title: Limitin, an interferon-like cytokine, transduces inhibitory signals on B-cell growth through activation of Tyk2, but not Stat1, followed by induction and nuclear translocation of Daxx.
abstract: OBJECTIVE
  Limitin, an interferon-like cytokine, suppresses B lymphopoiesis through ligation of the interferon-alpha/beta (IFN-alpha/beta) receptor. The aim of this study was to examine the intracellular signal transduction pathways activated by limitin.
  
  
  METHODS
  The effects of limitin on cell growth, the activation of Jak kinase and Stat proteins, and the induction of interferon regulatory factor-1 (IRF-1) and Daxx were examined using the mouse pre-B-cell line 18.81, wild-type, and Tyk2-deficient mouse bone marrow cells. In addition, the change of localization of the Daxx protein after limitin treatment in wild-type and Tyk2-deficient mice was examined.
  
  
  RESULTS
  Limitin phosphorylates Tyk2, Jak1, Stat1, and Stat2 and rapidly induces IRF-1 mRNA production. Phosphorylation of Stat1 by limitin is partially dependent on Tyk2. Suppression of B-cell growth by limitin, however, is severely impaired in the absence of Tyk2, whereas it is unaffected by the absence of Stat1. Limitin also induces the expression and nuclear translocation of Daxx, which is essential for IFN-alpha-induced inhibition of B-lymphocyte development. The absence of Tyk2 abrogates this induction of Daxx expression and nuclear translocation.
  
  
  CONCLUSIONS
  Limitin suppresses B-cell growth through activation of Tyk2, resulting in the up-regulation and nuclear translocation of Daxx. This limitin-mediated signaling pathway does not require Stat1.
authors.affiliation: The First Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Aoki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.forename: Kenji
authors.initials: K
authors.lastname: Oritani
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsuda
authors.forename: Kenjirou
authors.initials: K
authors.lastname: Kamezaki
authors.forename: Ryuta
authors.initials: R
authors.lastname: Muromoto
authors.forename: Akihiko
authors.initials: A
authors.lastname: Numata
authors.forename: Sadafumi
authors.initials: S
authors.lastname: Tamiya
authors.forename: Takashi
authors.initials: T
authors.lastname: Haro
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ishikawa
authors.forename: Ken
authors.initials: K
authors.lastname: Takase
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Taro
authors.initials: T
authors.lastname: Yumioka
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Koji
authors.initials: K
authors.lastname: Nagafuji
authors.forename: Hisashi
authors.initials: H
authors.lastname: Gondo
authors.forename: Seiho
authors.initials: S
authors.lastname: Nagafuchi
authors.forename: Kei-Ichi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Mine
authors.initials: M
authors.lastname: Harada
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D001854:Bone Marrow Cells; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D007136:Immunoglobulins / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C491473:Daxx protein, mouse; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; C480826:Mxra8 protein, mouse; D009687:Nuclear Proteins; D011506:Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse