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:

α1-antitrypsin increases interleukin-1 receptor antagonist production during pancreatic islet graft transplantation

Cellular & Molecular Immunology volume 11, pages 377–386 (2014)Cite this article

Abstract

Although islet transplantation for individuals with type 1 diabetes has been shown to yield superior blood glucose control, it remains inadequate for long-term control. This is partly due to islet injuries and stresses that can lead to beta cell loss. Inhibition of excess IL-1β activity might minimize islet injuries, thus preserving function. The IL-1 receptor antagonist (IL-1Ra), an endogenous inhibitor of IL-1β, protects islets from cytokine-induced necrosis and apoptosis. Therefore, an imbalance between IL-1β and IL-1Ra might influence the courses of allogeneic and autoimmune responses to islets. Our group previously demonstrated that the circulating serine-protease inhibitor human alpha-1-antitrypsin (hAAT), the levels of which increase in circulation during acute-phase immune responses, exhibits anti-inflammatory and islet-protective properties, as well as immunomodulatory activity. In the present study, we sought to determine whether the pancreatic islet allograft-protective activity of hAAT was mediated by IL-1Ra induction. Our results demonstrated that hAAT led to a 2.04-fold increase in IL-1Ra expression in stimulated macrophages and that hAAT-pre-treated islet grafts exhibited a 4.851-fold increase in IL-1Ra transcript levels, which were associated with a moderate inflammatory profile. Unexpectedly, islets that were isolated from IL-1Ra-knockout mice and pre-treated with hAAT before grafting into wild-type mice yielded an increase in intragraft IL-1Ra expression that was presumably derived from infiltrating host cells, albeit in the absence of hAAT treatment of the host. Indeed, hAAT-pre-treated islets generated hAAT-free conditioned medium that could induce IL-1Ra production in cultured macrophages. Finally, we demonstrated that hAAT promoted a distinct phosphorylation and nuclear translocation pattern for p65, a key transcription factor required for IL-1Ra expression.

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

Similar content being viewed by others

References

  1. Eizirik DL, Mandrup-Poulsen T . A choice of death—the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia 2001; 44: 2115–2133.

    Article  CAS  Google Scholar 

  2. van der Windt DJ, Bottino R, Casu A, Campanile N, Cooper DK . Rapid loss of intraportally transplanted islets: an overview of pathophysiology and preventive strategies. Xenotransplantation 2007; 14: 288–297.

    Article  Google Scholar 

  3. Mandrup-Poulsen T, Bendtzen K, Nerup J, Dinarello CA, Svenson M, Nielsen JH . Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans. Diabetologia 1986; 29: 63–67.

    Article  CAS  Google Scholar 

  4. van Belle TL, Coppieters KT, von Herrath MG . Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 2011; 91: 79–118.

    Article  CAS  Google Scholar 

  5. Filippi CM, von Herrath MG . Islet beta-cell death—fuel to sustain autoimmunity? Immunity 2007; 27: 183–185.

    Article  CAS  Google Scholar 

  6. 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  Google Scholar 

  7. Suarez-Pinzon WL, Power RF, Rabinovitch A . Fas ligand-mediated mechanisms are involved in autoimmune destruction of islet beta cells in non-obese diabetic mice. Diabetologia 2000; 43: 1149–1156.

    Article  CAS  Google Scholar 

  8. Ylipaasto P, Smura T, Gopalacharyulu P, Paananen A, Seppanen-Laakso T, Kaijalainen S et al. Enterovirus-induced gene expression profile is critical for human pancreatic islet destruction. Diabetologia 2012; 55: 3273–3283.

    Article  CAS  Google Scholar 

  9. Ramesh A, Chhabra P, Brayman KL . Pancreatic islet transplantation in type 1 diabetes mellitus: an update on recent developments. Curr Diabetes Rev 2013; 9: 294–311.

    Article  Google Scholar 

  10. Barshes NR, Wyllie S, Goss JA . Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: implications for intrahepatic grafts. J Leukoc Biol 2005; 77: 587–597.

    Article  CAS  Google Scholar 

  11. Schwarznau A, Hanson MS, Sperger JM, Schram BR, Danobeitia JS, Greenwood KK et al. IL-1beta receptor blockade protects islets against pro-inflammatory cytokine induced necrosis and apoptosis. J Cell Physiol 2009; 220: 341–347.

    Article  CAS  Google Scholar 

  12. Barshes NR, Wyllie S, Goss JA . Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: implications for intrahepatic grafts. J Leukoc Biol 2005; 77: 587–597.

    Article  CAS  Google Scholar 

  13. Dinarello CA . Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 2011; 117: 3720–3732.

    Article  CAS  Google Scholar 

  14. Arend WP . The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev 2002; 13: 323–340.

    Article  CAS  Google Scholar 

  15. Akash MS, Rehman K, Sun H, Chen S . Sustained delivery of IL-1Ra from PF127-gel reduces hyperglycemia in diabetic GK-rats. PloS ONE 2013; 8: e55925.

    Article  CAS  Google Scholar 

  16. Schwarznau A, Hanson MS, Sperger JM, Schram BR, Danobeitia JS, Greenwood KK et al. IL-1beta receptor blockade protects islets against pro-inflammatory cytokine induced necrosis and apoptosis. J Cell Physiol 2009; 220: 341–347.

    Article  CAS  Google Scholar 

  17. Larsen CM, Faulenbach M, Vaag A, Ehses JA, Donath MY, Mandrup-Poulsen T . Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care 2009; 32: 1663–1668.

    Article  CAS  Google Scholar 

  18. Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007; 356: 1517–1526.

    Article  CAS  Google Scholar 

  19. Arend WP, Malyak M, Guthridge CJ, Gabay C . Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol 1998; 16: 27–55.

    Article  CAS  Google Scholar 

  20. Glas R, Sauter NS, Schulthess FT, Shu L, Oberholzer J, Maedler K . Purinergic P2X7 receptors regulate secretion of interleukin-1 receptor antagonist and beta cell function and survival. Diabetologia 2009; 52: 1579–1588.

    Article  CAS  Google Scholar 

  21. Maedler K, Sergeev P, Ehses JA, Mathe Z, Bosco D, Berney T et al. Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets. Proc Natl Acad Sci USA 2004; 101: 8138–8143.

    Article  CAS  Google Scholar 

  22. Smith MF, Jr ., Eidlen D, Brewer MT, Eisenberg SP, Arend WP, Gutierrez-Hartmann A. Human IL-1 receptor antagonist promoter. Cell type-specific activity and identification of regulatory regions. J Immunol 1992; 149: 2000–2007.

    CAS  PubMed  Google Scholar 

  23. Andersson J, Bjork L, Dinarello CA, Towbin H, Andersson U . Lipopolysaccharide induces human interleukin-1 receptor antagonist and interleukin-1 production in the same cell. Eur J Immunol 1992; 22: 2617–2623.

    Article  CAS  Google Scholar 

  24. Jenkins JK, Arend WP . Interleukin 1 receptor antagonist production in human monocytes is induced by IL-1 alpha, IL-3, IL-4 and GM-CSF. Cytokine 1993; 5: 407–415.

    Article  CAS  Google Scholar 

  25. Luhm J, Langenkamp U, Hensel J, Frohn C, Brand JM, Hennig H et al. Beta-(1→3)-D-glucan modulates DNA binding of nuclear factors kappaB, AT and IL-6 leading to an anti-inflammatory shift of the IL-1beta/IL-1 receptor antagonist ratio. BMC Immunol 2006; 7: 5.

    Article  Google Scholar 

  26. Ishida Y, Kondo T, Kimura A, Matsushima K, Mukaida N . Absence of IL-1 receptor antagonist impaired wound healing along with aberrant NF-kappaB activation and a reciprocal suppression of TGF-beta signal pathway. J Immunol 2006; 176: 5598–5606.

    Article  CAS  Google Scholar 

  27. Smith MF Jr, Eidlen D, Arend WP, Gutierrez-Hartmann A . LPS-induced expression of the human IL-1 receptor antagonist gene is controlled by multiple interacting promoter elements. J Immunol 1994; 153: 3584–3593.

    CAS  PubMed  Google Scholar 

  28. Lewis EC . Expanding the clinical indications for alpha1-antitrypsin therapy. Mol Med 2012; 18: 957–970.

    Article  CAS  Google Scholar 

  29. Russi EW . Alpha-1 antitrypsin: now available, but do we need it? Swiss Med Wkly 2008; 138: 191–196.

    CAS  PubMed  Google Scholar 

  30. Toso C, Serre-Beinier V, Emamaullee J, Merani S, Armanet M, Wojtusciszyn A et al. The role of macrophage migration inhibitory factor in mouse islet transplantation. Transplantation 2008; 86: 1361–1369.

    Article  CAS  Google Scholar 

  31. Pott GB, Chan ED, Dinarello CA, Shapiro L . Alpha-1-antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood. J Leukoc Biol 2009; 85: 886–895.

    Article  CAS  Google Scholar 

  32. Ozeri E, Mizrahi M, Shahaf G, Lewis EC . alpha-1 antitrypsin promotes semimature, IL-10-producing and readily migrating tolerogenic dendritic cells. J Immunol 2012; 189: 146–153.

