Diabetologia

, Volume 39, Issue 9, pp 1005–1029

The role of interleukin-1 in the pathogenesis of IDDM

  • T. Mandrup-Poulsen
Review

Abbreviations

AA

Arachidonic acid

AcP

associated peptide

APC

antigen presenting cell

BB

BioBreeding

DAG

diacylglycerol

FACS

flourescence activated cell sorter

GTP

guanosine triphosphate

HLA

human leukocyte antigen

HSP

heat shock protein

ICAM

intercellular adhesion molecule

ICE

interleukin-1 converting enzyme

iCOX

inducible cyclooxygenase

IFN

interferon

IL

interleukin

IL-1Ra

IL-1 receptor antagonist

IL-1RT

IL-1 receptor type

LFA

lymphocyte function associated

LPS

lipopolysaccharide

MAPK

mitogen activated protein kinase

MHC

major histocompatibility complex

NK

natural killer

NO

nitric oxide

NOD

non-obese diabetic

PARP

poly(ADP)ribose polymerase

PBMNC

peripheral blood mononuclear cells

PGE2

prostaglandin E2

PHA

phytohaemagglutinin

PKC

protein kinase C

PLA

phospholipase A

PLAP

phospholipase A activating protein

PLC

phospholipase C

PPD

purified protein derivative of tuberculin

scid

severe combined immunodeficiency

SMnase

sphingomyelinase

SOD

Superoxide dismutase

Tc

T-cytotoxic

Th

T-helper

TNF

tumour necrosis factor

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References

  1. 1.
    Minkowski O (1929) Die Lehre vom Pankreas-Diabetes in ihrer geschichtlichen Entwicklung. Münchener Medizinische Wochenschrift 76: 311–315Google Scholar
  2. 2.
    Kroemer G, Martinez-A C (1992) Mechanisms of self tolerance. Immunol Today 13: 401–404Google Scholar
  3. 3.
    Dinarello CA (1994) The biological properties of interleukin-1. Eur Cytokine Netw 5: 517–531Google Scholar
  4. 4.
    Dustin ML, Springer TA (1991) Role of lymphocyte adhesion receptors in transient interactions and cell locomotion. Annu Rev Immunol 9: 27–66Google Scholar
  5. 5.
    Liu C-C, Walsh CM, Young JD-E (1995) Perforin: structure and function. Immunol Today 16: 194–201Google Scholar
  6. 6.
    Smyth MJ, Trapani JA (1995) Granzymes: exogenous proteinases that induce target cell apoptosis. Immunol Today 16: 202–207Google Scholar
  7. 7.
    Irmler M, Hertig S, Robson Macdonald H, et al. (1995) Granzyme A is an interleukin 1Β-converting enzyme. J ExpMed 181: 1917–1922Google Scholar
  8. 8.
    Doherty PC (1993) Cell-mediated cytotoxicity. Cell 75: 607–612Google Scholar
  9. 9.
    Romain PL, Schlossman SF (1984) Human T lymphocyte subsets. Functional heterogeneity and surface recognition structures. J Clin Invest 74: 1559–1565Google Scholar
  10. 10.
    Gumperz JE, Parham P (1995) The enigma of the natural killer cell. Nature 378: 245–248Google Scholar
  11. 11.
    Seljelid R (1987) Effector functions of macrophages. Acta Med Scand 715:[Suppl]131–138Google Scholar
  12. 12.
    Liblau RS, Singer SM, McDevitt HO (1995) Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 16: 34–38Google Scholar
  13. 13.
    Cohen JJ, Duke RC, Fadok VA, Sellins KS (1992) Apoptosis and programmed cell death in immunity. Annu Rev Immunol 10: 267–293Google Scholar
  14. 14.
    Foulis AK, Liddle CN, Farquharson MA, Richmond JA, Weir RS (1986) The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 29: 267–274Google Scholar
  15. 15.
    Foulis AK, McGill M, Farquharson MA (1991) Insulitis in type 1 (insulin-dependent) diabetes mellitus in man — macrophages, lymphocytes, and interferon-gamma containing cells. J Pathol 165: 97–103Google Scholar
  16. 16.
    Itoh N, Hanafusa T, Miyazaki A et al. (1993) Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest 92: 2313–2322Google Scholar
  17. 17.
    Sibley RK, Sutherland DER, Goetz F, Michael AF (1985) Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic immunohistochemical analysis of four cases. Lab Invest 53: 132–144Google Scholar
  18. 18.
    Hanenberg H, Kolb-Bachofen V, Kantwerk-Funke G, Kolb H (1989) Macrophage infiltration precedes and is a prerequisite for lymphocytic insulitis in pancreatic islets of pre-diabetic BB rats. Diabetologia 32: 126–134Google Scholar
  19. 19.
    Vorbij HA, Jeucken PH, Kabel PJ, Haan MD, Drexhage HA (1989) Dendritic cells and scavenger macrophages in pancreatic islets of prediabetic BB rats. Diabetes 38: 1623–1629Google Scholar
  20. 20.
    Jansen A, Homo-Delarche F, Hooijkaas H, Leenen PJ, Dardenne M, Drexhage HA (1994) Immunohistochemical characterization of monocytes — macrophages and dendritic cells involved in the initiation of the insulitis and beta-cell destruction in NOD mice. Diabetes 43: 667–675Google Scholar
  21. 21.
