Anti-inflammatory actions of Caesalpinin M2 in experimental colitis as a selective glucocoricoid receptor modulator
Anti-inflammatory actions of Caesalpinin M2 in experimental colitis as a selective glucocoricoid receptor modulator
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Caesalpinin M2 作为选择性糖皮质激素受体调节剂对实验性结肠炎的抗炎作用
DOI：
10.1016/j.bcp.2018.02.003
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发表时间：
2018
影响因子：
5.8
通讯作者：
Xu Qiang
中科院分区：
文献类型：
--
作者：
Xiang Gang;Fan Minmin;Ma Yuzhu;Wang Miao;Gao Jian;Chen Jingwei;Li Xin;Xue Wenwen;Wang Yixuan;Gao Huiyuan;Shen Yan;Xu Qiang
虽然炎症基因表达的抑制使得糖皮质激素（GC）成为强大的抗炎剂，但副作用限制了使用并推动了对改进的糖皮质激素受体（GR）配体的研究。GCs的抗炎作用主要是通过GR反式抑制NF-κB通路等主要炎症通路来实现的，而其副作用主要是通过GR的反式激活来实现的。本研究发现，从一种中药中分离得到的一种卡桑呋喃二萜类化合物-苏木素M2（C-M2）在体外和体内均具有抗炎作用。C-M2抑制LPS激活的骨髓源性巨噬细胞中促炎细胞因子IL-1β和IL-6的表达。同时，C-M2治疗减轻DSS诱导的小鼠实验性急性结肠炎，并且不引起副作用，如脾退化，如地塞米松治疗。分子对接和细胞热位移实验证明C-M2与GR在配体结合位点结合。我们发现C-M2通过激活GR介导基因抑制效应。更重要的是，C-M2未能诱导GR与糖皮质激素反应元件依赖性基因结合，进而激活其转录。但它确实通过促进GR和p65之间的相互作用抑制NF-κ B依赖的转录。两者合计，这种植物来源的非甾体化合物可以发挥抗炎作用作为一种选择性GR调节剂，并可能在炎症性疾病的治疗应用中具有巨大的潜力。
Although repression of inflammatory gene expression makes glucocorticoids (GCs) powerful anti-inflammatory agents, side effects limit usage and drive the search for improved glucocorticoid receptor (GR) ligands. It has been postulated that the anti-inflammatory effects of GCs are primarily mediated by GR’s activity in transrepressing major inflammation pathways such as NF-κB pathway, whereas their side effects are mostly mediated by GR’s transactivation. In this study, we found that Caesalpinin M2 (C-M2), a cassane furanoditerpene isolated from a Chinese medical plant, exerts an anti-inflammatory potential bothin vitroandin vivo. C-M2 inhibited the expression of proinflammatory cytokine IL-1β and IL-6 in LPS-activated bone marrow-derived macrophages. Meanwhile, C-M2 treatment attenuated DSS-induced experimental acute colitis in mice and did not cause side effects, such as spleen involution, like dexamethasone treatment. Molecular docking and cellular thermal shift assay demonstrated that C-M2 could bind to GR in the ligand binding site. We showed that C-M2 mediates gene-inhibitory effects by activating GR. More importantly, C-M2 failed to induce GR binding to glucocorticoid response element-dependent genes and in turn activate their transcription. But it did repress NF-κB-dependent transcription by facilitating the interaction between GR and p65. Taken together, this non-steroidal compound of plant origin may exert anti-inflammatory actions as a selective GR modulator and might hold great potential for therapeutic use in inflammatory diseases.