AMPK inhibition blocks ROS-NFκB signaling and attenuates endotoxemia-induced liver injury.
BACKGROUND
AMP-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.


RESULTS
RAW 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.


CONCLUSIONS
AICAR 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.
Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, China ; Department of Pharmacy, the First Affiliated Hospital of Nanchang University, Nanchang, China.
Yuan
Y
Guo
Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, China.
Yi
Y
Zhang
Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, China.
Kai
K
Hong
Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, China.
Fengyan
F
Luo
Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, China.
Qiuping
Q
Gu
Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, China.
Nonghua
N
Lu
Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, China.
Aiping
A
Bai
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D051550:I-kappa B Kinase; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide