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.

  • Research Article
  • Published:

Adenoviral overexpression of interleukin-1 receptor antagonist protein increases β-cell replication in rat pancreatic islets

Gene Therapy volume 12, pages 120–128 (2005)Cite this article

Abstract

The naturally occurring inhibitor of interleukin-1 (IL-1) action, interleukin-1 receptor antagonist protein (IRAP), binds to the type 1 IL-1 receptor but does not initiate IL-1 signal transduction. In this study, we have determined the effects of IL-1β and IRAP overexpression on adult β-cell replication and viability. IL-1β reduced dramatically β-cell replication in adult rat islets both at 5.5 mM (control: 0.29±0.04%; IL-1β: 0.02±0.02%, P<0.05) and 22.2 mM glucose (control: 0.84±0.2%; IL-1β: 0.05±0.05%, P<0.05). This effect was completely prevented in islets overexpressing IRAP after adenoviral gene transfer at 5.5 mM (Ad-IL-1Ra+IL-1β: 0.84±0.1%, P<0.05) and 22.2 mM glucose (Ad-IL-1Ra+IL-1β: 1.22±0.2%, P<0.05). Moreover, overexpression of IRAP increased glucose-stimulated β-cell replication in the absence of IL-1β exposure (Ad-IL-1Ra: 1.59±0.5%, P<0.05). β-Cell death (TUNEL technique) was increased in IL-1β-exposed islets but not in Ad-IL-1Ra-infected islets (control: 0.82±0.2%; control+IL-1β: 1.77±0.2; IRAP: 0.61±0.2%; IRAP+IL-1β: 0.86±0.1%, P<0.05). Comparable results were obtained by flow cytometry. To determine the effect of IRAP overexpression on β-cell replication in vivo, Ad-IL-1Ra-transduced islets were transplanted into streptozotocin diabetic rats. β-Cell replication was significantly increased in IRAP-overexpressing islet grafts (0.98±0.3%, P<0.05) compared to normal pancreas (0.35±0.02%), but not in control islet grafts (0.50±0.1%). This study shows that in addition to the effects of IL-1β on β-cell viability, this cytokine exerts a deleterious action on β-cell replication, which can be prevented by IRAP overexpression, and provides support for the potential use of IRAP as a therapeutic tool.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Bonner-Weir S . Perspective: postnatal pancreatic β cell growth. Endocrinology 2000; 141: 1926–1929.

    Article  CAS  PubMed  Google Scholar 

  2. Montanya E, Nacher V, Biarnés M, Soler J . Linear correlation between β-cell mass and body weight throughout the lifespan in Lewis rats. Diabetes 2000; 49: 1341–1346.

    Article  CAS  PubMed  Google Scholar 

  3. Sorenson RL, Brelje TC . Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones. Horm Metab Res 1997; 29: 301–307.

    Article  CAS  PubMed  Google Scholar 

  4. Bonner-Weir S, Deery D, Leahy JL, Weir GC . Compensatory growth of pancreatic β-cells in adult rats after short-term glucose infusion. Diabetes 1989; 38: 49–53.

    Article  CAS  PubMed  Google Scholar 

  5. Brockenbrough JS, Weir GC, Bonner-Weir S . Discordance of exocrine and endocrine growth after 90% pancreatectomy in rats. Diabetes 1988; 37: 232–236.

    Article  CAS  PubMed  Google Scholar 

  6. Liu YQ, Montanya E, Leahy JL . Increased islet DNA synthesis and glucose-derived lipid and aminoacid production in association with beta-cell hyperproliferation in normoglycemic 60% pancreatectomy rats. Diabetologia 2001; 44: 1026–1033.

    Article  CAS  PubMed  Google Scholar 

  7. Nacher V et al. β-Cell growth and mass are preserved in long-term syngeneic islet transplantation in streptozotocin-induced diabetic Lewis Rats. Diabetes 1996; 45: 1541–1546.

    Article  CAS  PubMed  Google Scholar 

  8. Eizirik DL, Mandrup-Poulsen T . A choice of death. The signal transduction of immune-mediated β-cell apoptosis. Diabetologia 2001; 44: 2115–2133.

    Article  CAS  PubMed  Google Scholar 

  9. Mathis D, Vence L, Benoist C . β-Cell death during progression to diabetes. Nature 2001; 414: 792–798.

    Article  CAS  PubMed  Google Scholar 

  10. Mandrup-Poulsen T . The role of interleukin-1 in the pathogenesis of insulin-dependent diabetes mellitus. Diabetologia 1996; 39: 1005–1029.

