Skip to main content
SpringerLink
Log in

Protection of human and murine hepatocytes against Fas-induced death by transferrin and iron

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Recent studies in a murine model show that transferrin (Tf) interferes with Fas-mediated hepatocyte death and liver failure by decreasing pro-apoptotic and increasing anti-apoptotic signals. We show here in vitro in murine and human hepatocyte cell lines and in vivo in mice that Fas-induced apoptosis is modulated by exogenous Tf and iron. The results obtained with iron-free Tf (ApoTf), iron-saturated Tf (FeTf), and the iron chelator salicylaldehyde isonicotinoyl hydrazone (SIH) in its iron-free and iron-saturated (FeSIH) forms indicate that apoptosis-modulating effects of Tf are not mediated by iron alone. Both the Tf molecule and iron affect multiple aspects of cell death, and the route of iron delivery to the cell may be critical for the final outcome of cellular Fas signaling. Survival of hepatocytes ‘stressed’ by Fas signals can be manipulated by Tf and iron and may be a target for prophylactic and therapeutic interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Crichton RR. Proteins of iron storage and transport. (Review). Adv. Protein Chem. 1990; 40: 281–363.

    Article  CAS  PubMed  Google Scholar 

  2. de Jong G, van Dijk JP, van Eijk HG. The biology of transferrin. (Review). Clinica Chimica Acta 1990; 190: 1–46.

    Google Scholar 

  3. Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin [Review]. Semi. Hematol. 1998; 35: 35–54.

    CAS  PubMed  Google Scholar 

  4. Lesnikova M, Lesnikov V, Arrighi S, Kistler G, Pierpaoli W, Deeg HJ. Upregulation of interleukin-10 and inhibition of alloantigen responses by transferrin and transferrin-derived glycans. J. Hematoth. Stem Cell Res. 2000; 9: 381–392.

    CAS  PubMed  Google Scholar 

  5. Lesnikov V, Lesnikova M, Deeg HJ. Pro-apoptotic and anti-apoptotic effects of transferrin and transferrin-derived glycans on hematopoietic cells and lymphocytes. Experim. Hematol. 2001; 29: 477–489.

    Article  CAS  PubMed  Google Scholar 

  6. Weinzimer SA, Gibson TB, Collett-Solberg PF, Khare A, Liu B, Cohen P. Transferrin is an insulin-like growth factor-binding protein-3 binding protein. J. Clin. Endocrinol. Metab. 2001; 86: 1806–1813.

    Article  CAS  Google Scholar 

  7. Storch S, Kubler B, Honing S, et al. Transferrin binds insulin-like growth factors and affects binding properties of insulin-like growth factor binding protein-3. FEBS Letters 2001; 509: 395–398.

    Article  CAS  PubMed  Google Scholar 

  8. Fassl S, Leisser C, Huettenbrenner S, et al. Transferrin ensures survival of ovarian carcinoma cells when apoptosis is induced by TNFalpha, FasL, TRAIL, or Myc. Oncogene 2003; 22: 8343–8355.

    Article  CAS  PubMed  Google Scholar 

  9. Ogasawara J, Watanabe-Fukunaga R, Adachi M, et al. Lethal effect of the anti-Fas antibody in mice [published erratum appears in Nature 1993 Oct 7;365(6446):568]. Nature 1993; 364: 806–809.

    Article  CAS  PubMed  Google Scholar 

  10. Lesnikov VA, Lesnikova MP, Shulman HM, et al. Prevention of Fas-mediated hepatic failure by transferrin. Laborat. Invest. 2004; 84: 342–352.

    Article  CAS  PubMed  Google Scholar 

  11. Templeton DM, Liu Y. Genetic regulation of cell function in response to iron overload or chelation (Review). Biochim. Biophys. Acta 2003; 1619: 113–124.

    CAS  PubMed  Google Scholar 

  12. van den Dobbelsteen DJ, Nobel CS, Schlegel J, Cotgreave IA, Orrenius S, Slater AF. Rapid and specific efflux of reduced glutathione during apoptosis induced by anti-Fas/APO-1 antibody. J. Biol. Chemis. 1996; 271: 15420–15427.

    PubMed  Google Scholar 

  13. Domenicotti C, Marengo B, Nitti M, et al. A novel role of protein kinase C-delta in cell signaling triggered by glutathione depletion. Biochem. Pharmacol. 2003; 66: 1521–1526.

    Article  CAS  PubMed  Google Scholar 

  14. Pierpaoli W, Lesnikov VA, Lesnikova MP, Arrighi S, Bardotti A. Unresponsiveness to human leukocytes in immunosuppressed mice by combined donor-derived human transferrin and antigens. Trans. Immunol. 1996; 4: 301–308.

    Article  CAS  PubMed  Google Scholar 

  15. Hermes-Lima M, Ponka P, Schulman HM. The iron chelator pyridoxal isonicotinoyl hydrazone (PIH) and its analogues prevent damage to 2-deoxyribose mediated by ferric iron plus ascorbate. Biochim. Biophy. Acta 2000; 1523: 154–160.

    CAS  PubMed  Google Scholar 

  16. Wu JC, Merlino G, Fausto N. Establishment and characterization of differentiated, nontransformed hepatocyte cell lines derived from mice transgenic for transforming growth factor alpha. Proc. Nat. Acad. Sci. USA 1994; 91: 674–678.

    CAS  PubMed  Google Scholar 

  17. Arsura M, FitzGerald MJ, Fausto N, Sonenshein GE. Nuclear factor-kappaB/Rel blocks transforming growth factor beta1-induced apoptosis of murine hepatocyte cell lines. Cell Growth & Differentiation 1997; 8: 1049–1059.

    CAS  Google Scholar 

  18. Buss JL, Neuzil J, Gellert N, Weber C, Ponka P. Pyridoxal isonicotinoyl hydrazone analogs induce apoptosis in hematopoietic cells due to their iron-chelating properties. Biochem. Pharmacol. 2003; 65: 161–172.

    CAS  PubMed  Google Scholar 

  19. Alcantara O, Javors M, Boldt DH. Induction of protein kinase C mRNA in cultured lymphoblastoid T cells by iron-transferrin but not by soluble iron. Blood 1991; 77: 1290–1297.

    CAS  PubMed  Google Scholar 

  20. Vercammen D, Brouckaert G, Denecker G, et al. Dual signaling of the Fas receptor: Initiation of both apoptotic and necrotic cell death pathways. J. Experim. Med. 1998; 188: 919–930.

    Article  CAS  PubMed  Google Scholar 

  21. Wang X, Ryter SW, Dai C et al. Necrotic cell death in response to oxidant stress involves the activation of the apoptogenic caspase-8/bid pathway. J. Biol. Chem. 2003; 278: 29184–29191.

    CAS  PubMed  Google Scholar 

  22. Quirk SM, Harman RM, Huber SC, Cowan RG. Responsiveness of mouse corpora luteal cells to Fas antigen (CD95)-mediated apoptosis. Biol. Reprod. 2000; 63: 49–56.

    CAS  PubMed  Google Scholar 

  23. Ferris CD, Jaffrey SR, Sawa A et al. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nature Cell Biol. 1999; 1: 152–157.

    CAS  PubMed  Google Scholar 

  24. Kakhlon O, Cabantchik ZI. The labile iron pool: Characterization, measurement, and participation in cellular processes (Review). Free Radical Biology & Medicine 2002; 33: 1037–1046.

    Article  CAS  Google Scholar 

  25. Susin SA, Lorenzo HK, Zamzami N et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999; 397: 441–446.

    CAS  PubMed  Google Scholar 

  26. Kim S, Ponka P. Effects of interferon-gamma and lipopolysaccharide on macrophage iron metabolism are mediated by nitric oxide-induced degradation of iron regulatory protein 2. J. Biol. Chem. 2000; 275: 6220–6226.

    CAS  PubMed  Google Scholar 

  27. Darnell G, Richardson DR. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents III: The effect of the ligands on molecular targets involved in proliferation. Blood 1999; 94: 781–792.

    CAS  PubMed  Google Scholar 

  28. Dhungana S, Taboy CH, Zak O, Larvie M, Crumbliss AL, Aisen P. Redox properties of human transferrin bound to its receptor. Biochem. 2004; 43: 205–209.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA

    V. A. Lesnikov, N. Abbasi, M. P. Lesnikova & H. J. Deeg

  2. University of Washington School of Medicine, Seattle, WA, 98109-1024, USA

    C. A. Lazaro, J. S. Campbell, N. Fausto & H. J. Deeg

  3. Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D1-100, Seattle, WA, PO Box 19024, 98109-1024, USA

    V. A. Lesnikov

Authors
  1. V. A. Lesnikov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. Abbasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. P. Lesnikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. A. Lazaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. S. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Fausto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. J. Deeg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. A. Lesnikov.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lesnikov, V.A., Abbasi, N., Lesnikova, M.P. et al. Protection of human and murine hepatocytes against Fas-induced death by transferrin and iron. Apoptosis 11, 79–87 (2006). https://doi.org/10.1007/s10495-005-3086-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-005-3086-2

Keywords

Search

Navigation