miR-135b-5p inhibits LPS-induced TNFα production via silencing AMPK phosphatase Ppm1e

Abstract

// Ping Li 1, Jian-bo Fan 2, Yanxia Gao 1, Ming Zhang 1, Li Zhang 1, Ning Yang 1, Xiaojing Zhao 1 1 Department of Emergency, the Second Affiliated Hospital of Xi'an Jiao Tong University, Xi’an, China 2 Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, China Correspondence to: Xiaojing Zhao, email: Zhao_xiandr@163.com Keywords: miR-135b-5p, Ppm1e, AMPK, LPS, TNFα Received: September 02, 2016     Accepted: October 05, 2016     Published: October 25, 2016 ABSTRACT AMPK activation in monocytes could suppress lipopolysaccharide (LPS)-induced tissue-damaging TNFa production. We are set to provoke AMPK activation via microRNA (“miRNA”) downregulating its phosphatase Ppm1e. In human U937 and THP-1 monocytes, forced expression of microRNA-135b-5p (“miR-135b-5p”) downregulated Ppm1e and activated AMPK signaling. Further, LPS-induced TNFα production in above cells was dramatically attenuated. Ppm1e shRNA knockdown in U937 cells also activated AMPK and inhibited TNFα production by LPS. AMPK activation is required for miR-135b-induced actions in monocytes, AMPKα shRNA knockdown or T172A dominant negative mutation almost abolished miR-135b-5p’s suppression on LPS-induced TNFα production. Significantly, miR-135b-5p inhibited LPS-induced reactive oxygen species (ROS) production, NFκB activation and TNFα mRNA expression in human macrophages. AMPKα knockdown or mutation again abolished above actions by miR-135b-5p. We conclude that miR-135b-5p expression downregulates Ppm1e to activate AMPK signaling, which inhibits LPS-induced TNFα production via suppressing ROS production and NFκB activation.