    Article  CAS  PubMed  Google Scholar 

  11. Eizirik DL . Interleukin-1β induces an early decrease in insulin release, (pro)insulin biosynthesis and insulin mRNA in mouse pancreatic islets by a mechanism dependent on gene transcription and protein synthesis. Autoimmunity 1991; 10: 107–113.

    Article  CAS  PubMed  Google Scholar 

  12. Sandler S, Andersson A, Hellerstrom C . Inhibitory effects of interleukin 1 on insulin secretion, insulin biosynthesis, and oxidative metabolism of isolated rat pancreatic islets. Endocrinology 1987; 121: 1424–1431.

    Article  CAS  PubMed  Google Scholar 

  13. Giannoukakis N, Rudert WA, Trucco M, Robbins PD . Protection of human islets from the effects of interleukin-1β by adenoviral gene transfer of an IκB repressor. J Biol Chem 2000; 275: 36509–36513.

    Article  CAS  PubMed  Google Scholar 

  14. Rabinovitch A et al. DNA fragmentation is an early event in cytokine-induced islet beta-cell destruction. Diabetologia 1994; 37: 733–738.

    Article  CAS  PubMed  Google Scholar 

  15. Delaney CA et al. Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells. Endocrinology 1997; 138: 2610–2614.

    Article  CAS  PubMed  Google Scholar 

  16. Stassi 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sjöholm Å . Inhibition of fetal rat pancreatic β-cell replication by interleukin-1β in vitro is not mediated through pertussis toxin-sensitive G-proteins, a decrease in cyclic AMP, or protease activation. FEBS Lett 1991; 289: 249–252.

    Article  PubMed  Google Scholar 

  18. Eizirik DL et al. Interleukin-1β depletes insulin messenger ribonucleic acid and increases the heat shock protein hsp70 in mouse pancreatic islets without impairing the glucose metabolism. Endocrinology 1990; 127: 2290–2297.

    Article  CAS  PubMed  Google Scholar 

  19. Southern C, Schulster D, Green IC . Inhibition of insulin secretion from rat islets of Langerhans by interleukin-6. An effect distinct from that of interleukin-1. Biochem J 1990; 272: 243–245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Maedler K et al. Glucose induces β-cell apoptosis via upregulation of the Fas receptor in human islets. Diabetes 2001; 50: 1683–1690.

    Article  CAS  PubMed  Google Scholar 

  21. Scarim AL et al. Evidence for the presence of type I IL-1 receptors on β-cells of islets of Langerhans. Biochim Biophys Acta 1997; 1361: 313–320.

    Article  CAS  PubMed  Google Scholar 

  22. Dripps DJ, Brandhuber BJ, Thompson RC, Eisenberg SP . Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 1991; 266: 10331–10336.

    CAS  PubMed  Google Scholar 

  23. Giannoukakis N et al. Adenoviral gene transfer of the interleukin-1 receptor antagonist protein to human islets prevents IL-1β-induced β-cell impairment and activation of islet cell apoptosis in vitro. Diabetes 1999; 48: 1730–1736.

    Article  CAS  PubMed  Google Scholar 

  24. Sandberg JO, Eizirik DL, Sandler S . IL-1 receptor antagonist inhibits recurrence of disease after syngeneic pancreatic islet transplantation to spontaneously diabetic non-obese (NOD) mice. Clin Exp Immunol 1997; 108: 314–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sandler S et al. Decreased cell replication and polyamine content in insulin-producing cells after exposure to human interleukin 1 beta. Immunol Lett 1989; 22: 267–272.

    Article  CAS  PubMed  Google Scholar 

  26. Sjöholm Å . Cytokines inhibit proliferation and insulin secretion by rat insulinoma cells (RINm5F) non-synergistically and in a pertussis toxin-insensitive manner. Immunol Lett 1991; 30: 81–86.

    Article  PubMed  Google Scholar 

  27. Sjoholm A . Differential effects of cytokines on long-term mitogenic and secretory responses of fetal rat pancreatic beta cells. Am J Cell Physiol 1992; 263: 114–120.

    Article  Google Scholar 

  28. Eizirik DL et al. Cytokines suppress human islet function irrespective of their effects on nitric oxide generation. J Clin Invest 1994; 93: 1968–1974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vargas F et al. Endotoxin contamination may be responsible for the unexplained failure of human pancreatic islet transplantation. Transplantation 1998; 65: 722–727.

