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Interferon γ Has Dual Potential in Inhibiting or Promoting Survival and Growth of Hematopoietic Progenitors: Interactions with Stromal Cell-Derived Factor 1

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Abstract

We explored the possibility that interferon γ (IFN-γ) has bidirectional functions in 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 hematopoietic growth factor (HGF) deprivation, and SDF-1 further enhanced cell survival. Short-term IFN-γ treatment of CD34+ cells in the absence of serum and HGFs 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 HGF-mediated survival of normal CD34+ cells. The addition of SDF-1 did not alter these outcomes. IFN-γ did not enhance SDF-1-induced activation of PI3K/Akt or up-regulate the expression of CXCR4 or its function in bone marrow CD34+ cells. IFN-γ up-regulated Socs1 messenger RNA expression in normal CD34+ cells, which was further enhanced with the addition of HGFs. 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 HGFs.

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References

  1. Zoumbos NC, Gascon P, Djeu JY, Young NS. Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possibly in vivo. Proc Nat Acad Sci U S A. 1985;82:188–192.

    Article  CAS  Google Scholar 

  2. Mamus SW, Beck-Schroeder S, Zanjani ED. Suppression of normal human erythropoiesis by gamma interferon in vitro: role of monocytes and T lymphocytes. J Clin Invest. 1985;75:1496–1503.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Nistico A, Young NS. Gamma-interferon gene expression in the bone marrow of patients with aplastic anemia. Ann Intern Med. 1994;120:463–469.

    Article  PubMed  CAS  Google Scholar 

  4. Dufour C, Corcione A, Svahn J, Haupt R, Battilana N, Pistoia V. Interferon γ and tumour necrosis factor α are overexpressed in bone marrow T lymphocytes from paediatric patients with aplastic anemia. Br J Haematol. 2001;115:1023–1031.

    Article  PubMed  CAS  Google Scholar 

  5. Yu J-M, Emmons RV, Hanazono Y, Sellers S, Young NS, Dunbar CE. Expression of interferon-γ by stromal cells inhibits murine long-term repopulating hematopoietic stem cell activity. Exp Hematol. 1999;27:895–903.

    Article  PubMed  CAS  Google Scholar 

  6. Selleri C, Sato T, Anderson S, Young NS, Maciejewski JP. Inter-feron-gamma and tumour necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol. 1995;165:538–546.

    Article  PubMed  CAS  Google Scholar 

  7. Shimozato O, Ortaldo JR, Komschlies KL, Young HA. Impaired NK cell development in an IFN-γ transgenic mouse: aberrantly expressed IFN-γ enhances hematopoietic stem cell apoptosis and affects NK cell differentiation. J Immunol. 2002;168:1746–1752.

    Article  PubMed  CAS  Google Scholar 

  8. Murray PJ, Young RA, Daley GQ. Hematopoietic remodelling in interferon-γ-deficient mice infected with mycobacteria. Blood. 1998;91:2914–2924.

    PubMed  CAS  Google Scholar 

  9. Gabriele L, Phung J, Fukumoto J, et al. Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein. J Exp Med. 1999;190:411–422.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Maciejewski J, Selleri C, Anderson S, Young NS. Fas antigen expression on CD34+ human marrow cells is induced by interferon gamma and tumour necrosis factor alpha and potentiates cytokinemediated hematopoietic suppression in vitro. Blood. 1995;85:3183–3190.

    PubMed  CAS  Google Scholar 

  11. Dai C, Krantz SB. Interferon-γ induces upregulation and activation of caspases 1, 3, and 8 to produce apoptosis in human erythroid progenitor cells. Blood. 1999;93:3309–3316.

    PubMed  CAS  Google Scholar 

  12. Richman CM, Slapak CA, Toh B. Interferon protects normal human granulocyte/macrophage colony-forming cells from Ara-C cytotoxicity. J Biol Response Mod. 1990;9:570–575.

    PubMed  CAS  Google Scholar 

  13. Caux C, Moreau I, Saeland S, Bancherau J. Interferon-gamma enhances factor-dependent myeloid proliferation of human CD34+ hematopoietic progenitor cells. Blood. 1992;79:2628–2635.

    PubMed  CAS  Google Scholar 

  14. Shiohara M, Koike K, Nakahata T. Synergism of interferon-gamma and stem cell factor on the development of murine hematopoietic progenitors in serum-free culture. Blood. 1993;81:1435–1441.

    PubMed  CAS  Google Scholar 

  15. Kawano Y, Takaue Y, Hirao A, et al. Synergy among erythropoietin, interleukin 3, stem cell factor (c-kit ligand) and interferongamma on early human hematopoiesis. Stem Cells. 1994;12:514–520.

    Article  PubMed  CAS  Google Scholar 

  16. Snoeck HW, Lenjou M, Nys G, et al. Interleukin 4 and interferon gamma costimulate the expansion of early human myeloid colonyforming cells: proposal of a model for the regulation of myelopoiesis by interleukin 4 and interferon gamma and its integration with the regulation of the immune response. Leukemia. 1996;10:117–122.

    CAS  PubMed  Google Scholar 

  17. Choi I, Muta K, Wickrema A, Krantz SB, Nawata H. Interferon gamma delays apoptosis of mature erythroid progenitor cells in the absence of erythropoietin. Blood. 2000;95:3742–3749.

    CAS  PubMed  Google Scholar 

  18. Tsuji-Takayama K, Tahata H, Harachima A, et al. Interferon-gamma enhances megakaryocyte colony-stimulating activity in murine bone marrow cells. J Interferon Cytokine Res. 1996;16:701–708.

    Article  CAS  PubMed  Google Scholar 

  19. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NDO/SCID mice on CXCR4. Science. 1999;283:845–848.

    Article  PubMed  CAS  Google Scholar 

  20. Lataillade JJ, Clay D, Dupuy C, et al. Chemokine SDF-1 enhances circulating CD34+ cell proliferation in synergy with cytokines: possible role in progenitor survival. Blood. 2000;95:756–768.

    PubMed  CAS  Google Scholar 

  21. Lee Y-H, Gotoh A, Kwon H-J, et al. Enhancement of intracellular signalling associated with hematopoietic progenitor cell survival in response to SDF-1/CXCL12 in synergy with other cytokines. Blood. 2002;99:4307–4317.

    Article  PubMed  CAS  Google Scholar 

  22. Aiuti A,Webb IJ, Springer T, Gutierrez-Ramos JC. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral Blood. J Exp Med. 1997;185:111–120.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Grafte-Faure S, Leveque C, Ketata E, et al. Recruitment of primitive peripheral blood cells: synergism of interleukin 12 with inter-leukin 6 and stromal cell-derived factor-1. Cytokine. 2000;12:1–7.

    Article  PubMed  CAS  Google Scholar 

  24. Broxmyeler HE, Cooper S, Kohli L, et al. Transgenic expression of stromal cell-derived factor-1/CXC chemokine ligand 12 enhances myeloid progenitor cell survival/antiapoptosis in vitro in response to growth factor withdrawal and enhances myelopoiesis in vivo. J Immunol. 2003;170:421–429.

    Article  Google Scholar 

  25. Rosu-Myles M, Bhatia M. SDF-1 enhances the expansion and maintenance of highly purified human hematopoietic progenitors. Hematol J. 2003;4:137–145.

    Article  PubMed  CAS  Google Scholar 

  26. Lataillade J-J, Clay D, Bourin P, et al. Stromal cell-derived factor-1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G0/G1 transition in CD34+ cells: evidence for an autocrine/paracrine mechanism. Blood. 2002;99:1117–1129.

    Article  PubMed  CAS  Google Scholar 

  27. Cashman J, Clark-Lewis I, Eaves A, Eaves C. Stromal-derived factor-1 inhibits the cycling of very primitive human hematopoietic cells in vitro and in NOD/SCID mice. Blood. 2002;99:792–799.

    Article  PubMed  CAS  Google Scholar 

  28. Nguyen H, Ramana CV, Bayes J, Stark GR. Roles of phos-phatidylinositol 3-kinase in interferon-γ-dependent phosphorylation of STAT1 on serine 727 and activation of gene expression. J Biol Chem. 2001;276:33361–33368.

    Article  PubMed  CAS  Google Scholar 

  29. Krebs DL, Hilton DJ. SOCS protein: negative regulators of cytokine signalling. Stem Cells. 2001;19:378–387.

    Article  PubMed  CAS  Google Scholar 

  30. Turnley AM, Starr R, Bartlett PF. SOCS1 regulates interferon-γ mediated sensory neuron survival. Neuroreport. 2001;12:3443–3445.

    Article  PubMed  CAS  Google Scholar 

  31. De Sepulveda P, Okkenhaug K, Rose JL, Hawley RG, Dubreuil P, Rottapel R. Socs1 binds to multiple signaling proteins and suppresses Steel factor-dependent proliferation. EMBO J. 1999;18:904–915.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ratajczak J, Kucia M, Reca R, Zhang J, Machalinski B, Ratajczak MZ. Quiescent CD34+ early erythroid progenitors are resistant to several erythropoietic ‘inhibitory’ cytokines: role of FLIP. Br J Haematol. 2003;123:160–169.

    Article  PubMed  CAS  Google Scholar 

  33. Jonsson M, Engstrom M, Jonsson JI. FLT3 ligand regulates apoptosis through AKT-dependent inactivation of transcription factor FoxO3. Biochem Biophy Res Commun. 2004;318:899–903.

    Article  CAS  Google Scholar 

  34. Myklebust JH, Blomhoff HK, Rusten LS, Stokke T, Smeland EB. Activation of phosphatidylinositol 3-kinase is important for ery-thropoietin-induced erythropoiesis from CD34+ hematopoietic progenitor cells. Exp Hematol. 2002;30:990–1000.

    Article  PubMed  CAS  Google Scholar 

  35. Sporn MB, Robert AB. Peptide growth factors are multifunctional. Nature. 1998;332:217–219.

    Article  Google Scholar 

  36. Nakajima K, Yamanaka Y, Nakae K, et al. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemic cells. EMBO J. 1996;15:3651–3658.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Asao H, Fu X-Y. Interferon-γ has dual potential in inhibiting or promoting cell proliferation. J Biol Chem. 2000;275:867–874.

    Article  PubMed  CAS  Google Scholar 

  38. Budd RC. Death receptors couple to both cell proliferation and apoptosis. J Clin Invest. 2002;109:437–441.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Muhl H, Pfeilschifter J. Anti-inflammatory properties of proinflammatory interferon γ. Int Immunopharmacol. 2003;3:1247–1255.

    Article  CAS  PubMed  Google Scholar 

Download references

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Correspondence to Deog-Yeon Jo.

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Hwang, JH., Kim, SW., Lee, HJ. et al. Interferon γ Has Dual Potential in Inhibiting or Promoting Survival and Growth of Hematopoietic Progenitors: Interactions with Stromal Cell-Derived Factor 1. Int J Hematol 84, 143–150 (2006). https://doi.org/10.1532/IJH97.A30606

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  • DOI: https://doi.org/10.1532/IJH97.A30606

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