Kato Kouji, Kamezaki Kenjirou, Shimoda Kazuya, Numata Akihiko, Haro Takashi, Aoki Kenichi, Ishikawa Fumihiko, Takase Ken, Ariyama Hiroshi, Matsuda Tadashi, Miyamoto Toshihiro, Nagafuji Koji, Gondo Hisashi, Nakayama Kei-Ichi, Harada Mine
The First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Higashi-ku, Fukuoka, Japan.
Br J Haematol. 2003 Nov;123(3):528-35. doi: 10.1046/j.1365-2141.2003.04650.x.
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.
干扰素（IFN）-α和IFN-γ可抑制造血祖细胞的生长。IFN-α激活Janus激酶-1（Jak1）和酪氨酸激酶-2（Tyk2），随后信号转导子和转录激活子Stat1和Stat2发生磷酸化。IFN-γ激活Jak1和Jak2，随后激活Stat1。活化的Stat蛋白结合IFN诱导基因的启动子区域。我们评估了Tyk2和Stat1在IFN介导的造血祖细胞生长抑制中的作用。虽然IFN-α（1000 U/ml）可抑制野生型小鼠骨髓细胞中粒细胞-巨噬细胞集落形成单位（CFU-GM）或红系爆式集落形成单位（BFU-E）的数量，但这种抑制作用因Tyk2缺陷而部分受到抑制，因Stat1缺陷而完全受到抑制。高水平的IFN-α（10000 U/ml）可抑制Stat1缺陷小鼠的CFU-GM或BFU-E，但不能抑制Tyk2缺陷小鼠细胞的这种生长。在Tyk2缺陷细胞中，Stat1可被IFN-α磷酸化，尽管磷酸化水平比野生型小鼠中观察到的要弱。因此，IFN-α介导的对造血祖细胞的抑制信号可能通过两条信号通路转导，一条由Tyk2调节，另一条依赖于Stat1。IFN-γ也可抑制CFU-GM或BFU-E的数量，且该途径由IFN-γ以Stat1依赖的方式介导，与Tyk2无关。
