International Journal of Hematology

, Volume 84, Issue 2, pp 143–150 | Cite as

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

  • Jin-Hee Hwang
  • Seong-Woo Kim
  • Hyo-Jin Lee
  • Hwan-Jung Yun
  • Samyong Kim
  • Deog-Yeon Jo
Review Article


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.

Key words

Interferon-γ Hematopoietic progenitor cells Survival Dual potential SDF-1 


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  1. 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.CrossRefGoogle Scholar
  2. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 8.
    Murray PJ, Young RA, Daley GQ. Hematopoietic remodelling in interferon-γ-deficient mice infected with mycobacteria. Blood. 1998;91:2914–2924.PubMedGoogle Scholar
  9. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 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.PubMedGoogle Scholar
  11. 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.PubMedGoogle Scholar
  12. 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.PubMedGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.Google Scholar
  17. 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.Google Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 29.
    Krebs DL, Hilton DJ. SOCS protein: negative regulators of cytokine signalling. Stem Cells. 2001;19:378–387.CrossRefPubMedGoogle Scholar
  30. 30.
    Turnley AM, Starr R, Bartlett PF. SOCS1 regulates interferon-γ mediated sensory neuron survival. Neuroreport. 2001;12:3443–3445.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 35.
    Sporn MB, Robert AB. Peptide growth factors are multifunctional. Nature. 1998;332:217–219.CrossRefGoogle Scholar
  36. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Asao H, Fu X-Y. Interferon-γ has dual potential in inhibiting or promoting cell proliferation. J Biol Chem. 2000;275:867–874.CrossRefPubMedGoogle Scholar
  38. 38.
    Budd RC. Death receptors couple to both cell proliferation and apoptosis. J Clin Invest. 2002;109:437–441.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Muhl H, Pfeilschifter J. Anti-inflammatory properties of proinflammatory interferon γ. Int Immunopharmacol. 2003;3:1247–1255.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2006

Authors and Affiliations

  • Jin-Hee Hwang
    • 1
  • Seong-Woo Kim
    • 1
  • Hyo-Jin Lee
    • 1
  • Hwan-Jung Yun
    • 1
  • Samyong Kim
    • 1
  • Deog-Yeon Jo
    • 1
  1. 1.Division of Hematology/Oncology, Department of Internal MedicineChungnam National University HospitalDaejonKorea

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