Intracellular signal transduction of interferon on the suppression of haematopoietic progenitor cell growth

Summary. Interferon (IFN)-α and IFN-γ suppress the growth of haematopoietic progenitor cells. IFN-α 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-γ 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-α (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-α (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-α 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-α may be transduced by two signalling pathways, one regulated by Tyk2 and the other dependent on Stat1. IFN-γ also suppressed the number of CFU-GM or BFU-E, and this pathway was mediated by IFN-γ in a Stat1-dependent manner, independently of Tyk2.