AMPK Inhibition Blocks ROS-NFκB Signaling and Attenuates Endotoxemia-Induced Liver Injury

Yuan Guo,Nonghua Lu,Qiuping Gu,Aiping Bai,Kai Hong,Fengyan Luo,Yi Zhang,Mengwei Zang

doi:10.1371/journal.pone.0086881

Abstract

BackgroundAMP-activated protein kinase (AMPK) is an important enzyme in regulation of cellular energy homeostasis. We have previously shown that AMPK activation by 5-aminoimidazole-4-carboxamide (AICAR) results in suppression of immune responses, indicating the pivotal role of AMPK in immune regulation. However, the cellular mechanism underpinning AMPK inhibition on immune response remains largely to be elucidated. The study aimed to investigate the effects of AMPK inhibition on reactive oxygen species (ROS)-nuclear factor κB (NFκB) signaling and endotoxemia-induced liver injury.Methodology/Principal FindingsRAW 264.7 cells were pretreated with AMPK activator or inhibitor, followed by LPS challenge. In addition, LPS was injected intraperitoneally into mice to induce systemic inflammation. The parameters of liver injury and immune responses were determined, and survival of mice was monitored respectively. LPS challenge in RAW 264.7 cells resulted in AMPK activation which was then inhibited by compound C treatment. Both AMPK activation by AICAR or inhibition by compound C diminished LPS-induced ROS generation, inhibited phosphorylation of IKK, IκB, and NFκB p65, and consequently, decreased TNF production of RAW 264.7 cells. AICAR or compound C treatment decreased ALT, AST, and TNF levels in serum, reduced CD68 expression and MPO activity in liver tissue of mice with endotoxemia. Moreover, AICAR or compound C treatment improved survival of endotoxemic mice.ConclusionsAICAR or compound C treatment attenuates LPS-induced ROS-NFκB signaling, immune responses and liver injury. Strategies to activate or inhibit AMPK signaling may provide alternatives to the current clinical approaches to inhibit immune responses of endotoxemia.

Highlights

Endotoxemia is one of the critical clinical diseases with high mortality and poor prognosis
As the most potent microbial mediators implicated in endotoxemia, bacterial components such as lipopolysaccharide (LPS), termed endotoxin, can initiate excessive activation of immune cells, and induce large amounts of proinflammatory cytokine and chemokine productions, which results in shock and multiple organ injury [1]
Compound C Blocks AICAR-induced AMPK Activation It has been recently recognized that AMPK signal controls inflammatory responses of immune disease models [14]

Summary

Introduction

Endotoxemia is one of the critical clinical diseases with high mortality and poor prognosis. As the most potent microbial mediators implicated in endotoxemia, bacterial components such as lipopolysaccharide (LPS), termed endotoxin, can initiate excessive activation of immune cells, and induce large amounts of proinflammatory cytokine and chemokine productions, which results in shock and multiple organ injury [1]. Immune cells such as macrophages and neutrophils, are recognized as primary pathogenic cells playing an important role in tissue damage, organ injury, and death in humans and other animals during the process of endotoximia [2,3]. The study aimed to investigate the effects of AMPK inhibition on reactive oxygen species (ROS)-nuclear factor kB (NFkB) signaling and endotoxemia-induced liver injury

Methods

Results

Conclusion