title: The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice.
abstract: OBJECTIVE
  The response of AMP-activated protein kinase (AMPK) to oxidative stress has been recently reported but the downstream signals of this response are largely unknown. Meanwhile, the upstream events for the activation of nuclear factor erythroid-2-related factor-2 (Nrf2), a critical transcriptional activator for antioxidative responses, remain unclear. In the present study, we investigated the relationship between AMPK and Nrf2 signal pathways in lipopolysaccharide (LPS)-triggered inflammatory system, in which berberine (BBR), a known AMPK activator, was used for inflammation suppression.
  
  
  RESULTS
  In inflammatory macrophages, BBR attenuated LPS-induced expression of inflammatory genes (inducible nitric oxide synthase [iNOS], cyclooxygenase-2 [COX2], interleukin [IL]-6), and the generation of nitric oxide and reactive oxygen species, but increased the transcription of Nrf2-targeted antioxidative genes (NADPH quinone oxidoreductase-1 [NQO-1], heme oxygenase-1 [HO-1]), as well as the nuclear localization and phosphorylation of Nrf2 protein. Importantly, we found BBR-induced activation of Nrf2 is AMPK-dependent, as either pharmacologically or genetically inactivating AMPK blocked the activation of Nrf2. Consistent with in vitro experiments, BBR down-regulated the expression of proinflammatory genes but upregulated those of Nrf2-targeted genes in lungs of LPS-injected mice, and these effects were attenuated in Nrf2-deficient mice. Moreover, the effect of BBR on survival time extension and plasma redox regulation in endotoxin-shocked mice was largely weakened when Nrf2-depleted.
  
  
  CONCLUSIONS
  Our results demonstrate convergence between AMPK and Nrf2 pathways and this intersection is essential for anti-inflammatory effect of BBR in LPS-stimulated macrophages and endotoxin-shocked mice. Uncovering this intersection is significant for understanding the relationship between energy homeostasis and antioxidative responses and may be beneficial for developing new therapeutic strategies against inflammatory diseases. Antioxid. Redox Signal. 20, 574-588.
authors.affiliation: 1 Lab for Aging Research, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University , Chengdu, China .
authors.forename: Chunfen
authors.initials: C
authors.lastname: Mo
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Satoshi
authors.initials: S
authors.lastname: Numazawa
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Tang
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Han
authors.forename: Junhong
authors.initials: J
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.forename: Dandan
authors.initials: D
authors.lastname: Wei
authors.forename: Hengyi
authors.initials: H
authors.lastname: Xiao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001599:Berberine / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D020239:Receptor Cross-Talk
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D001599:Berberine; D009569:Nitric Oxide; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases