title: ERK1/2 antagonize AMPK-dependent regulation of FcεRI-mediated mast cell activation and anaphylaxis.
abstract: BACKGROUND
  Extracellular signal-regulated kinases 1/2 (ERK1/2) make important contributions to allergic responses via their regulation of degranulation, eicosanoid production, and cytokine expression by mast cells, yet the mechanisms underlying their positive effects on FcεRI-dependent signaling are not fully understood. Recently, we reported that mast cell activation and anaphylaxis are negatively regulated by AMP-activated protein kinase (AMPK). However, little is known about the relationship between ERK1/2-mediated positive and the AMPK-mediated negative regulation of FcεRI signaling in mast cells.
  
  
  OBJECTIVE
  We investigated possible interactions between ERK1/2 and AMPK in the modulation of mast cell signaling and anaphylaxis.
  
  
  METHODS
  Wild-type or AMPKα2(-/-) mice, or bone marrow-derived mast cells obtained from these mice, were treated with either chemical agents or small interfering RNAs that modulated the activity or expression of ERK1/2 or AMPK to evaluate the functional interplay between ERK1/2 and AMPK in FcεRI-dependent signaling.
  
  
  RESULTS
  The ERK1/2 pathway inhibitor U0126 and the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside similarly inhibited FcεRI-mediated mast cell signals in vitro and anaphylaxis in vivo. ERK1/2-specific small interfering RNA also mimicked this effect on FcεRI signals. Moreover, AMPKα2 knockdown or deficiency led to increased FcεRI-mediated mast cell activation and anaphylaxis that were insensitive to U0126 or activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside, suggesting that the suppression of FcεRI signals by the inhibition of the ERK1/2 pathway relies largely on AMPK activation. ERK1/2 controlled AMPK activity by regulating its subcellular translocation.
  
  
  CONCLUSIONS
  ERK1/2 ablated the AMPK-dependent negative regulatory axis, thereby activating FcεRI signals in mast cells.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
authors.forename: Seung-Lark
authors.initials: SL
authors.lastname: Hwang
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Korea; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
authors.forename: Xian
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
authors.forename: Yong Deuk
authors.initials: YD
authors.lastname: Kim
authors.affiliation: Department of Allergy and Clinical Immunology, Asan Medical Center, College of Medicine, Ulsan University, Seoul, Korea.
authors.forename: You Sook
authors.initials: YS
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
authors.forename: Yurndong
authors.initials: Y
authors.lastname: Jahng
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
authors.forename: Jong-Keun
authors.initials: JK
authors.lastname: Son
authors.affiliation: Department of Pharmacology, School of Medicine, Catholic University of Daegu, Daegu, Korea.
authors.forename: Youn Ju
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Korea.
authors.forename: Wonku
authors.initials: W
authors.lastname: Kang
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Taketomi
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Tae Chul
authors.initials: TC
authors.lastname: Moon
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Korea. Electronic address: hwchang@yu.ac.kr.
authors.forename: Hyeun Wook
authors.initials: HW
authors.lastname: Chang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000707:Anaphylaxis / Q000209:etiology / Q000276:immunology*; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006967:Hypersensitivity / Q000150:complications / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology; D017452:Receptors, IgG / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002070:Butadienes; C485701:Fcgr1 protein, mouse; D009570:Nitriles; D017452:Receptors, IgG; D012263:Ribonucleosides; C113580:U 0126; D000620:Aminoimidazole Carboxamide; C011651:acadesine; C534978:Prkaa2 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; ERK1/2; Mast cell; anaphylaxis