    Kolb-Bachofen V, Epstein S, Kiesel U, Kolb H (1988) Low-dose streptozocin-induced diabetes in mice. Electron microscopy reveals single-cell insulitis before diabetes onset. Diabetes 37: 21–27Google Scholar
  22. 22.
    Drell DW, Notkins AL (1987) Multiple immunological abnormalities in patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 30: 132–143Google Scholar
  23. 23.
    Salvi M, Fukazawa H, Bernard N, Hiromatsu Y, How J, Wall JR (1988) Role of autoantibodies in the pathogenesis and association of endocrine autoimmune disorders. Endocr Rev 9: 450–466Google Scholar
  24. 24.
    Svenningsen A, Dyrberg T, Gerling I, Lernmark A, MacKay P, Rabinovitch A (1983) Inhibition of insulin release after passive transfer of immunoglobulin from insulin-dependent diabetic children to mice. J Clin Endocrinol Metab 57: 1301–1304Google Scholar
  25. 25.
    Tingle AJ, Lim G, Wright VJ, Dimmick JE, Hunt JA (1979) Transplacental passage of islet cell antibodies in infants of diabetic mothers. Pediatr Res 13: 1323–1325Google Scholar
  26. 26.
    Boitard C, Feutren G, Castano L et al. (1987) Effect of cyclosporin A treatment on the production of antibody in insulin-dependent (type 1) diabetic patients. J Clin Invest 80: 1607–1612Google Scholar
  27. 27.
    Mandrup-Poulsen T, MØlvig J, Andersen HU et al. (1990) Lack of predictive value of islet cell antibodies, insulin antibodies and HLA-DR phenotype for remission in cyclosporin-treated IDDM patients. Diabetes 39: 204–210Google Scholar
  28. 28.
    Petersen JS, Dyrberg T, Karlsen AE et al. (1994) Glutamic acid decarboxylase (GAD65) autoantibodies in prediction of Β-cell function and remission in recent-onset IDDM after cyclosporin treatment. Diabetes 43: 1291–1296Google Scholar
  29. 29.
    Bendelac A, Boitard C, Bedossa P, Bazin H, Bach J-F, Carnaud C (1988) Adoptive T cell transfer of autoimmune nonobese diabetic mouse diabetes does not require recruitment of host B lymphocytes. J Immunol 141: 2625–2628Google Scholar
  30. 30.
    Vardi P, Dibella EE, Pasquarello TJ, Srikanta S (1987) Islet cell autoantibodies: pathobiology and clinical applications. Diabetes Care 10: 645–656Google Scholar
  31. 31.
    Weetman AP, McGregor AM (1994) Autoimmune thyroid disease: further developments in our understanding. Endocr Rev 15: 788–830Google Scholar
  32. 32.
    Via CS, Shearer GM (1988) T-cell interactions in autoimmunity: insights from a murine model of graft-versus-host disease. Immunol Today 9: 207–213Google Scholar
  33. 33.
    Ffrench-Constant C (1994) Pathogenesis of multiple sclerosis. Lancet 343: 271–275Google Scholar
  34. 34.
    Jiang H, Zhang S-L, Pernis B (1992) Role of CD8+ T cells in murine experimental allergic encephalomyelitis. Science 256: 1213–1215Google Scholar
  35. 35.
    Ellerman KE, Powers JM, Brostoff SW (1988) A suppressor T-lymphocyte cell line for autoimmune encephalomyelitis. Nature 331: 265–267Google Scholar
  36. 36.
    Charles MA, Suzuki M, Waldeck N et al. (1983) Immune islet killing mechanisms associated with insulin-dependent diabetes: in vitro expression of cellular and antibody-mediated islet cell cytotoxicity in humans. J Immunol 130: 1189–1194Google Scholar
  37. 37.
    Maruyama T, Takei I, Taniyama M, Kataoka K, Matsuki S (1984) Immunological aspect of non-obese diabetic mice: immune islet cell-killing mechanism and cell-mediated immunity. Diabetologia 27: 121–123Google Scholar
  38. 38.
    MacKay P, Boulton A, Rabinovitch A (1985) Lymphoid cells of BB/W diabetic rats are cytotoxic to islet beta cells in vitro. Diabetes 34: 706–709Google Scholar
  39. 39.
    Weringer EJ, Like AA (1985) Immune attack on pancreatic islet transplants in the spontaneously diabetic Bio-Breeding/Worcester (BB/W) rat is not MHC restricted. J Immunol 134: 2382–2386Google Scholar
  40. 40.
    Nomikos IN, Prowse SJ, Carotenuto P, Lafferty KJ (1986) Combined treatment with nicotinamide and desferrioxamine prevents islet allograft destruction in NOD mice. Diabetes 35: 1302–1304Google Scholar
  41. 41.
    Katz J, Benoist C, Mathis D (1993) Major histocompatibility complex class I molecules are required for the development of insulitis in non-obese diabetic mice. Eur J Immunol 23: 3358–3360Google Scholar
  42. 42.
    Huber H, Berschick P, Kolb H (1991) Analysis of IL-2 receptor positive CD8+-T-lymphocytes grown from islets of NOD mice. Diabetes Res 16: 69–73Google Scholar
  43. 43.
    Edouard P, Hiserodt JC, Plamondon C, Poussier P (1993) CD8+ T-cells are required for adoptive transfer of the BB rat diabetic syndrome. Diabetes 42: 390–397Google Scholar
