Intracellular signal transduction of interferon on the suppression of haematopoietic progenitor cell growth.
Interferon (IFN)-alpha and IFN-gamma suppress the growth of haematopoietic progenitor cells. IFN-alpha activates Janus kinase-1 (Jak1) and Tyrosine kinase-2 (Tyk2), followed by the phosphorylation of the signal transducers and activators of transcription, Stat1 and Stat2. IFN-gamma activates Jak1 and Jak2, followed by the activation of Stat1. Activated Stats bind the promoter regions of IFN-inducible genes. We evaluated the role of Tyk2 and Stat1 in the IFN-mediated inhibition of haematopoietic progenitor cell growth. While IFN-alpha (1000 U/ml) suppressed the number of granulocyte-macrophage colony-forming units (CFU-GM) or erythroid burst-forming units (BFU-E) from wild-type mouse bone marrow cells, this suppression was partially inhibited by a deficiency in Tyk2 and completely inhibited by a deficiency in Stat1. High levels of IFN-alpha (10,000 U/ml) suppressed the CFU-GM or BFU-E obtained from Stat1-deficient mice, but did not suppress this growth in cells from Tyk2-deficient mice. Stat1 was phosphorylated by IFN-alpha in Tyk2-deficient cells, although the level of phosphorylation was weaker than that observed in wild type mice. Thus, the inhibitory signal on haematopoietic progenitor cells mediated by IFN-alpha may be transduced by two signalling pathways, one regulated by Tyk2 and the other dependent on Stat1. IFN-gamma also suppressed the number of CFU-GM or BFU-E, and this pathway was mediated by IFN-gamma in a Stat1-dependent manner, independently of Tyk2.
Kato
Kouji
K
The First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Higashi-ku, Fukuoka, Japan.
Kamezaki
Kenjirou
K
Shimoda
Kazuya
K
Numata
Akihiko
A
Haro
Takashi
T
Aoki
Kenichi
K
Ishikawa
Fumihiko
F
Takase
Ken
K
Ariyama
Hiroshi
H
Matsuda
Tadashi
T
Miyamoto
Toshihiro
T
Nagafuji
Koji
K
Gondo
Hisashi
H
Nakayama
Kei-Ichi
K
Harada
Mine
M
D000818:Animals; D002455:Cell Division / Q000502:physiology; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003864:Depression, Chemical; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D011506:Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D007372:Interferons; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse