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

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Abstract
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.