  44. 44.
    Nagata M, Yoon J-W (1992) Studies on autoimmunity for T-cell-mediated Β-cell destruction. Distinct difference in Β-cell destruction between CD4+ and CD8+ T-cell clones derived from lymphocytes infiltrating the islets of NOD mice. Diabetes 41: 998–1007Google Scholar
  45. 45.
    Miller BJ, Appel MC, O'Neil JJ, Wicker LS (1988) Both the LYT-2+ and L3T4+ T cell subsets are required for the transfer of diabetes in nonobese diabetic mice. J Immunol 140: 52–58Google Scholar
  46. 46.
    Bradley BJ, Haskins K, La Rosa FG, Lafferty KJ (1992) CD8 T cells are not required for islet destruction induced by a CD4+ islet-specific T-cell clone. Diabetes 41: 1603–1608Google Scholar
  47. 47.
    Yagi H, Matsumoto M, Kunimoto K, Kawaguchi J, Makino S, Harada M (1992) Analysis of the roles of CD4+ and CD8+ T cells in autoimmune diabetes of NOD mice using transfer to NOD athymic nude mice. Eur J Immunol 22: 2387–2393Google Scholar
  48. 48.
    Christianson SW, Schultz LD, Leiter EH (1993) Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice — relative contributions of CD4+ and CD8+ T cells from diabetic versus prediabetic NOD.NON-thy-1a donors. Diabetes 42: 44–55Google Scholar
  49. 49.
    Katz JD, Benoist C, Mathis D (1995) T helper cell subsets in insulin-dependent diabetes. Science 268: 1185–1188Google Scholar
  50. 50.
    Lagoo AS, Eldridge JH, Lagoodeenadaylan S et al. (1994) Peyers patch CD8+ memory T cells secrete T-helper type 1 and type 2 cytokines and provide help for immunoglobin secretion. Eur J Immunol 24: 3087–3092Google Scholar
  51. 51.
    Seder RA, Gros GGL (1995) The functional role of CD8+ T helper type 2 cells. J Exp Med 181: 5–7Google Scholar
  52. 52.
    Lipes MA, Rosenzweig A, Tan K-N et al. (1993) Progression to diabetes in nonobese diabetic (NOD) mice with transgenic T cell receptors. Science 259: 1165–1169Google Scholar
  53. 53.
    Kolb-Bachofen V, Kolb H (1989) A role for macrophages in the pathogenesis of type 1 diabetes. Autoimmunity 3: 145–155Google Scholar
  54. 54.
    Schwitzer RW, Leiter EH, Evans R (1984) Macrophage-mediated cytotoxicity against cultured pancreatic islet cells. Transplantation 37: 539–544Google Scholar
  55. 55.
    Appels B, Burkart V, Kantwerk-Funke G, Funda J, Kolb-Bachofen V, Kolb H (1989) Spontaneous cytotoxicity of macrophages against pancreatic islet cells. J Immunol 142: 3803–3808Google Scholar
  56. 56.
    Varsanyi Nagy M, Chan EK, Teruya M, Forrest LE, Likhite V, Charles MA (1989) Macrophage-mediated islet cell cytotoxicity in BB rats. Diabetes 38: 1329–1331Google Scholar
  57. 57.
    Davies AJ, Bone AJ, Wilkin TJ, Rokos H, Cole DR (1994) Serum biopterin — a novel marker for immune activation during pre-diabetes in the BB rat. Diabetologia 37: 466–470Google Scholar
  58. 58.
    Brenner HH, Burkart V, Rothe H, Kolb H (1993) Oxygen radical production is increased in macrophages from diabetes prone BB rats. Autoimmunity 15: 93–98Google Scholar
  59. 59.
    Shimada A, Takei I, Maruyama T et al. (1994) Acceleration of diabetes in young NOD mice with peritoneal macrophages. Diabetes Res Clin Pract 24: 69–76Google Scholar
  60. 60.
    Oschilewski U, Kiesel U, Kolb H (1985) Administration of silica prevents diabetes in BB-rats. Diabetes 34: 197–199Google Scholar
  61. 61.
    Amano K, Yoon J-W (1990) Studies on autoimmunity for initiation of Β-cell destruction. V. Decrease of macrophage-dependent T-lymphocytes and natural killer cytotoxicity in silica-treated BB-rats. Diabetes 39: 590–596Google Scholar
  62. 62.
    Hutchings P, Rosen H, O'Reilly L, Simpson E, Gordon S, Cooke A (1990) Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages. Nature 348: 639–642Google Scholar
  63. 63.
    Kröncke K, Kolb-Bachofen V, Berschick B, Burkart V, Kolb H (1991) Activated macrophages kill pancreatic syngeneic islet cells via arginine-dependent nitric oxide generation. Biochem Biophys Res Commun 175: 752–758Google Scholar
  64. 64.
    Kröncke K, Funda J, Berschick B, Kolb H, Kolb-Bachofen V (1991) Macrophage cytotoxicity towards isolated rat islet cells: neither lysis nor its protection by nicotinamide are beta-cell specific. Diabetologia 34: 232–238Google Scholar
  65. 65.
    Ihm S-H, Yoon J-W (1990) Studies on autoimmunity for initiation of Β-cell destruction. VI. Macrophages essential for development of Β-cell specific cytotoxic effectors and insulitis in NOD mice. Diabetes 39: 1273–1278Google Scholar
  66. 66.
    Krall G, Martens G, Kuystermans K (1993) Systemic elimination of macrophages using liposomes does not prevent the induction of type I diabetes. Int Arch Allergy Immunol 100: 115–120Google Scholar
