title: Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock.
abstract: BACKGROUND
  The circadian clock temporally gates signaling through the high-affinity IgE receptor (FcεRI) in mast cells, thereby generating a marked day/night variation in allergic reactions. Thus manipulation of the molecular clock in mast cells might have therapeutic potential for IgE-mediated allergic reactions.
  
  
  OBJECTIVE
  We determined whether pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling was reduced (ie, when core circadian protein period 2 [PER2] is upregulated) resulted in suppression of IgE-mediated allergic reactions.
  
  
  METHODS
  We examined the effects of PF670462, a selective inhibitor of the key clock component casein kinase 1δ/ε, or glucocorticoid, both of which upregulated PER2 in mast cells, on IgE-mediated allergic reactions both in vitro and in vivo.
  
  
  RESULTS
  PF670462 or corticosterone (or dexamethasone) suppressed IgE-mediated allergic reactions in mouse bone marrow-derived mast cells or basophils and passive cutaneous anaphylactic reactions in mice in association with increased PER2 levels in mast cells or basophils. PF670462 or dexamethasone also ameliorated allergic symptoms in a mouse model of allergic rhinitis and downregulated allergen-specific basophil reactivity in patients with allergic rhinitis.
  
  
  CONCLUSIONS
  Pharmacologically resetting the molecular clock in mast cells or basophils to times when FcεRI signaling is reduced can inhibit IgE-mediated allergic reactions. The results suggest a new strategy for controlling IgE-mediated allergic diseases. Additionally, this study suggests a novel mechanism underlying the antiallergic actions of glucocorticoids that relies on the circadian clock, which might provide a novel insight into the pharmacology of this drug in allergic patients.
authors.affiliation: Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakano
authors.affiliation: Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ishimaru
authors.affiliation: Department of Dermatology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ando
authors.affiliation: Department of Pathology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katoh
authors.affiliation: Department of Clinical and Laboratory Medicine, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
authors.forename: Katsue
authors.initials: K
authors.lastname: Suzuki-Inoue
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Fukuoka, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagki
authors.affiliation: Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan; Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan. Electronic address: anakao@yamanashi.ac.jp.
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Nakao
mesh_terms: D000707:Anaphylaxis / Q000188:drug therapy* / Q000276:immunology; D000818:Animals; D001491:Basophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D048149:Casein Kinase 1 epsilon / Q000037:antagonists & inhibitors; D048148:Casein Kinase Idelta / Q000037:antagonists & inhibitors; D057906:Circadian Clocks / Q000187:drug effects* / Q000276:immunology; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D056950:Period Circadian Proteins / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D017455:Receptors, IgE / Q000378:metabolism; D065631:Rhinitis, Allergic / Q000188:drug therapy* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D007093:Imidazoles; D007155:Immunologic Factors; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D011743:Pyrimidines; D017455:Receptors, IgE; C522839:PF-670462; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta
keywords: Circadian clock; IgE; allergy; basophils; mast cells