Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Biochem Biophys Res Commun. 2018 Sep 10;503(3):1696-1702. doi: 10.1016/j.bbrc.2018.07.101. Epub 2018 Jul 26.
Acute pancreatitis (AP) is a common inflammatory disease in gastrointestinal tract. Our previous study has shown that caerulin induces TNF receptor-associated factor 3 (TRAF3)-p38 signaling activation and pro-inflammatory response in macrophages, causing damage to co-cultured pancreatic acinar cells. Dihydromyricetin (DHM) is a flavonoid extracted from Ampelopsis grossedentata, which has displayed anti-inflammation and anti-oxidant functions. Our results here show that DHM potently inhibited caerulin-induced expression and productions of multiple pro-inflammatory cytokines (IL-1β, TNF-α and IL-17) in murine bone marrow-derived macrophages (BMDMs). DHM significantly inhibited caerulin-induced TRAF3 protein stabilization, TRAF3-mitogen-activated protein kinase kinase 3 (MKK3) association and following MKK3-p38 activation in BMDMs. Significantly, DHM was ineffective against caerulin in TRAF3-silenced BMDMs. Importantly, DHM supplement attenuated the cytotoxicity of caerulin-activated BMDMs to co-cultured pancreatic acinar cells, resulting in significantly decreased acinar cell death and apoptosis. In vivo, DHM co-administration largely attenuated pancreatic and systemic inflammation in caerulin-injected AP mice. Together, DHM inhibits caerulin-induced TRAF3-p38 signaling activation and AP response. DHM could be further studied as a potential anti-AP agent.
急性胰腺炎（AP）是一种常见的胃肠道炎症性疾病。我们之前的研究表明，钙网蛋白诱导肿瘤坏死因子受体相关因子 3（TRAF3）-p38 信号通路激活和巨噬细胞中的促炎反应，导致共培养的胰腺腺泡细胞损伤。二氢杨梅素（DHM）是从葡萄科蛇葡萄属蛇葡萄中提取的一种黄酮类化合物，具有抗炎和抗氧化作用。我们的研究结果表明，DHM 能够强烈抑制钙网蛋白诱导的小鼠骨髓来源的巨噬细胞（BMDMs）中多种促炎细胞因子（IL-1β、TNF-α和 IL-17）的表达和产生。DHM 显著抑制钙网蛋白诱导的 TRAF3 蛋白稳定、TRAF3-丝裂原活化蛋白激酶激酶 3（MKK3）结合以及随后的 MKK3-p38 在 BMDMs 中的激活。重要的是，TRAF3 沉默的 BMDMs 中 DHM 对钙网蛋白无效。重要的是，DHM 补充剂可减轻钙网蛋白激活的 BMDMs 对共培养的胰腺腺泡细胞的细胞毒性，导致腺泡细胞死亡和凋亡明显减少。在体内，DHM 共同给药可显著减轻钙网蛋白注射诱导的 AP 小鼠的胰腺和全身炎症。总之，DHM 抑制钙网蛋白诱导的 TRAF3-p38 信号通路激活和 AP 反应。DHM 可进一步作为潜在的抗 AP 药物进行研究。