  67. 67.
    Serreze DV, Gaedeke JW, Leiter EH (1993) Hematopoietic stem-cell defects underlying abnormal macrophage development and maturation in NOD/Lt mice: defective regulation of cytokine receptors and protein kinase C. Proc Natl Acad Sci 90: 9625–9629Google Scholar
  68. 68.
    Tafuri A, Bowers WE, Handler ES et al. (1993) High stimulatory activity of dendritic cells from diabetes-prone Bio-Breeding/Worcester rats exposed to macrophage-derived factors. J Clin Invest 91: 2040–2048Google Scholar
  69. 69.
    Woda BA, Biron CA (1986) Natural killer cell number and function in the spontaneously diabetic BB/W rat. J Immunol 137: 1860–1866Google Scholar
  70. 70.
    MacKay P, Jacobsen J, Rabinovitch A (1986) Spontaneous diabetes mellitus in the Bio-breeding/Worcester rat. Evidence in vitro for natural killer cell lysis of islet cells. J Clin Invest 77: 916–924Google Scholar
  71. 71.
    Like AA, Biron CA, Weringer EJ, Byman K, Sroczynski E, Guberski DL (1986) Prevention of diabetes in Bio-Breeding/Worcester rats with monoclonal antibodies that recognize T lymphocytes or natural killer cells. J Exp Med 164: 1145–1159Google Scholar
  72. 72.
    Ellerman K, Wrobleski M, Rabinovitch A, Like AA (1993) Natural killer cell depletion and diabetes mellitus in the BB/Wor rat (revisited). Diabetologia 36: 596–601Google Scholar
  73. 73.
    Lernmark A, Kloppel G, Stenger D et al. (1995) Heterogeneity of islet pathology in two infants with recent onset diabetes mellitus. Virchows Arch 425: 631–640Google Scholar
  74. 74.
    Mandrup-Poulsen T, Bendtzen K, Nielsen JH, Bendixen G, Nerup J (1985) Cytokines cause functional and structural damage to isolated islets of Langerhans. Allergy 40: 424–429Google Scholar
  75. 75.
    Mandrup-Poulsen T, Bendtzen K, Nerup J, Egeberg J, Nielsen JH (1986) Mechanisms of pancreatic islet cell destruction. Dose-dependent cytotoxic effect of soluble blood mononuclear cell mediators on isolated islets of Langerhans. Allergy 41: 250–259Google Scholar
  76. 76.
    Mandrup-Poulsen T, Bendtzen K, Nerup J, Dinarello CA, Svenson M, Nielsen JH (1986) Affinity-purified human interleukin 1 is cytotoxic to isolated islets of Langerhans. Diabetologia 29: 63–67Google Scholar
  77. 77.
    Bendtzen K, Mandrup-Poulsen T, Nerup J, Nielsen JH, Dinarello CA, Svenson M (1986) Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science 232: 1545–1547Google Scholar
  78. 78.
    Mandrup-Poulsen T, Egeberg J, Nerup J, Bendtzen K, Nielsen JH, Dinarello CA (1987) Ultrastructural study of time-course and cellular specificity of interleukin-1 mediated islet cytotoxicity. APMIS 95: 55–63Google Scholar
  79. 79.
    Sandler S, Bendtzen K, Borg LAH, Eizirik DL, Strandell E, Welsh N (1989) Studies on the mechanisms causing inhibition of insulin secretion in rat pancreatic islets exposed to human interleukin-Β indicate a perturbation in the mitochondrial function. Endocrinology 124: 1492–1501Google Scholar
  80. 80.
    Helqvist S, Zumsteg UW, Spinas GA et al. (1991) Repetitive exposure of pancreatic islets to interleukin-Β. An in vitro model of pre-diabetes? Autoimmunity 10: 311–318Google Scholar
  81. 81.
    Sandler S, Andersson A, Hellerström C (1987) Inhibitory effects of interleukin 1 on insulin secretion, insulin biosynthesis, and oxidative metabolism of isolated rat pancreatic islets. Endocrinology 121: 1424–1431Google Scholar
  82. 82.
    Delaney CA, Green MHL, Lowe JE, Green IC (1993) Endogenous nitric oxide induced by interleukin-Β in rat islets of Langerhans and HIT-T15 cells causes significant DNA damage as measured by the “cometi” assay. FEBS Lett 333: 291–295Google Scholar
  83. 83.
    Bolaffi JL, Rodd GG, Wang J, Grodsky GM (1994) Interrelationship of changes in islet nicotine adeninedinucleotide, insulin secretion, and cell viability induced by interleukin-Β. Endocrinology 134: 537–542Google Scholar
  84. 84.
    Sandler S, Bendtzen K, Eizirik DL, Sjöholm å, Welsh N (1989) Decreased cell replication and polyamine content in insulin-producing cells after exposure to human interleukin 1Β. Immunol Lett 22: 267–272Google Scholar
  85. 85.
    Janjic D, Asfari M (1992) Effects of cytokines on rat insulinoma INS-1 cells. J Endocrinol 132: 67–76Google Scholar
  86. 86.
    Hamaguchi K, Leiter EH (1990) Comparison of cytokine effects on mouse pancreatic α-cell and Β-cell lines. Viability, secretory function and MHC antigen expression. Diabetes 39: 415–425Google Scholar
  87. 87.
    Wogensen LD, Kolb-Bachofen V, Christensen P et al. (1990) Functional and morphological effects of interleukin-Β on the perfused rat pancreas. Diabetologia 33: 15–23Google Scholar
  88. 88.
    Mandrup-Poulsen T, Bendtzen K, Dinarello CA, Nerup J (1987) Human tumor necrosis factor potentiates human interleukin 1-mediated rat pancreatic Β-cell cytotoxicity. J Immunol 139: 4077–4082Google Scholar
  89. 89.
    Eizirik DL (1988) Interleukin-1 induced impairment in pancreatic islet oxidative metabolism of glucose is potentiated by tumor necrosis factor. Acta Endocrinol 119: 321–325Google Scholar
  90. 90.
    Sandler S, Sternesjö J (1995) Interleukin 4 impairs rat pancreatic islet function in vitro by an action different to that of interleukin 1. Cytokine 7: 296–300Google Scholar
  91. 91.
    Corbett JA, McDaniel ML (1995) Intraislet release of interleukin 1 inhibits Β cell function by inducing Β cell expression of inducible nitric oxide synthase. J Exp Med 181: 559–568Google Scholar
  92. 92.
    Nielsen JH, Mandrup-Poulsen T, Spinas GA et al. (1986) Possible role of interleukin.1 (IL-1) in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). In: Jaworsky M (ed) The immunology of diabetes mellitus. Excerpta Medica Int Congr Ser 717, Amsterdam, pp 97–103Google Scholar
  93. 93.
    Rabinovitch A, Pukel C, Baquerizo H (1988) Interleukin-1 inhibits glucose-modulated insulin and glucagon secretion in rat islet monolayer cultures. Endocrinology 122: 2393–2398Google Scholar
  94. 94.
    Corbett JA, Wang JL, Sweetland MA, Lancaster JR Jr, McDaniel ML (1992) Interleukin 1Β induces the formation of nitric oxide by Β-cells purified from rodent islets of Langerhans. Evidence for the Β cell as a source and site of action of nitric oxide. J Clin Invest 90: 2384–2391Google Scholar
  95. 95.
    Zhidong L, In't Veld PA, Pipeleers DG (1993) Interaction of interleukin-1 with islet Β-cells. Distinction between indirect, aspecific cytotoxicity and direct, specific functional suppression. Diabetes 42: 56–65Google Scholar
  96. 96.
    Pukel C, Baquerizo H, Rabinovitch A (1988) Destruction of rat islet cell monolayers by cytokines. Synergistic interactions of interferon-gamma, tumor necrosis factor, lymphotoxin and interleukin 1. Diabetes 37: 133–136Google Scholar
  97. 97.
    Rabinovitch A, Baquerizo H, Pukel C, Sumoski W (1989) Effects of cytokines on rat pancreatic islet cell monolayer cultures: distinction between functional and cytotoxic effects on islet Β-cells. Reg Immunol 2: 77–82Google Scholar
  98. 98.
    Eizirik DL, Welsh M, Strandell E, Welsh N, Sandler S (1990) Interleukin-Β depletes insulin messenger ribonucleic acid and increases the heat shock protein hsp70 in mouse pancreatic islets without impairing the glucose metabolism. Endocrinology 127: 2290–2297Google Scholar
  99. 99.
    Eizirik DL (1991) 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 10: 107–113Google Scholar
  100. 100.
    Welsh N, Sandler S (1992) Interleukin-1Β induces nitric oxide production and inhibits the activity of aconitase without decreasing glucose oxidation rates in isolated mouse pancreatic islets. Biochem Biophys Res Commun 182: 333–340Google Scholar
  101. 101.
    Campbell IL, Ischaro A, Harrison LC (1988) IFN-gamma and tumor necrosis factor-α. Cytotoxicity to murine islets of Langerhans. J Immunol 141: 2325–2329Google Scholar
  102. 102.
    Kawahara DJ, Everts M, Sandborg C, Berman M, Buckingham B (1988) Cytokine-mediated killing of bovine islets is prevented by an interleukin-1 inhibitor. Diabetes 37:[Suppl 1]19A (Abstract)Google Scholar
  103. 103.
    Arias J, Vara E, Gómez M, Garcia C, Moreno A, Balibrea JL (1992) Effect of cytokines on “de novoi” lipid synthesis and hormone secretion by isolated human islets. Transplant Proc 24: 2909–2912Google Scholar
  104. 104.
    Zumsteg UW, Reimers JI, Pociot F et al. (1993) Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats. Diabetologia 36: 759–766Google Scholar
  105. 105.
    Mandrup-Poulsen T (1988) On the pathogenesis of insulin-dependent diabetes mellitus. Dan Med Bull 35: 438–460Google Scholar
  106. 106.
    Kawahara DJ, Kenney JS (1991) Species differences in human and rat islet sensitivity to human cytokines. Monoclonal anti-interleukin-1 (IL-1) influences on direct and indirect IL-1-mediated islet effects. Cytokine 3: 117–124Google Scholar
  107. 107.
    Eizirik DL, Welsh N, Hellerström C (1993) Predominance of stimulatory effects of interleukin-Β on isolated human pancreatic islets. J Clin Endocrinol Metab 76: 399–403Google Scholar
  108. 108.
