Skip to main content
SpringerLink
Log in

Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death

  • Research Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Pancreatic beta cell damage caused by pro-inflammatory cytokines interleukin-1β (IL-1β), interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) is a key event in the pathogenesis of type 1 diabetes. The suppressor of cytokine signaling-1 (SOCS-1) blocks IFNγ-induced signaling and prevents diabetes in the non-obese diabetic mouse. Here, we investigated if SOCS-1 overexpression in primary beta cells provides protection from cytokine-induced islet cell dysfunction and death. We demonstrate that SOCS-1 does not prevent increase in NO production and decrease in glucose-stimulated insulin secretion in the presence of IL-1β, IFNγ, TNFα. However, it decreases the activation of caspase-3, -8 and -9, and thereby, promotes a robust protection from cytokine-induced beta cell death. Our data suggest that SOCS-1 overexpression may not be sufficient in preventing all the biological activities of IFNγ in beta cells. In summary, we show that interference with IFNγ signal transduction pathways by SOCS-1 inhibits cytokine-stimulated pancreatic beta cell death.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Chandra J, Zhivotovsky B, Zaitsev S, Juntti-Berggren L, Berggren PO, Orrenius S (2001) Role of apoptosis in pancreatic beta-cell death in diabetes. Diabetes 50(Suppl 1):S44–S47

    Article  CAS  PubMed  Google Scholar 

  2. Mandrup-Poulsen T (2003) Beta cell death and protection. Ann N Y Acad Sci 1005:32–42

    Article  PubMed  Google Scholar 

  3. Hultcrantz M, Jacobson S, Hill NJ, Santamaria P, Flodstrom-Tullberg M (2009) The target cell response to cytokines governs the autoreactive T cell repertoire in the pancreas of NOD mice. Diabetologia 52:299–305

    Article  CAS  PubMed  Google Scholar 

  4. Flodstrom-Tullberg M, Yadav D, Hagerkvist R, Tsai D, Secrest P, Stotland A, Sarvetnick N (2003) Target cell expression of suppressor of cytokine signaling-1 prevents diabetes in the NOD mouse. Diabetes 52:2696–2700

    Article  PubMed  Google Scholar 

  5. Chong MM, Chen Y, Darwiche R, Dudek NL, Irawaty W, Santamaria P, Allison J, Kay TW, Thomas HE (2004) Suppressor of cytokine signaling-1 overexpression protects pancreatic beta cells from CD8 + T cell-mediated autoimmune destruction. J Immunol 172:5714–5721

    CAS  PubMed  Google Scholar 

  6. Barral AM, Thomas HE, Ling EM, Darwiche R, Rodrigo E, Christen U, Ejrnaes M, Wolfe T, Kay TW, von Herrath MG (2006) SOCS-1 protects from virally-induced CD8 T cell mediated type 1 diabetes. J Autoimmun 27:166–173

    Article  CAS  PubMed  Google Scholar 

  7. Corbett JA, Sweetland MA, Wang JL, Lancaster J R Jr, McDaniel ML (1993) Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. Proc Natl Acad Sci USA 90:1731–1735

    Article  CAS  PubMed  Google Scholar 

  8. Southern C, Schulster D, Green IC (1990) Inhibition of insulin secretion by interleukin-1 beta and tumour necrosis factor-alpha via an L-arginine-dependent nitric oxide generating mechanism. FEBS Lett 276:42–44

    Article  CAS  PubMed  Google Scholar 

  9. Hadjivassiliou V, Green MH, James RF, Swift SM, Clayton HA, Green IC (1998) Insulin secretion, DNA damage, and apoptosis in human and rat islets of Langerhans following exposure to nitric oxide, peroxynitrite, and cytokines. Nitric Oxide 2:429–441

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Cetkovic-Cvrlje M, Eizirik DL (1994) TNF-alpha and IFN-gamma potentiate the deleterious effects of IL-1 beta on mouse pancreatic islets mainly via generation of nitric oxide. Cytokine 6:399–406

    Article  CAS  PubMed  Google Scholar 

  12. Zaitsev SV, Appelskog IB, Kapelioukh IL, Yang SN, Kohler M, Efendic S, Berggren PO (2001) Imidazoline compounds protect against interleukin 1beta-induced beta-cell apoptosis. Diabetes 50(Suppl 1):S70–S76

    Article  CAS  PubMed  Google Scholar 

  13. Todaro M, Di Gaudio F, Lavitrano M, Stassi G, Papaccio G (2003) Islet beta-cell apoptosis triggered in vivo by interleukin-1beta is not related to the inducible nitric oxide synthase pathway: evidence for mitochondrial function impairment and lipoperoxidation. Endocrinology 144:4264–4271

    Article  CAS  PubMed  Google Scholar 

  14. Kohler M, Zaitsev SV, Zaitseva II, Leibiger B, Leibiger IB, Turunen M, Kapelioukh IL, Bakkman L, Appelskog IB, de Monvel JB, Imreh G, Berggren PO (2003) On-line monitoring of apoptosis in insulin-secreting cells. Diabetes 52:2943–2950

    Article  PubMed  Google Scholar 

  15. Augstein P, Bahr J, Wachlin G, Heinke P, Berg S, Salzsieder E, Harrison LC (2004) Cytokines activate caspase-3 in insulinoma cells of diabetes-prone NOD mice directly and via upregulation of Fas. J Autoimmun 23:301–309

    Article  CAS  PubMed  Google Scholar 

  16. Riedl SJ, Shi Y (2004) Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 5:897–907

    Article  CAS  PubMed  Google Scholar 

  17. Zaitseva II, Storling J, Mandrup-Poulsen T, Berggren PO, Zaitsev SV (2008) The imidazoline RX871024 induces death of proliferating insulin-secreting cells by activation of c-jun N-terminal kinase. Cell Mol Life Sci 65:1248–1255

    Article  CAS  PubMed  Google Scholar 

  18. Suk K, Kim S, Kim YH, Kim KA, Chang I, Yagita H, Shong M, Lee MS (2001) IFN-gamma/TNF-alpha synergism as the final effector in autoimmune diabetes: a key role for STAT1/IFN regulatory factor-1 pathway in pancreatic beta cell death. J Immunol 166:4481–4489

    CAS  PubMed  Google Scholar 

  19. Contreras JL, Smyth CA, Bilbao G, Young CJ, Thompson JA, Eckhoff DE (2002) 17beta-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality. Transplantation 74:1252–1259

    Article  CAS  PubMed  Google Scholar 

  20. Chong MMW, Thomas HE, Kay TWH (2002) Suppressor of cytokine signaling-1 regulates the sensitivity of pancreatic beta cells to tumor necrosis factor. J Biol Chem 277:27945–27952

    Article  CAS  PubMed  Google Scholar 

  21. Hoorens A, Stange G, Pavlovic D, Pipeleers D (2001) Distinction between interleukin-1-induced necrosis and apoptosis of islet cells. Diabetes 50:551–557

    Article  CAS  PubMed  Google Scholar 

  22. Stephens LA, Thomas HE, Ming L, Grell M, Darwiche R, Volodin L, Kay TW (1999) Tumor necrosis factor-alpha-activated cell death pathways in NIT-1 insulinoma cells and primary pancreatic beta cells. Endocrinology 140:3219–3227

    Article  CAS  PubMed  Google Scholar 

  23. Platanias LC (2005) Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5:375–386

    Article  CAS  PubMed  Google Scholar 

  24. O’Shea JJ, Gadina M, Schreiber RD (2002) Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109(Suppl):S121–S131

    Article  PubMed  Google Scholar 

  25. Wesemann DR, Qin H, Kokorina N, Benveniste EN (2004) TRADD interacts with STAT1-alpha and influences interferon-gamma signaling. Nat Immunol 5:199–207

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Nguyen H, Chatterjee-Kishore M, Jiang Z, Qing Y, Ramana CV, Bayes J, Commane M, Li X, Stark GR (2003) IRAK-dependent phosphorylation of Stat1 on serine 727 in response to interleukin-1 and effects on gene expression. J Interferon Cytokine Res 23:183–192

    Article  CAS  PubMed  Google Scholar 

  28. Wormald S, Hilton DJ (2004) Inhibitors of cytokine signal transduction. J Biol Chem 279:821–824

    Article  CAS  PubMed  Google Scholar 

  29. Qing Y, Costa-Pereira AP, Watling D, Stark GR (2005) Role of tyrosine 441 of interferon-gamma receptor subunit 1 in SOCS-1-mediated attenuation of STAT1 activation. J Biol Chem 280:1849–1853

    Article  CAS  PubMed  Google Scholar 

  30. Davey GM, Heath WR, Starr R (2006) SOCS1: a potent and multifaceted regulator of cytokines and cell-mediated inflammation. Tissue Antigens 67:1–9

