Punicalagin, a PTP1B inhibitor, induces M2c phenotype polarization via up-regulation of HO-1 in murine macrophages
Punicalagin, a PTP1B inhibitor, induces M2c phenotype polarization via up-regulation of HO-1 in murine macrophages
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Punicalagin 是一种 PTP1B 抑制剂，通过上调小鼠巨噬细胞中的 HO-1 诱导 M2c 表型极化
DOI：
10.1016/j.freeradbiomed.2017.06.014
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发表时间：
2017
影响因子：
7.4
通讯作者：
Liu Qingquan
中科院分区：
文献类型：
--
作者：
Xu Xiaolong;Guo Yuhong;Zhao Jingxia;He Shasha;Wang Yan;Lin Yan;Wang Ning;Liu Qingquan
目前的研究表明，石榴鞣花单宁（punicalagin， PUN）是一种从石榴中分离出来的鞣花单宁，具有抗炎和抗氧化的特性；然而，其直接目标尚未被报道。这是首次报道PTP1B作为PUN的直接靶点，ic50值为1.04 μM。NPOI结果进一步表明，Konand Koffof PUN-PTP1B复合物分别为3.38e2 M−1s−1和4.13e-3 s−1。通过计算模拟和点突变，确定了PTP1B的活性位点Arg24是PUN的关键结合位点。此外，双关语抑制PTP1B可促进m2c样巨噬细胞极化，增强抗炎细胞因子表达，包括IL-10和M-CSF。根据基因表达谱，我们发现双关语处理显著上调了275个基因，下调了1059个基因。m1样巨噬细胞标记基因asTlr4、Irf1/2、Hmgb1、stat1下调，M2标记基因tmem171、Gpr35、Csf1、Il1rn、Cebpb、Fos、Vegfα、Slc11a1、bhlhe40上调。编码HO-1蛋白的Hmox-1基因优先表达，变化16倍。抑制HO-1可明显恢复punn诱导的M2极化和IL-10分泌。此外，Akt和STAT3的磷酸化也参与了punn诱导的HO-1表达。本研究为研究punn介导的抗炎和抗氧化活性的机制提供了新的见解，并为炎症性疾病的治疗提供了新的策略。
Current data have shown that punicalagin (PUN), an ellagitannin isolated from pomegranate, possesses anti-inflammatory and anti-oxidant properties; however, its direct targets have not yet been reported. This is the first report that PTP1B serves as a direct target of PUN, with IC50value of 1.04 μM. Results from NPOI further showed that the Konand Koffof PUN-PTP1B complex were 3.38e2 M−1s−1and 4.13e-3 s−1, respectively. The active site Arg24 of PTP1B was identified as a key binding site of PUN by computation simulation and point mutation. Moreover, inhibition of PTP1B by PUN promoted an M2c-like macrophage polarization and enhanced anti-inflammatory cytokines expression, including IL-10 and M-CSF. Based on gene expression profile, we elucidated that PUN treatment significantly up-regulated 275 genes and down-regulated 1059 genes. M1-like macrophage marker genes, such asTlr4, Irf1/2,Hmgb1, and Stat1were down-regulated, while M2 marker genes, includingTmem171, Gpr35,Csf1,Il1rn,Cebpb, Fos, Vegfα,Slc11a1, andBhlhe40were up-regulated in PUN-treated macrophages.Hmox-1, a gene encoding HO-1 protein, was preferentially expressed with 16-fold change. Inhibition of HO-1 obviously restored PUN-induced M2 polarization and IL-10 secretion. In addition, phosphorylation of both Akt and STAT3 contributed to PUN-induced HO-1 expression. This study provided new insights into the mechanisms of PUN-mediated anti-inflammatory and anti-oxidant activities and provided new therapeutic strategies for inflammatory diseases.