    Soldevila G, Buscema M, Doshi M, James RFL, Bottazzo GF, Pujol-Borrel R (1991) Cytotoxic effects of IFN-gamma plus TNFα on human islet cells. J Autoimmun 4: 291–306Google Scholar
  109. 109.
    Rabinovitch A, Sumoski W, Rajotte RV, Warnock GL (1990) Cytotoxic effects of cytokines on human pancreatic islet cells in monolayer culture. J Clin Endocrinol Metab 71: 152–156Google Scholar
  110. 110.
    Rabinovitch A, Suarez-Pinzon WL, Strynadka K et al. (1994) Human pancreatic islet Β-cell destruction by cytokines is independent of nitric oxide production. J Clin Endocrinol Metab 79: 1058–1062Google Scholar
  111. 111.
    Eizirik DL, Pipeleers DG, Ling Z, Welsh N, Hellerström C, Andersson A (1994) Major species differences between humans and rodents in the susceptibility to pancreatic Β-cell injury. Proc Natl Acad Sci 91: 9253–9256Google Scholar
  112. 112.
    Welsh N, Margulis B, Borg LAH et al. (1995) Differences in the expression of heat-shock proteins and antioxidant enzymes between human and rodent pancreatic islets: implications for the pathogenesis of insulin-dependent diabetes mellitus. Molecular Medicine 1: 806–820Google Scholar
  113. 113.
    Margulis B, Sandler S, Eizirik DL, Welsh N, Welsh M (1991) Liposomal delivery of purified heat shock protein hsp70 into rat pancreatic islets as protection against interleukin 1Β-induced impaired Β-cell function. Diabetes 40: 1418–1421Google Scholar
  114. 114.
    Reimers JI, Andersen HU, Mauricio D et al. (1996) Strain-dependent differences in sensitivity of rat beta-cells to IL-1Β in vitro and in vivo: association with islet nitric oxide synthesis. Diabetes 45: 771–778Google Scholar
  115. 115.
    Held W, MacDonald HR, Weissman IL, Hess MW, Mueller C (1990) Genes encoding tumor necrosis factor α and granzyme A are expressed during development of autoimmune diabetes. Proc Natl Acad Sci 87: 2239–2243Google Scholar
  116. 116.
    Jiang Z, Woda BA (1991) Cytokine gene expression in the islets of the diabetic BioBreeding/Worcester rat. J Immunol 146: 2990–2994Google Scholar
  117. 117.
    Zunino SJ, Jiang N, Sambrook JF, Gething MJH (1992) Interleukin-1 α expression in islets of NOD mice. FASEB J 6:A1780 (Abstract)Google Scholar
  118. 118.
    Toyoda H, Formby B, Magalong D et al. (1994) In situ islet cytokine gene expression during development of type I diabetes in the non-obese diabetic mouse. Immunol Lett 39: 283–288Google Scholar
  119. 119.
    Huang X, Hultgren B, Dybdal N, Stewart TA (1994) Islet expression of interferon-α precedes diabetes in both the BB rat and streptozotocin-treated mice. Immunity 1: 469–478Google Scholar
  120. 120.
    Rabinovitch A, Suarez-Pinzon WL, Sorensen O, Bleackley RC, Power RF (1995) INF-gamma gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in NOD mice. J Immunol 154: 4874–4882Google Scholar
  121. 121.
    Rothe H, Burkart V, Faust A, Kolb H (1996) Interleukin-12 gene expression is associated with rapid development of diabetes mellitus in non-obese diabetic mice. Diabetologia 39: 119–122Google Scholar
  122. 122.
    Campbell IL, Kay TWH, Oxbrow L, Harrison LC (1991) Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. J Clin Invest 87: 739–742Google Scholar
  123. 123.
    Welsh M, Welsh N, Bendtzen K et al. (1995) Comparison of mRNA contents of interleukin-Β and nitric oxide synthase in pancreatic islets isolated from female and male nonobese diabetic mice. Diabetologia 38: 153–160Google Scholar
  124. 124.
    Chosich N, Rockett E, Harrison LC (1994) Endogenous TNF production differs between high and low diabetes incidence non-obese diabetic (NOD) mice. Autoimmunity 18: 163–168Google Scholar
  125. 125.
    Rothe H, Fehsel K, Kolb H (1990) Tumor necrosis factor alpha production is upregulated in diabetes prone BB rats. Diabetologia 33: 573–575Google Scholar
  126. 126.
    Lapchak PH, Guilbert LJ, Rabinovitch A (1992) Tumor necrosis factor production is deficient in diabetes-prone BB rats and can be corrected by complete Freund's adjuvant: a possible immunoregulatory role of tumor necrosis factor in the prevention of diabetes. Clin Immunol Immunopathol 65: 129–134Google Scholar
  127. 127.
    Setoguchi J, Hashiramoto K et al. (1992) Prediction of insulin dependent diabetes mellitus in non-obese diabetic mice by the endogeneous tumor necrosis factor-alpha level. Diabetes Res 19: 63–67Google Scholar
  128. 128.
    Wogensen LD, Reimers JI, Nerup J et al. (1992) Repetitive in vivo treatment with human recombinant interleukin-Β modifies beta-cell function in normal rats. Diabetologia 35: 331–339Google Scholar
  129. 129.
    Reimers JI, Bjerre U, Mandrup-Poulsen T, Nerup J (1994) Interleukin 1Β induces diabetes and fever in normal rats by nitric oxide via induction of different nitric oxide synthases. Cytokine 6: 512–520Google Scholar
  130. 130.
    Shimizu H, Tanaka S, Mori M (1992) Adrenalectomy enhances the susceptibility of pancreatic islets to interleukin-1Β: immunohistochemical study. Endocrinol Japon 39: 485–490Google Scholar
  131. 131.
    Wang Y, Goodman M, Lumerman J et al. (1989) In vivo administration of interleukin-1 inhibits glucose-stimulated insulin release. Diabetes Res Clin Pract 7: 205–211Google Scholar
  132. 132.
    Sutton R, Gray DWR, McShane P, Dallman MJ, Morris PJ (1989) The specificity of rejection and the absence of susceptibility of pancreatic islet Β cells to nonspecific immune destruction in mixed strain islets grafted beneath the renal capsule in the rat. J Exp Med 170: 751–762Google Scholar
  133. 133.
    Korsgren O, Jansson L (1994) Characterization of mixed syngeneic-allogeneic and syngeneic-xenogeneic islet-graft rejections in mice. J Clin Invest 93: 1113–1119Google Scholar
  134. 134.
    Simeonovic CJ, Ceredig R, Wilson JD (1990) Effect of GK 1.5 monoclonal antibody dosage on survival of pig proislet xenografts in CD4+ T cell-depleted mice. Transplantation 49: 849–856Google Scholar
  135. 135.
    Kaufman DB, Platt JL, Rabe FL, Dunn DL, Bach FH, Sutherland DER (1990) Differential roles of Mac-1+ cells, and CD4+ and CD8+ T lymphocytes in primary nonfunction and classic rejection of islet allografts. J Exp Med 172: 291–302Google Scholar
  136. 136.
    Dallman MJ, Porter ACG, Larsen CP, Morris PJ, Larsen CP, Morris PJ (1989) Lymphokine production in allografts — analysis of RNA by Northern blotting. Transplant Proc 21: 296–298Google Scholar
  137. 137.
    O'Connell PJ, Pacheco-Silva A, Nickerson PW et al. (1993) Unmodified pancreatic islet allograft rejection results in the preferential expression of certain T cell activation transcripts. J Immunol 150: 1093–1104Google Scholar
  138. 138.
    Sandberg J-O, Eizirik DL, Sandler S, Tracey DE, Andersson A (1993) Treatment with an interleukin-1 receptor antagonist protein prolongs mouse islet allograft survival. Diabetes 42: 1845–1851Google Scholar
  139. 139.
    Taverne J (1993) Transgenic mice in the study of cytokine function. Int J Exp Pathol 74: 525–546Google Scholar
  140. 140.
    Stewart TA, Hultgren B, Huang X, Pitts-Meek S, Hully J, MacLachlan NJ (1993) Induction of type 1 diabetes by interferon-α in transgenic mice. Science 260: 1942–1946Google Scholar
  141. 141.
    Sarvetnick N, Liggitt D, Pitts SL, Hansen SE, Stewart TA (1988) Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell 52: 773–782Google Scholar
  142. 142.
    Allison J, Malcolm L, Chosich N, Miller JF (1992) Inflammation but not autoimmunity occurs in transgenic mice expressing constitutive levels of interleukin-2 in islet beta cells. Eur J Immunol 22: 1115–1121Google Scholar
  143. 143.
    DiCosmo BF, Picarella D, Flavell RA (1994) Local production of human IL-6 promotes insulitis but retards the onset of insulin-dependent diabetes mellitus in non-obese diabetic mice. Int Immunol 6: 1829–1837Google Scholar
  144. 144.
    Higuchi Y, Herrera P, Muniesa P et al. (1992) Expression of a tumor necrosis factor α transgene in murine pancreatic Β cells results in severe and permanent insulitis without evolution towards diabetes. J Exp Med 176: 1719–1731Google Scholar
  145. 145.
    Picarella DE, Kratz A, Chang-ben L, Ruddle NH, Flavell RA (1992) Insulitis in transgenic mice expressing tumor necrosis factor Β (lymphotoxin) in the pancreas. Proc Natl Acad Sci 89: 10036–10040Google Scholar
  146. 146.
    Wogensen LD, Huang X, Sarvetnick N (1993) Leukocyte extravasation into the pancreatic tissue in transgenic mice expressing interleukin 10 in the islets of Langerhans. J Exp Med 178: 175–185Google Scholar
  147. 147.
    Allison J, McClive P, Oxbrow L, Baxter A, Morahan G, Miller JFAP (1994) Genetic requirements for acceleration of diabetes in non-obese diabetic mice expressing interleukin-2 in islet Β-cells. Eur J Immunol 24: 2535–2541Google Scholar
  148. 148.
    Wogensen LD, Myung-Shik L, Sarvetnick N (1994) Production of interleukin 10 by islet cells accelerates immune-mediated destruction of Β cells in nonobese diabetic mice. J Exp Med 179: 1379–1384Google Scholar
  149. 149.
    Moritani M, Yoshimoto K, Tashiro F et al. (1994) Transgenic expression of IL-10 in pancreatic islet A cells accelerates autoimmune insulitis and diabetes in non-obese diabetic mice. Int Immunol 6: 1927–1936Google Scholar
