Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Pre-Clinical Studies

Fludarabine induces growth arrest and apoptosis of cytokine- or alloantigen-stimulated peripheral blood mononuclear cells, and decreases production of Th1 cytokines via inhibition of nuclear factor κB

Abstract

Fludarabine is a purine analog that has demonstrated significant activity in B-cell malignancies, including CLL. Fludarabine also possesses an immunosuppressive effect and is being used to prevent GVHD in hematopoietic stem cell transplantation. However, the molecular mechanism by which fludarabine inhibits immunoreaction remains to be fully elucidated. This study found that fludarabine inhibited tumor necrosis factor α (TNF-α)-stimulated degradation of IκBα, resulting in blockade of nuclear translocation of nuclear factor κB (NF-κB) in Jurkat T cells, as measured by western blot analysis and immunocytochemistry. The ability of fludarabine to inhibit NF-κB was further confirmed by electrophoretic mobility shift assay. We also found that fludarabine induced growth arrest and apoptosis of alloreactive and TNF-α-stimulated PBMCs. In addition, fludarabine inhibited TNF-α-stimulated production of IL-2 and IFN-γ, which play important roles in the onset of GVHD, in Jurkat cells. Taken together, fludarabine is useful for management of immune diseases, including GVHD, through inactivation of NF-κB.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Keating MJ, Kantarjian H, Talpaz M, Redman J, Koller C, Barlogie B et al. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood 1989; 74: 9–25.

    Google Scholar 

  2. Noker PE, Duncan GF, El Dareer SM, Hill DL . Disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5′-phosphate in mice and dogs. Cancer Treat Rep 1983; 67: 445–456.

    CAS  PubMed  Google Scholar 

  3. Frank DA, Mahajan S, Ritz J . Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat Med 1999; 5: 444–447.

    Article  CAS  PubMed  Google Scholar 

  4. Wang Y, Wu TR, Cai S, Welte T, Chin YE . Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappaB activation. Mol Cell Biol 2000; 20: 4505–4512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Aggarwal BB . Nuclear factor-kappaB: the enemy within. Cancer Cell 2004; 6: 203–208.

    Article  CAS  PubMed  Google Scholar 

  6. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004; 431: 461–466.

    Article  CAS  PubMed  Google Scholar 

  7. Ikezoe T, Yang Y, Heber D, Taguchi H, Koeffler HP . PC-SPES: potent inhibitor of nuclear factor-kappa B rescues mice from lipopolysaccharide-induced septic shock. Mol Pharmacol 2003; 64: 1521–1529.

    Article  CAS  PubMed  Google Scholar 

  8. Xun CQ, Thompson JS, Jennings CD, Brown SA, Widmer MB . Effect of total body irradiation, busulfan–cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft versus host disease in H-2 incompatible transplanted SCID mice. Blood 1994; 83: 2360–2367.

    CAS  PubMed  Google Scholar 

  9. Gonzalez M, Quezada SA, Blazar BR, Panoskaltsis-Mortari A, Rudensky AY, Noelle RJ . The balance between donor T cell anergy and suppression versus lethal graft-versus-host disease is determined by host conditioning. J Immunol 2002; 169: 5581–5589.

    Article  CAS  PubMed  Google Scholar 

  10. Reddy P . Pathophysiology of acute graft-versus-host disease. Hematol Oncol 2003; 21: 149–161.

    Article  PubMed  Google Scholar 

  11. Shlomchik WD, Couzens MS, Tang CB, McNiff J, Robert ME, Liu J et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999; 285: 412–415.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang Y, Shlomchik WD, Joe G, Louboutin JP, Zhu J, Rivera A et al. APCs in the liver and spleen recruit activated allogeneic CD8+ T cells to elicit hepatic graft-versus-host disease. J Immunol 2002; 169: 7111–7118.

    Article  CAS  PubMed  Google Scholar 

  13. Schmaltz C, Alpdogan O, Muriglan SJ, Kappel BJ, Rotolo JA, Ricchetti ET et al. Donor T cell-derived TNF is required for graft-versus-host disease and graft-versus-tumor activity after bone marrow transplantation. Blood 2003; 101: 2440–2445.

    Article  CAS  PubMed  Google Scholar 

  14. Ikezoe T, Tanosaki S, Krug U, Liu B, Cohen P, Taguchi H et al. Insulin-like growth factor binding protein-3 antagonizes the effects of retinoids in myeloid leukemia cells. Blood 2004; 104: 237–242.

    Article  CAS  PubMed  Google Scholar 

  15. Baldwin Jr AS . The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol 1996; 14: 649–683.

    Article  CAS  PubMed  Google Scholar 

  16. Osborn L, Kunkel S, Nabel GJ . Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci USA 1989; 86: 2336–2340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Israel A, Le Bail O, Hatat D, Piette J, Kieran M, Logeat F et al. TNF stimulates expression of mouse MHC class I genes by inducing an NF kappa B-like enhancer binding activity which displaces constitutive factors. EMBO J 1989; 8: 3793–3800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Blanco B, Perez-Simon JA, Sanchez-Abarca LI, Carvajal-Vergara X, Mateos J, Vidriales B et al. Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blood 2006; 107: 3575–3583.

    Article  CAS  PubMed  Google Scholar 

  19. Sanhes L, Tang R, Delmer A, DeCaprio JA, Ajchenbaum-Cymbalista F . Fludarabine-induced apoptosis of B chronic lymphocytic leukemia cells includes early cleavage of p27kip1 by caspases. Leukemia 2003; 17: 1104–1111.

    Article  CAS  PubMed  Google Scholar 

  20. Nishioka C, Ikezoe T, Yang J, Koeffler HP, Taguchi H . Fludarabine induces apoptosis of human T-cell leukemia virus type 1-infected T cells via inhibition of the nuclear factor-kappaB signal pathway. Leukemia 2007; 21: 1044–1049.

    Article  CAS  PubMed  Google Scholar 

  21. Via CS, Finkelman FD . Critical role of interleukin-2 in the development of acute graft-versus-host disease. Int Immunol 1993; 5: 565–572.

    Article  CAS  PubMed  Google Scholar 

  22. Ferrara JL, Marion A, McIntyre JF, Murphy GF, Burakoff SJ . Amelioration of acute graft vs host disease due to minor histocompatibility antigens by in vivo administration of anti-interleukin 2 receptor antibody. J Immunol 1986; 137: 1874–1877.

    CAS  PubMed  Google Scholar 

  23. Herve P, Wijdenes J, Bergerat JP, Bordigoni P, Milpied N, Cahn JY et al. Treatment of corticosteroid resistant acute graft-versus-host disease by in vivo administration of anti-interleukin-2 receptor monoclonal antibody (B-B10). Blood 1990; 76: 2639–2640.

    Google Scholar 

  24. Li XC, Demirci G, Ferrari-Lacraz S, Groves C, Coyle A, Malek TR et al. IL-15 and IL-2: a matter of life and death for T cells in vivo. Nat Med 2001; 7: 114–118.

    Article  CAS  PubMed  Google Scholar 

  25. Szebeni J, Wang MG, Pearson DA, Szot GL, Sykes M . IL-2 inhibits early increases in serum γ-interferon levels associated with graft-versus-host disease. Transplantation 1994; 58: 1385–1393.

    CAS  PubMed  Google Scholar 

  26. Wang MG, Szebeni J, Pearson DA, Szot GL, Sykes M . Inhibition of graft-versus-host disease by interleukin-2 treatment is associated with altered cytokine production by expanded graft-versus-host-reactive CD4+ helper cells. Transplantation 1995; 60: 481–490.

    Article  CAS  PubMed  Google Scholar 

  27. Troutt AB, Maraskovsky E, Rogers LA, Pech MH, Kelso A . Quantitative analysis of lymphokine expression in vivo and in vitro. Immunol Cell Biol 1992; 70: 51–57.

    Article  CAS  PubMed  Google Scholar 

  28. Velardi A, Varese P, Terenzi A, Dembech C, Albi N, Grossi CE et al. Lymphokine production by T-cell clones after human bone marrow transplantation. Blood 1989; 74: 1665–1672.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture Sports, Science, and Technology of Japan and the Fund for Academic Research from Kochi University.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to T Ikezoe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nishioka, C., Ikezoe, T., Togitani, K. et al. Fludarabine induces growth arrest and apoptosis of cytokine- or alloantigen-stimulated peripheral blood mononuclear cells, and decreases production of Th1 cytokines via inhibition of nuclear factor κB. Bone Marrow Transplant 41, 303–309 (2008). https://doi.org/10.1038/sj.bmt.1705901

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705901

Keywords

This article is cited by

Search

Quick links