A novel AMPK activator hernandezine inhibits LPS-induced TNFα production

// Ping Li 1, * , Xiaofang Li 2, * , Yonghong Wu 3 , Manxiang Li 4 and Xiaochuang Wang 5 1 Department of Emergency, The Second Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, China 2 Department of Gastroenterology, The Third People’s Hospital of Xi’an, Xi’an, China 3 Staff Room of Clinical Immunology and Pathogen Detection, Medical Technology Department, Xi’an Medical College, Xi’an, China 4 Department of Respiratory Medicine, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, China 5 Department of Critical Care Medicine, The Second Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, China * These authors have contributed equally to this work Correspondence to: Xiaochuang Wang, email: wangxiaochuangyshi@126.com Manxiang Li, email: drli_manxiang88@163.com Keywords: hernandezine, LPS, AMPK, TNFα, NFκB Received: March 08, 2017     Accepted: May 03, 2017     Published: June 05, 2017 ABSTRACT 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 ex-vivo 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.