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.
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.
Aoki
Kenichi
K
The First Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Shimoda
Kazuya
K
Oritani
Kenji
K
Matsuda
Tadashi
T
Kamezaki
Kenjirou
K
Muromoto
Ryuta
R
Numata
Akihiko
A
Tamiya
Sadafumi
S
Haro
Takashi
T
Ishikawa
Fumihiko
F
Takase
Ken
K
Yamamoto
Tetsuya
T
Yumioka
Taro
T
Miyamoto
Toshihiro
T
Nagafuji
Koji
K
Gondo
Hisashi
H
Nagafuchi
Seiho
S
Nakayama
Kei-Ichi
K
Harada
Mine
M
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
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