    Article  CAS  Google Scholar 

  33. Tawara I, Sun Y, Lewis EC, Toubai T, Evers R, Nieves E et al. Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. Proc Natl Acad Sci USA 2012; 109: 564–569.

    Article  CAS  Google Scholar 

  34. Shahaf G, Moser H, Ozeri E, Mizrahi M, Abecassis A, Lewis EC . alpha-1-antitrypsin gene delivery reduces inflammation, increases T-regulatory cell population size and prevents islet allograft rejection. Mol Med 2011; 17: 1000–1011.

    Article  CAS  Google Scholar 

  35. Subramanian S, Shahaf G, Ozeri E, Miller LM, Vandenbark AA, Lewis EC et al. Sustained expression of circulating human alpha-1 antitrypsin reduces inflammation, increases CD4+FoxP3+ Treg cell population and prevents signs of experimental autoimmune encephalomyelitis in mice. Metab Brain Dis 2011; 26: 107–113.

    Article  CAS  Google Scholar 

  36. Toldo S, Seropian IM, Mezzaroma E, Van Tassell BW, Salloum FN, Lewis EC et al. Alpha-1 antitrypsin inhibits caspase-1 and protects from acute myocardial ischemia-reperfusion injury. J Mol Cell Cardiol 2011; 51: 244–251.

    Article  CAS  Google Scholar 

  37. Wang Y, He Y, Abraham B, Rouhani FN, Brantly ML, Scott DE et al. Cytosolic, autocrine alpha-1 proteinase inhibitor (A1PI) inhibits caspase-1 and blocks IL-1beta dependent cytokine release in monocytes. PloS ONE 2012; 7: e51078.

    Article  CAS  Google Scholar 

  38. Stoller JK, Aboussouan LS . A review of alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 2012; 185: 246–259.

    Article  CAS  Google Scholar 

  39. Kalis M, Kumar R, Janciauskiene S, Salehi A, Cilio CM . alpha 1-antitrypsin enhances insulin secretion and prevents cytokine-mediated apoptosis in pancreatic beta-cells. Islets 2010; 2: 185–189.

    Article  Google Scholar 

  40. Zhang B, Lu Y, Campbell-Thompson M, Spencer T, Wasserfall C, Atkinson M et al. Alpha1-antitrypsin protects beta-cells from apoptosis. Diabetes 2007; 56: 1316–1323.

    Article  CAS  Google Scholar 

  41. Zhou X, Shapiro L, Fellingham G, Willardson BM, Burton GF . HIV replication in CD4+ T lymphocytes in the presence and absence of follicular dendritic cells: inhibition of replication mediated by alpha-1-antitrypsin through altered IkappaBalpha ubiquitination. J Immunol 2011; 186: 3148–3155.

    Article  CAS  Google Scholar 

  42. Chan ED, Pott GB, Silkoff PE, Ralston AH, Bryan CL, Shapiro L . Alpha-1-antitrypsin inhibits nitric oxide production. J Leukoc Biol 2012; 92: 1251–1260.

    Article  CAS  Google Scholar 

  43. Churg A, Dai J, Zay K, Karsan A, Hendricks R, Yee C et al. Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects. Lab Invest 2001; 81: 1119–1131.

    Article  CAS  Google Scholar 

  44. Tilg H, Vannier E, Vachino G, Dinarello CA, Mier JW . Antiinflammatory properties of hepatic acute phase proteins: preferential induction of interleukin 1 (IL-1) receptor antagonist over IL-1 beta synthesis by human peripheral blood mononuclear cells. J Exp Med 1993; 178: 1629–1636.

    Article  CAS  Google Scholar 

  45. Lewis EC, Mizrahi M, Toledano M, Defelice N, Wright JL, Churg A et al. alpha1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice. Proc Natl Acad Sci USA 2008; 105: 16236–16241.

    Article  CAS  Google Scholar 

  46. Mendez J, Stillman B . Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis. Mol Cell Biol 2000; 20: 8602–8612.

    Article  CAS  Google Scholar 

  47. Pott GB, Chan ED, Dinarello CA, Shapiro L . Alpha-1-antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood. J Leukoc Biol 2009; 85: 886–895.

    Article  CAS  Google Scholar 

  48. Tawara I, Sun Y, Lewis EC, Toubai T, Evers R, Nieves E et al. Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. Proc Natl Acad Sci USA 2012; 109: 564–569.

    Article  CAS  Google Scholar 

  49. Kline JN, Fisher PA, Monick MM, Hunninghake GW . Regulation of interleukin-1 receptor antagonist by Th1 and Th2 cytokines. Am J Physiol 1995; 269: L92–L98.

