Skip to main content

1,25-dihydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the fas receptor

Abstract

Beta cell loss occurs at the onset of type 1 diabetes and after islet graft. It results from the dysfunction and destruction of beta cells mainly achieved by apoptosis. One of the mediators believed to be involved in beta cell apoptosis is Fas, a transmembrane cell surface receptor transducing an apoptotic death signal and contributing to the pathogenesis of several autoimmune diseases. Fas expression is particularly induced in beta cells by inflammatory cytokines secreted by islet-infiltrating mononuclear cells and makes cells susceptible to apoptosis by interaction with Fas-ligand expressing cells. We have previously demonstrated that 1,25 (OH)2 D3, the active metabolite of vitamin D, known to exhibit immunomodulatory properties and prevent the development of type 1 diabetes in NOD mice, is efficient against apoptosis induced by cytokines in human pancreatic islets in vitro. The effects were mainly mediated by the inactivation of NF-kappa-B. In this study we demonstrated that 1,25 (OH)2 D3 was also able to counteract cytokine-induced Fas expression in human islets both at the mRNA and protein levels. These results were reinforced by our microarray analysis highlighting the beneficial effects of 1,25 (OH)2 D3 on death signals induced by Fas activation. Our results provides additional evidence that 1,25 (OH)2 D3 may be an interesting tool to help prevent the onset of type 1 diabetes and improve islet graft survival.

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

References

  1. 1.

    Paraskevas S, Aikin R, Maysinger D, et al. Activation and expression of ERK, INK, and p38 MAP-kinases in isolated islets of Langerhans: Implications for cultured islet survival. FEES Lett. 1999; 455: 203–208.

    Article  CAS  Google Scholar 

  2. 2.

    Tobiasch E, Gunther L, Bach FH. Heme oxygenase-1 protects pancreatic beta cells from apoptosis caused by various stimuli. J. Investig. Med. 2001; 49: 566–571.

    CAS  PubMed  Google Scholar 

  3. 3.

    Yamada K, Takane-Gyotoku N, Yuan X, Ichikawa F, Inada C, Nonaka K. Mouse islet cell lysis mediated by interleukin-1-induced Fas. Diabetologia 1996; 39: 1306–1312.

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Nagata S. Apoptosis by death factor. Cell 1997; 88: 355–365.

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    De Maria R, Testi R. Fas-FasL interactions: a common pathogenetic mechanism in organ-specific autoimmunity. Immunol. Today 1998; 19: 121–125.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Leithauser F, Dhein J, Mechtersheimer G, et al. Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells. Lab Invest 1993; 69: 415–429.

    CAS  PubMed  Google Scholar 

  7. 7.

    Stassi G, Todaro M, Richiusa P, et al. Expression of apoptosis-inducing CD95 (Fas/Apo- 1) on human beta-cells sorted by flow-cytometry and cultured in vitro. Transplant Proc. 1995; 27: 3271–3275.

    CAS  PubMed  Google Scholar 

  8. 8.

    Loweth AC, Williams GT, James RF, Scarpello JH, Morgan NG. Human islets of Langerhans express Fas ligand and undergo apoptosis in response to interleukin-1 beta and Fas ligation. Diabetes 1998; 47: 727–732.

    CAS  PubMed  Google Scholar 

  9. 9.

    Moriwaki M, Itoh N, Miyagawa J, et al. Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset Type I diabetes mellitus. Diabetologia 1999; 42: 1332–1340.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Savinov AY, Tcherepanov A, Green EA, Flavell RA, Chervonsky AV. Contribution of Fas to diabetes development. Proc Natl Acad Sci USA 2003; 100: 628–632.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Stassi G, De Maria R, Trucco G, et al. Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus. J Exp Med 1997; 186: 1193–1200.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Rescigno M, Piguet V, Valzasina B, et al. Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-lbeta, and the production of interferon gamma in the absence of IL-12 during DC-T cell cognate interaction: a new role for Fas ligand in inflammatory responses. J. Exp. Med. 2000; 192: 1661–1668.

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Casteels K, Bouillon R, Waer M, Mathieu C. Immunomodulatory effects of 1,25-dihydroxyvitamin D3. Curr. Opin. Nephrol. Hypertens. 1995; 4: 313–318.

    CAS  PubMed  Google Scholar 

  14. 14.

    O'Herrin JK, Hullett DA, Heisey DM, Sollinger HW, Becker BN. A retrospective evaluation of 1,25-dihydroxyvitamin D(3) and its potential effects on renal allograft function. Am J Nephrol 2002; 22: 515–520.

    PubMed  Google Scholar 

  15. 15.

    Cippitelli M, Fionda C, Di Bona D, et al. Negative regulation of CD95 ligand gene expression by vitamin D3 in T lymphocytes. J Immunol 2002; 168: 1154–1166.

    CAS  PubMed  Google Scholar 

  16. 16.

    Riachy R, Vandewalle B, Kerr Conta J, et al. 1,25-dihydroxyvitamin D3 protects RINmSF and human islet cells against cytokine-induced apoptosis: implication of the antiapoptotic protein A20. Endocrinology 2002; 143: 4809–4819.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Riachy R, Vandewalle B, Belaich S, et al. Beneficial effect of 1,25 dihydroxyvitamin D3 on cytokine-treated human pancreatic islets. J Endocrinol 2001; 169: 161–168.

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Vandewalle B, Douillard C, Kerr CJ, et al. Human pancreatic islet quality control: easy assessment of metabolic functions. Exp Clin Endocrinol Diabetes 1999; 107: 214–219.

    CAS  PubMed  Google Scholar 

  19. 19.

    Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680–685.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Lowin B, Hahne M, Mattmann C, Tschopp J. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 1994; 370: 650–652.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    McDermott MF, Ramachandran A, Ogunkolade BW, et al. Allelic variation in the vitamin D receptor influences susceptibility to IDDM in Indian Asians. Diabetologia 1997; 40: 971–975.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Pani MA, Knapp M, Dormer H, et al. Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans. Diabetes 2000; 49: 504–507.

    CAS  PubMed  Google Scholar 

  23. 23.

    Chang TJ, Lei HH, Yeh JI, et al. Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population. Clin Endocrinol (Oxf) 2000; 52: 575–580.

    Article  CAS  Google Scholar 

  24. 24.

    Manolagas SC, Hustmyer FG, Yu XP. Immunomodulating properties of 1,25-dihydroxyvitamin D3. Kidney Int Suppl 1990; 29: S9–S16.

    CAS  PubMed  Google Scholar 

  25. 25.

    Mathieu C, Laureys J, Sobis H, Vandeputte M, Waer M, Bouillon R. 1,25-Dihydroxyvitamin D3 prevents insulitis in NOD mice. Diabetes 1992; 41: 1491–1495.

    CAS  PubMed  Google Scholar 

  26. 26.

    Chatterjee M. Vitamin D and genomic stability. Mutat Res 2001; 475: 69–87.

    CAS  PubMed  Google Scholar 

  27. 27.

    Sardar S, Chakraborty A, Chatterjee M. Comparative effectiveness of vitamin D3 and dietary vitamin E on peroxidation of lipids and enzymes of the hepatic antioxidant system in Sprague—Dawley rats. Int J Vitam Nutr Res 1996; 66: 39–45.

    CAS  PubMed  Google Scholar 

  28. 28.

    Darville MI, Liu D, Chen MC, Eizirik DL. Molecular regulation of Fas expression in beta-cells. Diabetes 2001; 50 (Suppl 1): S83.

    CAS  PubMed  Google Scholar 

  29. 29.

    Grey ST, Arvelo MB, Hasenkamp W, Bach FH, Ferran C. A20 inhibits cytokine- induced apoptosis and nuclear factor kappaB-dependent gene activation in islets. J Exp Med 1999; 190: 1135–1146.

    CAS  Google Scholar 

  30. 30.

    Ferran C, Stroka DM, Badrichani AZ, et al. A20 inhibits NF-kappaB activation in endothelial cells without sensitizing to tumor necrosis factor-mediated apoptosis. Blood 1998; 91: 2249–2258.

    CAS  PubMed  Google Scholar 

  31. 31.

    Heyninck K, Beyaert R. The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6. FEBS Lett 1999; 442: 147–150.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Darville MI, Eizirik DL. Cytokine induction of Fas gene expression in insulin-producing cells requires the transcription factors NF-kappaB and C/EBP. Diabetes 2001; 50: 1741–1748.

    CAS  PubMed  Google Scholar 

  33. 33.

    Heimberg H, Heremans Y, Jobin C, et al. Inhibition of cytokine-induced NF-kappaB activation by adenovirus-mediated expression of a NF-kappaB super-repressor prevents beta-cell apoptosis. Diabetes 2001; 50: 2219–2224.

    CAS  PubMed  Google Scholar 

  34. 34.

    Song HY, Rothe M, Goeddel DV. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proc Natl Acad Sci USA 1996; 93: 6721–6725.

    CAS  PubMed  Google Scholar 

  35. 35.

    Scaffidi C, Fulda S, Srinivasan A, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J 1998; 17: 1675–1687.

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Levkau B, Scatena M, Giachelli CM, Ross R, Raines EW. Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-kappa B loop. Nat Cell Biol 1999; 1: 227–233.

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Ayroldi E, Migliorati G, Bruscoli S, et al. Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB. Blood 2001; 98: 743–753.

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    D'Adamio F, Zollo O, Moraca R, et al. A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death. Immunity 1997; 7: 803–812.

    PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to B. Vandewalle.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Riachy, R., Vandewalle, B., Moerman, E. et al. 1,25-dihydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the fas receptor. Apoptosis 11, 151–159 (2006). https://doi.org/10.1007/s10495-006-3558-z

Download citation

Key words:

  • apoptosis
  • Fas regulation
  • human pancreatic islets
  • Vitamin d3