Genistein protects against DSS-induced colitis by inhibiting NLRP3 inflammasome via TGR5-cAMP signaling
Genistein protects against DSS-induced colitis by inhibiting NLRP3 inflammasome via TGR5-cAMP signaling
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金雀异黄素通过 TGR5-cAMP 信号传导抑制 NLRP3 炎症小体，预防 DSS 诱导的结肠炎
DOI：
10.1016/j.intimp.2019.01.021
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发表时间：
2019-06-01
影响因子：
5.6
通讯作者：
Zhu, Yubing
中科院分区：
文献类型：
--
作者：
Chen, Yu;Thi Ha Le;Zhu, Yubing
据报道，NLRP 3炎性小体与包括结肠炎在内的炎性肠病相关，因为其具有诱导IL-1 β分泌的潜在能力。新兴的研究表明，染料木黄酮，一个主要的代谢产物，具有潜在的抗炎作用，在小鼠模型结肠炎。然而，其抗炎机制仍不清楚。本研究通过靶向NLRP 3炎性小体，探讨染料木黄酮对葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎的影响。此外，染料木黄酮在DSS诱导的结肠炎中的保护作用机制可能与TGR 5信号转导有关。染料木黄酮治疗不仅显着减轻体重减轻和结肠长度缩短，而且显着减少血清和结肠中的炎性细胞浸润和促炎介质的产生。此外，在佛波醇肉豆蔻酸酯乙酸酯（PMA）分化的单核细胞THP-1细胞和U937细胞中，Genistein处理下调半胱天冬酶-1和IL-1 β的产生，并增加细胞内cAMP水平，这与INT-777（一种半合成TGR 5激动剂）的处理相似。Genistein的这些保护作用可能归因于NLRP 3的泛素化，该泛素化是由于cAMP与NLRP 3相互作用而诱导的。此外，Genistein对NLRP 3炎性小体的作用在TGR 5沉默的U937细胞中消失。总之，我们的研究揭示了Genistein能够通过巨噬细胞中的TGR 5-cAMP信号转导抑制NLRP 3炎性小体。因此，它可能是一个潜在的有效药物治疗炎症性肠病。
NLRP3 inflammasome has been reported to be associated with inflammatory bowel disease including colitis due to its potential ability to induce IL-1 beta secretion. Emerging studies have demonstrated that Genistein, a major isoflavone, has potential anti-inflammatory effects in murine model colitis. However, its anti-inflammatory mechanism remains unclear. The effects of Genistein in dextran sulfate sodium (DSS)-induced murine colitis via targeting NLRP3 inflammasome was investigated in this study. Also, the mechanisms of protective action of Genistein in DSS-induced colitis may relate to TGR5 signaling. Genistein treatment not only remarkably attenuated loss of body weight and shortening of colon length but also significantly reduced inflammatory cells infiltration and pro-inflammatory mediator production in serum and colon. Moreover, Genistein treatment down-regulated production of caspase-1 and IL-1 beta and increased intracellular cAMP level, which were similar to the treatment for INT-777, a semi-synthetic TGR5 agonist, in phorbol myristate acetate (PMA)-differentiated monocytic THP-1 cells and U937 cells. These protective effects of Genistein might be attributed by ubiquination of NLRP3 which was induced due to interaction of cAMP with NLRP3. Furthermore, the effects of Genistein on NLRP3 inflammasome disappeared in TGR5-silenced U937 cells. In conclusion, our study unveils that Genistein was able to inhibit NLRP3 inflammasome via TGR5-cAMP signaling in macrophages. It therefore might be a potential effective drug for inflammatory bowel diseases.