Key Points• IFN-g impairs maintenance ofHSCs by directly reducing their proliferative capacity and impairing their restoration upon viral infection.• IFN-g induces SOCS1 expression in HSCs, which inhibits TPO-induced STAT5 phosphorylation, thereby deregulating key cell-cycle genes.Balancing the processes of hematopoietic stem cell (HSC) differentiation and selfrenewal is critical for maintaining a lifelong supply of blood cells. The bone marrow (BM) produces a stable output of newly generated cells, but immunologic stress conditions inducing leukopenia increase the demand for peripheral blood cell supply.Here we demonstrate that the proinflammatory cytokine interferon-g (IFN-g) impairs maintenance of HSCs by directly reducing their proliferative capacity and that IFN-g impairs restoration of HSC numbers upon viral infection. We show that IFN-g reduces thrombopoietin (TPO)-mediated phosphorylation of signal transducer and activator of transcription (STAT) 5, an important positive regulator of HSC self-renewal. IFN-g also induced expression of suppressor of cytokine signaling (SOCS) 1 in HSCs, and we demonstrate that SOCS1 expression is sufficient to inhibit TPO-induced STAT5 phosphorylation. Furthermore, IFN-g deregulates expression of STAT5-mediated cell-cycle genes cyclin D1 and p57. These findings suggest that IFN-g is a negative modulator of HSC self-renewal by modifying cytokine responses and expression of genes involved in HSC proliferation. We postulate that the occurrence of BM failure in chronic inflammatory conditions, such as aplastic anemia, HIV, and graft-versus-host disease, is related to a sustained impairment of HSC self-renewal caused by chronic IFN-g signaling in these disorders. (Blood. 2013;121(18):3578-3585)

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The proinflammatory cytokine interferon-γ (IFN-γ) is well known for its important role in innate and adaptive immunity against intracellular infections and for tumor control. Yet, it has become clear that IFN-γ also has a strong impact on bone marrow (BM) output during inflammation, as it affects the differentiation of most hematopoietic progenitor cells. Here, we review the impact of IFN-γ on hematopoiesis, including the function of hematopoietic stem cells (HSCs) and more downstream progenitors. We discuss which hematopoietic lineages are functionally modulated by IFN-γ and through which underlying molecular mechanism(s). We propose the novel concept that IFN-γ acts through upregulation of suppressor of cytokine signaling molecules, which impairs signaling of several cytokine receptors. IFN-γ has also gained clinical interest from different angles, and we discuss how chronic IFN-γ production can lead to the development of anemia and BM failure and how it is involved in malignant hematopoiesis. Overall, this review illustrates the wide-ranging effect of IFN-γ on the (patho-)physiological processes in the BM.