    Article  CAS  PubMed  Google Scholar 

  30. Berney T et al. Endotoxin-mediated delayed islet graft function is associated with increased intra-islet cytokine production and islet cell apoptosis. Transplantation 2001; 71: 125–132.

    Article  CAS  PubMed  Google Scholar 

  31. Ozasa T et al. Cytokine gene expression in pancreatic islet grafts in the rat. Transplantation 1997; 64: 1152–1159.

    Article  CAS  PubMed  Google Scholar 

  32. Hoorens A, Stangé G, Pavlovic D, Pipeleers D . Distinction between interleukin-1-induced necrosis and apoptosis of islet cells. Diabetes 2001; 50: 551–557.

    Article  CAS  PubMed  Google Scholar 

  33. Donath MY, Gross DJ, Cerasi E, Kaiser N . Hyperglycemia-induced β-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes 1999; 48: 738–744.

    Article  CAS  PubMed  Google Scholar 

  34. Hoorens A, Van de Casteele M, Kloppel G, Pipeleers D . Glucose promotes survival of rat pancreatic beta cells by activating synthesis of proteins which suppress a constitutive apoptotic program. J Clin Invest 1996; 98: 1568–1574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Eizirik DL, Darville MI . Beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes. Diabetes 2001; 50 (Suppl 1): S64–S69.

    Article  CAS  PubMed  Google Scholar 

  36. Kloppel G et al. Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res 1985; 4: 110–125.

    CAS  PubMed  Google Scholar 

  37. Butler AE et al. β-Cell deficit and increased beta cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52: 102–110.

    Article  CAS  PubMed  Google Scholar 

  38. Swenne I . Pancreatic β-cell growth and diabetes mellitus. Diabetologia 1992; 35: 193–201.

    Article  CAS  PubMed  Google Scholar 

  39. Sjoholm A . Diabetes mellitus and impaired pancreatic β-cell proliferation. J Int Med 1996; 239: 211–220.

    Article  CAS  Google Scholar 

  40. Zhu M et al. Poor capacity for proliferation of pancreatic β-cells in Otsuka-Long-Evans-Tokushima Fatty rat. A model of spontaneous NIDDM. Diabetes 1996; 45: 941–946.

    Article  CAS  PubMed  Google Scholar 

  41. Movassat J, Saulnier C, Portha B . Insulin administration enhances growth of the β-cell mass in streptozotocin-treated newborn rats. Diabetes 1997; 46: 1445–1452.

    Article  CAS  PubMed  Google Scholar 

  42. Maedler K et al. Glucose-induced beta cell production of IL-1β contributes to glucotoxicity in human pancreatic islets. J Clin Invest 2002; 110: 851–860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Persidsky MD, Baillie GS . Fluorometric test of cell membrane integrity. Cryobiology 1977; 14: 322–331.

    Article  CAS  PubMed  Google Scholar 

  44. Biarnes M et al. β-Cell death and mass in syngeneically transplanted islets exposed to short- and long-term hyperglycaemia. Diabetes 2002; 51: 66–72.

    Article  CAS  PubMed  Google Scholar 

  45. Giulietti A et al. An overview of real-time quantitative PCR: applications to quantify cytokine gene expression. Methods 2001; 25: 386–401.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work has been supported by a grant from the Juvenile Diabetes Foundation International (1-2002-687), FIS 03/0047 and the Instituto de Salud Carlos III, RCMN (C03/08). N Téllez was partly supported by Grant FIS 00/091 and M Montolio by a grant from Fundació August Pi i Sunyer. We thank Jessica Escoriza for skillful technical assistance.

Author information

Authors and Affiliations

  1. Laboratory of Diabetes and Experimental Endocrinology, Endocrine Unit, Hospital Universitari Bellvitge, University of Barcelona, Barcelona, Spain

    N Téllez, M Montolio, M Biarnés, J Soler & E Montanya

  2. Biology Unit, Serveis Científico-Tècnics, Campus Bellvitge, University of Barcelona, Barcelona, Spain

    E Castaño

Authors
  1. N Téllez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Montolio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Biarnés
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Castaño
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Soler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E Montanya
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Téllez, N., Montolio, M., Biarnés, M. et al. Adenoviral overexpression of interleukin-1 receptor antagonist protein increases β-cell replication in rat pancreatic islets. Gene Ther 12, 120–128 (2005). https://doi.org/10.1038/sj.gt.3302351

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302351

Keywords

This article is cited by

Search

Advanced search

Quick links