    Article  CAS  PubMed  Google Scholar 

  31. Mansell A, Smith R, Doyle SL, Gray P, Fenner JE, Crack PJ, Nicholson SE, Hilton DJ, O’Neill LA, Hertzog PJ (2006) Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol 7:148–155

    Article  CAS  PubMed  Google Scholar 

  32. Nakagawa R, Naka T, Tsutsui H, Fujimoto M, Kimura A, Abe T, Seki E, Sato S, Takeuchi O, Takeda K, Akira S, Yamanishi K, Kawase I, Nakanishi K, Kishimoto T (2002) SOCS-1 participates in negative regulation of LPS responses. Immunity 17:677–687

    Article  CAS  PubMed  Google Scholar 

  33. Kinjyo I, Hanada T, Inagaki-Ohara K, Mori H, Aki D, Ohishi M, Yoshida H, Kubo M, Yoshimura A (2002) SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17:583–591

    Article  CAS  PubMed  Google Scholar 

  34. Flodstrom M, Maday A, Balakrishna D, Cleary MM, Yoshimura A, Sarvetnick N (2002) Target cell defense prevents the development of diabetes after viral infection. Nat Immunol 3:373–382

    Article  CAS  PubMed  Google Scholar 

  35. Solomon M, Flodstrom-Tullberg M, Sarvetnick N (2005) Differences in suppressor of cytokine signaling-1 (SOCS-1) expressing islet allograft destruction in normal BALB/c and spontaneously-diabetic NOD recipient mice. Transplantation 79:1104–1109

    Article  CAS  PubMed  Google Scholar 

  36. Lernmark A (1974) The preparation of, and studies on, free cell suspensions from mouse pancreatic islets. Diabetologia 10:431–438

    Article  CAS  PubMed  Google Scholar 

  37. Wollheim CB, Meda P, Halban PA (1990) Isolation of pancreatic islets and primary culture of the intact microorgans or of dispersed islet cells. Methods Enzymol 192:188–223

    Article  CAS  PubMed  Google Scholar 

  38. Zaitseva II, Sharoyko V, Storling J, Efendic S, Guerin C, Mandrup-Poulsen T, Nicotera P, Berggren PO, Zaitsev SV (2006) RX871024 reduces NO production but does not protect against pancreatic beta-cell death induced by proinflammatory cytokines. Biochem Biophys Res Commun 347:1121–1128

    Article  CAS  PubMed  Google Scholar 

  39. Efanova IB, Zaitsev SV, Zhivotovsky B, Kohler M, Efendic S, Orrenius S, Berggren PO (1998) Glucose and tolbutamide induce apoptosis in pancreatic beta-cells: A process dependent on intracellular Ca2+ concentration. J Biol Chem 273:33501–33507

    Article  CAS  PubMed  Google Scholar 

  40. Zaitsev SV, Efanov AM, Efanova IB, Larsson O, Ostenson CG, Gold G, Berggren PO, Efendic S (1996) Imidazoline compounds stimulate insulin release by inhibition of K(ATP) channels and interaction with the exocytotic machinery. Diabetes 45:1610–1618

    Article  CAS  PubMed  Google Scholar 

  41. Laffranchi R, Spinas GA (1997) Interferon-gamma inhibits insulin release and induces cell death in the pancreatic beta-cell line INS-1 independently of nitric oxide production. Exp Cell Res 237:217–222

    Article  CAS  PubMed  Google Scholar 

  42. Thomas HE, Darwiche R, Corbett JA, Kay TWH (2002) Interleukin-1 plus gamma-interferon-induced pancreatic beta-cell dysfunction is mediated by beta-cell nitric oxide production. Diabetes 51:311–316

    Article  CAS  PubMed  Google Scholar 

  43. Piro S, Lupi R, Dotta F, Patane G, Rabuazzo MA, Marselli L, Santangelo C, Realacci M, Del GS, Purrello F, Marchetti P (2001) Bovine islets are less susceptible than human islets to damage by human cytokines. Transplantation (Baltimore) 71:21–26

    CAS  Google Scholar 

  44. Reed JC (2000) Mechanisms of apoptosis. Am J Pathol 157:1415–1430

    CAS  PubMed  Google Scholar 

  45. Cattan P, Berney T, Schena S, Molano RD, Pileggi A, Vizzardelli C, Ricordi C, Inverardi L (2001) Early assessment of apoptosis in isolated islets of Langerhans. Transplantation 71:857–862

