Li Ping, Li Xiaofang, Wu Yonghong, Li Manxiang, Wang Xiaochuang
Department of Emergency, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.
Department of Gastroenterology, The Third People's Hospital of Xi'an, Xi'an, China.
Oncotarget. 2017 Jun 5;8(40):67218-67226. doi: 10.18632/oncotarget.18365. eCollection 2017 Sep 15.
Here, we found that hernandezine, a novel AMPK activator, inhibited LPS-induced TNFα expression/production in human macrophage cells (THP-1 and U937 lines). Activation of AMPK is required for hernandezine-induced anti-LPS response. AMPKα shRNA or dominant negative mutation (T172A) blocked hernandezine-induced AMPK activation, which almost completely reversed anti-LPS activity by hernandezine. Exogenous expression of the constitutively activate AMPKα (T172D, caAMPKα) also suppressed TNFα production by LPS. Remarkably, hernandezine was unable to further inhibit LPS-mediated TNFα production in caAMPKα-expressing cells. Hernandezine inhibited LPS-induced reactive oxygen species (ROS) production and nuclear factor kappa B (NFκB) activation. Treatment of hernandezine in cultured primary human peripheral blood mononuclear cells (PBMCs) also largely attenuated LPS-induced TNFα production. Together, we conclude that AMPK activation by hernandezine inhibits LPS-induced TNFα production in macrophages/monocytes.
在此，我们发现新的AMPK激活剂汉防己甲素可抑制人巨噬细胞（THP-1和U937细胞系）中LPS诱导的TNFα表达/产生。汉防己甲素诱导的抗LPS反应需要AMPK激活。AMPKα shRNA或显性负性突变（T172A）可阻断汉防己甲素诱导的AMPK激活，这几乎完全逆转了汉防己甲素的抗LPS活性。组成型激活的AMPKα（T172D，caAMPKα）的外源性表达也可抑制LPS诱导的TNFα产生。值得注意的是，汉防己甲素无法进一步抑制表达caAMPKα的细胞中LPS介导的TNFα产生。汉防己甲素可抑制LPS诱导的活性氧（ROS）产生和核因子κB（NFκB）激活。在培养的原代人外周血单核细胞（PBMC）中用汉防己甲素处理也可大大减弱LPS诱导的TNFα产生。总之，我们得出结论，汉防己甲素激活AMPK可抑制巨噬细胞/单核细胞中LPS诱导的TNFα产生。
