GSK621 activates AMPK signaling to inhibit LPS-induced TNFα production

作者：Wu, Yong-hong; Li, Quan; Li, Ping^*; Liu, Bei^*

来源：Biochemical and Biophysical Research Communications, 2016, 480(3): 289-295.

DOI：10.1016/j.bbrc.2016.10.001

• LPS
• TNF alpha
• AMPK
• GSK621
• ROS and NFKB

LPS stimulation in macrophages/monocytes induces TNF alpha production. We here tested the potential effect of GSK621, a novel AMP-activated protein kinase (AMPK) activator, against the process. In RAW264.7 macrophages, murine bone marrow-derived macrophages (BMDMs), and chronic obstructive pulmonary disease (COPD) patients' monocytes, GSK621 significantly inhibited LPS-induced TNFa protein secretion and mRNA synthesis. Inhibition of AMPK, through AMPK alpha shRNA knockdown or dominant negative mutation (T172A), almost abolished GSK621's suppression on TNF alpha in RAW264.7 cells. Reversely, forced expression of a constitutively-active AMPK alpha (T172D) mimicked GSK621 actions and reduced LPS-induced TNF alpha production. Molecularly, GSK621 suppressed LPS-induced reactive oxygen species (ROS) production and nuclear factor kappa B (NF kappa B) activation. In vivo, GSK621 oral administration inhibited LPS-induced TNF alpha production and endotoxin shock in mice. In summary, GSK621 activates AMPK signaling to inhibit LPS-induced TNF alpha production in macrophages/monocytes.

• 出版日期2016-11-18
• 单位西安医学院; 苏州大学; 西安交通大学