    Article  CAS  PubMed  Google Scholar 

  46. Jin Z, El-Deiry WS (2005) Overview of cell death signaling pathways. Cancer Biol Ther 4:139–163

    Article  CAS  PubMed  Google Scholar 

  47. Fulda S, Debatin KM (2002) IFNgamma sensitizes for apoptosis by upregulating caspase-8 expression through the Stat1 pathway. Oncogene 21:2295–2308

    Article  CAS  PubMed  Google Scholar 

  48. Paraskevas S, Aikin R, Vlaysinger D, Lakey JRT, Cavanagh TJ, Agapitos D, Wang R, Rosenberg L (2001) Modulation of JNK and p38 stress activated protein kinases in isolated islets of Langerhans: Insulin as an autocrine survival signal. Ann Surg 233:124–133

    Article  CAS  PubMed  Google Scholar 

  49. Herr I, Debatin KM (2001) Cellular stress response and apoptosis in cancer therapy. Blood 98:2603–2614

    Article  CAS  PubMed  Google Scholar 

  50. He Y, Zhang W, Zhang R, Zhang H, Min W (2006) SOCS1 inhibits tumor necrosis factor-induced activation of ASK1-JNK inflammatory signaling by mediating ASK1 degradation. J Biol Chem 281:5559–5566

    Article  CAS  PubMed  Google Scholar 

  51. Kimura A, Naka T, Nagata S, Kawase I, Kishimoto T (2004) SOCS-1 suppresses TNF-alpha-induced apoptosis through the regulation of Jak activation. Int Immunol 16:991–999

    Article  CAS  PubMed  Google Scholar 

  52. Morita Y, Naka T, Kawazoe Y, Fujimoto M, Narazaki M, Nakagawa R, Fukuyama H, Nagata S, Kishimoto T (2000) Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor alpha-induced cell death in fibroblasts. Proc Natl Acad Sci USA 97:5405–5410

    Article  CAS  PubMed  Google Scholar 

  53. Andersen NA, Larsen CM, Mandrup-Poulsen T (2000) TNFalpha and IFNgamma potentiate IL-1beta induced mitogen activated protein kinase activity in rat pancreatic islets of Langerhans. Diabetologia 43:1389–1396

    Article  CAS  PubMed  Google Scholar 

  54. Kim WH, Lee JW, Gao B, Jung MH (2005) Synergistic activation of JNK/SAPK induced by TNF-alpha and IFN-gamma: apoptosis of pancreatic beta-cells via the p53 and ROS pathway. Cell Signal 17:1516–1532

    Article  CAS  PubMed  Google Scholar 

  55. Gysemans CA, Ladriere L, Callewaert H, Rasschaert J, Flamez D, Levy DE, Matthys P, Eizirik DL, Mathieu C (2005) Disruption of the gamma-interferon signaling pathway at the level of signal transducer and activator of transcription-1 prevents immune destruction of beta-cells. Diabetes 54:2396–2403

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Grant N5-2001-34 from the Juvenile Diabetes Foundation International, the Swedish Foundation for Strategic Research, the European Foundation for the Study of Diabetes, the Swedish Research Council, the Swedish Diabetes Association, funds from Karolinska Institutet, the Novo Nordisk Foundation, The Family Erling-Persson Foundation, Berth von Kantzow’s Foundation, and Novo Nordisk A/S. Stella Jacobson is greatly acknowledged for assistance with the genotyping of the mice.

Author information

Authors and Affiliations

  1. The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, L1, 171 76, Stockholm, Sweden

    Irina I. Zaitseva, Vladimir Sharoyko, Sergei V. Zaitsev & Per-Olof Berggren

  2. Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, F59, 141 86, Stockholm, Sweden

    Monica Hultcrantz & Malin Flodström-Tullberg

  3. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992, Moscow, Russia

    Sergei V. Zaitsev

Authors
  1. Irina I. Zaitseva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monica Hultcrantz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vladimir Sharoyko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Malin Flodström-Tullberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sergei V. Zaitsev
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Per-Olof Berggren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sergei V. Zaitsev.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zaitseva, I.I., Hultcrantz, M., Sharoyko, V. et al. Suppressor of cytokine signaling-1 inhibits caspase activation and protects from cytokine-induced beta cell death. Cell. Mol. Life Sci. 66, 3787–3795 (2009). https://doi.org/10.1007/s00018-009-0151-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-009-0151-y

Keywords

Search

Navigation