    CAS  PubMed  Google Scholar 

  50. Marie C, Pitton C, Fitting C, Cavaillon JM . IL-10 and IL-4 synergize with TNF-alpha to induce IL-1ra production by human neutrophils. Cytokine 1996; 8: 147–151.

    Article  CAS  Google Scholar 

  51. Jenkins JK, Malyak M, Arend WP . The effects of interleukin-10 on interleukin-1 receptor antagonist and interleukin-1 beta production in human monocytes and neutrophils. Lymphokine Cytokine Res 1994; 13: 47–54.

    CAS  PubMed  Google Scholar 

  52. Cassatella MA, Meda L, Gasperini S, Calzetti F, Bonora S . Interleukin 10 (IL-10) upregulates IL-1 receptor antagonist production from lipopolysaccharide-stimulated human polymorphonuclear leukocytes by delaying mRNA degradation. J Exp Med 1994; 179: 1695–1699.

    Article  CAS  Google Scholar 

  53. Tamassia N, Castellucci M, Rossato M, Gasperini S, Bosisio D, Giacomelli M et al. Uncovering an IL-10-dependent NF-kappaB recruitment to the IL-1ra promoter that is impaired in STAT3 functionally defective patients. FASEB J 2010; 24: 1365–1375.

    Article  CAS  Google Scholar 

  54. Subramanian S, Shahaf G, Ozeri E, Miller LM, Vandenbark AA, Lewis EC et al. Sustained expression of circulating human alpha-1 antitrypsin reduces inflammation, increases CD4+FoxP3+ Treg cell population and prevents signs of experimental autoimmune encephalomyelitis in mice. Metab Brain Dis 2011; 26: 107–113.

    Article  CAS  Google Scholar 

  55. Ozeri E, Mizrahi M, Shahaf G, Lewis EC . Alpha-1 antitrypsin promotes semi-mature, interleukin-10-producing and readily migrating tolerogenic dendritic cells. J Immunol 2012; 189: 146–153.

    Article  CAS  Google Scholar 

  56. Koulmanda M, Bhasin M, Hoffman L, Fan Z, Qipo A, Shi H et al. Curative and beta cell regenerative effects of alpha1-antitrypsin treatment in autoimmune diabetic NOD mice. Proc Natl Acad Sci USA 2008; 105: 16242–16247.

    Article  CAS  Google Scholar 

  57. Goldstein S, Reddy P . Tolerance without toxicity? alpha1-antitrypsin as a novel alternative to immunosuppression. Expert Rev Clin Immunol 2012; 8: 397–399.

    Article  CAS  Google Scholar 

  58. Thoms HC, Loveridge CJ, Simpson J, Clipson A, Reinhardt K, Dunlop MG et al. Nucleolar targeting of RelAp65 is regulated by COMMD1-dependent ubiquitination. Cancer Res 2010; 70: 139–149.

    Article  CAS  Google Scholar 

  59. Makowiec F, Koveker G, Weber P, Jenss H, Starlinger M . Crohn's disease: disease activity and recurrence following surgery. Deut Med Wochenschr 1990; 115: 1659–1664. German.

    Article  CAS  Google Scholar 

  60. Hochrainer K, Racchumi G, Zhang S, Iadecola C, Anrather J . Monoubiquitination of nuclear RelA negatively regulates NF-kappaB activity independent of proteasomal degradation. Cell Mol Life Sci 2012; 69: 2057–2073.

    Article  CAS  Google Scholar 

  61. Nita IM, Serapinas D, Janciauskiene SM . alpha1-Antitrypsin regulates CD14 expression and soluble CD14 levels in human monocytes in vitro. Int J Biochem Cell Biol 2007; 39: 1165–1176.

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Avishag Abecassis and Ronen Schuster: These authors contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er-Sheva, Israel

    Avishag Abecassis, Ronen Schuster, Galit Shahaf, Eyal Ozeri, Ross Green, David E Ochayon, Peleg Rider & Eli C Lewis

Authors
  1. Avishag Abecassis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronen Schuster
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Galit Shahaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eyal Ozeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ross Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David E Ochayon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peleg Rider
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eli C Lewis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eli C Lewis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abecassis, A., Schuster, R., Shahaf, G. et al. α1-antitrypsin increases interleukin-1 receptor antagonist production during pancreatic islet graft transplantation. Cell Mol Immunol 11, 377–386 (2014). https://doi.org/10.1038/cmi.2014.17

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2014.17

Keywords

This article is cited by

Search

Advanced search

Quick links