 LPS 诱导的促炎细胞因子，这依赖于抑制 JNK、ERK1/2 和 NF-κB p65 信号通路。此外，抑制作用与调节 CD14/TLR4/MD2 复合物的表达或拮抗其与 LPS 的结合能力无关。此外，C646 还下调了巨噬细胞上 FcγR III/II 和 CR3 的水平，损害了对大肠杆菌的吞噬能力，并阻断了吞噬体-溶酶体融合。与此一致，C646 抑制了与巨噬细胞相关的杀菌能力。总之，这些数据表明 C646 在产生促炎细胞因子和细菌吞噬作用方面对巨噬细胞表现出强大的免疫调节作用。
