Despite many apparently contradictory reports, IFN-γ is well known as a hematopoiesis-inhibitory cytokine and is implicated in the pathogenesis of aplastic anemia. It has been shown that IFN-γ intrinsically and simultaneously induces specific and conflicting signalling pathways and transcriptional programs that contribute to the potential dual effects of IFN-γ in promoting or inhibiting proliferation of murine pro-B cells (

Asao et al,
J Biol Chem
275
:
867
,
2000
). We explored the dual roles of IFN-γ in the inhibition or promotion of the survival and growth of hematopoietic progenitors, especially with regard to interactions with stromal cell-derived factor-1 (SDF-1). IFN-γ partially rescued normal bone marrow CD34+ cells and colony-forming cells from apoptosis induced by serum- and growth factor-deprivation. SDF-1 further enhanced cell survival, in synergy with IFN-γ. Short-term IFN-γ treatment of CD34+ cells enhanced the clonal growth of the cells in synergy with SDF-1. In contrast, IFN-γ inhibited the clonal growth of hematopoietic progenitor cells in a standard methylcellulose clonogenic assay and inhibited the growth factor-mediated survival of normal CD34+ cells, CD34+ cells from patients with chronic myeloid leukaemia, and MO7e cells. The addition of SDF-1 did not alter these outcomes. IFN-γ did not activate PI3K/Akt, enhance SDF-1-induced activation of PI3K/Akt, or up-regulate the expression of CXCR4 or its chemotactic function in bone marrow CD34+ cells. IFN-γ up-regulated the expression of Socs1 mRNA in CD34+ cells and MO7e cells. Referring to a previous report describing that Socs1 binds to multiple signalling proteins and suppresses stem cell factor-dependent proliferation of bone marrow-derived mast cells (De Sepulveda et al, EMBO J 18: 904,1999), it is suggested that IFN-γ-induced inhibition of the growth factor-dependent survival of CD34+ cells might be mediated, at least in part, through the induction of Socs1. Paradoxically, IFN-γ down-regulated SDF-1 production in primary human bone marrow stromal cells. These results indicate that IFN-γ, partly in concert with SDF-1, exerts dual effects on the survival and growth of hematopoietic progenitor cells; the effects of IFN-γ on hematopoietic progenitor cells can differ depending on the particular in vitro experimental conditions, especially the presence of hematopoietic growth factors.

Topics:
fibrinogen, hematopoietic system, interferon type ii, stromal cell-derived factor 1, suppressor of cytokine signaling 1 protein, 1-phosphatidylinositol 3-kinase, proto-oncogene proteins c-akt, aplastic anemia, cxcr4 receptors, cytokine

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2005, The American Society of Hematology
2004
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