title: AMP-activated protein kinase negatively regulates FcεRI-mediated mast cell signaling and anaphylaxis in mice.
abstract: BACKGROUND
  Aggregation of FcεRI activates a cascade of signaling events leading to mast cell activation, followed by inhibitory signals that turn off the activating signals. However, the overall view of negative signals in mast cells is still incomplete. Although AMP-activated protein kinase (AMPK), which is generally known as a regulator of energy metabolism, is also associated with anti-inflammation, little is known about the role of AMPK in mast cells.
  
  
  OBJECTIVE
  We investigated the role of AMPK and its regulatory mechanism in mast cells.
  
  
  METHODS
  The roles of AMPK in FcεRI-dependent activation of bone marrow-derived mast cells (BMMCs) were evaluated by using chemical agents, small interfering RNAs (siRNAs), or adenovirus that modulated the activity or expression of AMPK signaling components. In addition, AMPKα2(-/-) mice were used to verify the role of AMPK in anaphylactic models.
  
  
  RESULTS
  FcεRI signaling and associated effector functions in BMMCs were suppressed by the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) and were conversely augmented by siRNA knockdown of AMPKα2 or liver kinase B1 (LKB1), an upstream kinase of AMPK. Furthermore, AMPKα2 deficiency led to increased FcεRI-mediated BMMC activation and anaphylaxis that were insensitive to AICAR, whereas enforced expression of AMPKα2 in AMPKα2(-/-) BMMCs reversed the hypersensitive FcεRI signaling to normal levels. Pharmacologic inhibition or siRNA knockdown of Fyn mimicked AMPK activation, suggesting that Fyn counterregulates the LKB1-AMPK axis. Mechanistically, Fyn controlled AMPK activity by regulating LKB1 localization.
  
  
  CONCLUSIONS
  The Fyn-regulated LKB1-AMPK axis acts as a novel inhibitory module for mast cell activation, which points to AMPK activators as therapeutic drugs for allergic diseases.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Korea; Department of Internal Medicine, Research Institute of Aging and Metabolism, WCU Program, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Seung-Lark
authors.initials: SL
authors.lastname: Hwang
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: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
authors.forename: Ye
authors.initials: Y
authors.lastname: Jin
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Korea.
authors.forename: Yong-Tae
authors.initials: YT
authors.lastname: Jeong
authors.affiliation: Department of Internal Medicine, Research Institute of Aging and Metabolism, WCU Program, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Yong Deuk
authors.initials: YD
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Research Institute of Aging and Metabolism, WCU Program, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
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: Hiroyasu
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Allergy and Clinical Immunology, Asan Medical Center, Ulsan University, College of Medicine, Seoul, Korea.
authors.forename: You Sook
authors.initials: YS
authors.lastname: Cho
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. Electronic address: murakami-mk@igakuken.or.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
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 / Q000235:genetics / Q000276:immunology*; D000707:Anaphylaxis / Q000276:immunology*; D000818:Animals; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000276:immunology; D017455:Receptors, IgE / Q000276:immunology*
chemical_list: D017455:Receptors, IgE; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: ACC; AICAR; AMP-activated protein kinase; AMPK; Acetyl-CoA carboxylase; Activator 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside; BMMC; Bone marrow–derived mast cell; CA-AMPK; Catalytically active AMPKα2; ERK; Extracellular signal-regulated kinase; Fyn; GRB2-associated-binding protein 2; Gab2; HSA; Human serum albumin; IKK; IκB kinase; JNK; LKB1; LTC(4); Leukotriene C(4); Liver kinase B1; MAPK; Mammalian target of rapamycin; Mast cell; Mitogen-activated protein kinase; NF-κB; Nuclear factor κB; PCA; PGD(2); PLCγ; PSA; Passive cutaneous anaphylaxis; Passive systemic anaphylaxis; Phospholipase Cγ; Prostaglandin D(2); Small interfering RNA; Spleen tyrosine kinase; Syk; WT; Wild-type; anaphylaxis; c-Jun N-terminal kinase; liver kinase B1; mTOR; siRNA; β-Hex; β-Hexosaminidase