  150. 150.
    Myung-Shik L, Wogensen LD, Shizuru J, Oldstone MBA, Sarvetnick N (1994) Pancreatic islet production of murine interleukin-10 does not inhibit immune-mediated tissue destruction. J Clin Invest 93: 1332–1338Google Scholar
  151. 151.
    Guerder S, Picarella D, Linsley PS, Flavell RA (1994) Costimulator B7-1 confers antigen-presenting-cell function to parenchymal tissue and in conjunction with tumor necrosis factor alpha leads to autoimmunity in transgenic mice. Proc Natl Acad Sci 91: 5138–5142Google Scholar
  152. 152.
    Wilson CA, Jacobs C, Baker P, Baskin DG, Dower S, Lernmark A et al. (1990) IL-1Β modulation of spontaneous autoimmune diabetes and thyroiditis in the BB rat. J Immunol 144: 3784–3788Google Scholar
  153. 153.
    Vertrees S, Wilson CA, Ubungen R et al. (1991) Interleukin-1Β regulation of islet and thyroid autoimmunity in the BB rat. J Autoimmun 4: 717–732Google Scholar
  154. 154.
    Jacob CO, Aiso S, Michie SA, McDevitt HO, Acha-Orbea H (1990) Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-α and interleukin-1. Proc Natl Acad Sci 87: 968–972Google Scholar
  155. 155.
    Reimers JI, MØrch L, Markholst H et al. (1994) Interleukin-1Β (IL-1) does not reduce the diabetes incidence in diabetes-prone BB rats. Autoimmunity 17: 105–118Google Scholar
  156. 156.
    Formby B, Jacobs C, Dubuc P, Shao T (1992) Exogenous administration of IL-α inhibits active and adoptive transfer autoimmune diabetes in NOD mice. Autoimmunity 12: 21–27Google Scholar
  157. 157.
    Kolb H, Zielasek J, Treichel U, Freytag G, Wrann M, Kiesel U (1986) Recombinant interleukin 2 enhances spontaneous insulin-dependent diabetes in BB rats. Eur J Immunol 16: 209–212Google Scholar
  158. 158.
    Burstein D, Handler ES, Schindler J, Seals J, Mordes JP, Rossini AA (1987) Effect of interleukin-2 on diabetes in the BB/Wor rat. Diabetes Res 5: 163–167Google Scholar
  159. 159.
    Serreze DV, Hamaguchi K, Leiter EH (1989) Immunostimulation circumvents diabetes in NOD/Lt mice. J Autoimmun 2: 759–776Google Scholar
  160. 160.
    Satoh J, Seino H, Shintani S, et al. (1990) Inhibition of type 1 diabetes in BB rats with recombinant human tumor necrosis factor-α. J Immunol 145: 1395–1399Google Scholar
  161. 161.
    Yang X-D, Tisch R, Singer SM et al. (1994) Effect of tumor necrosis factor a on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J Exp Med 180: 995–1004Google Scholar
  162. 162.
    Satoh J, Seino H, Abo R et al. (1989) Recombinant tumor necrosis factor α suppresses autoimmune diabetes in nonobese diabetic mice. J Clin Invest 84: 1345–1348Google Scholar
  163. 163.
    Zunino S, Simons L, Sambrook JF, Gething MJH (1994) Interleukin-1 promotes hyperglycemia and insulitis in mice normally resistant to streptozotocin-induced diabetes. Am J Pathol 145: 661–670Google Scholar
  164. 164.
    Takahashi K, Satoh J, Seino H et al. (1993) Prevention of type I diabetes with lymphotoxin in BB rats. Clin Immunol Immunopathol 69: 318–323Google Scholar
  165. 165.
    Seino H, Takahashi K, Satoh J et al. (1993) Prevention of autoimmune diabetes with lymphotoxin in NOD mice. Diabetes 42: 398–404Google Scholar
  166. 166.
    Trembleau S, Penna G, Bosi E, Mortara A, Gately MK, Adorini L (1995) Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med 181: 817–821Google Scholar
  167. 167.
    Rapoport MJ, Jaramillo A, Zipris D et al. (1993) Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice. J Exp Med 178: 87–99Google Scholar
  168. 168.
    Pennline KJ, Roque-Gaffney E, Monahan M (1994) Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse. Clin Immunol Immunopathol 71: 169–175Google Scholar
  169. 169.
    Watanabe Y, Inoue I, Inaba T et al. (1993) Effect of macrophage colony-stimulating factor on the development of diabetes mellitus in BB rats. Horm Metab Res 25: 323–324Google Scholar
  170. 170.
    Campbell IL, Oxbrow L, Harrison LC (1991) Reduction in insulitis following administration of IFN-gamma and TNF-α in the NOD mouse. J Autoimmun 4: 249–262Google Scholar
  171. 171.
    Sobel DO, Newsome J, Ewel CH et al. (1992) Poly I:C induces development of diabetes mellitus in BB rat. Diabetes 41: 515–520Google Scholar
  172. 172.
    Dayer-Métroz M-D, Duhamel D, Rufer N et al. (1992) IL-1 receptor antagonist delays spontaneous autoimmune diabetes in BB rats. Eur J Clin Invest 22:A50 (Abstract)Google Scholar
  173. 173.
    Lukic M, Stosic S (1993) Interleukin I receptor antagonists prevent the induction of autoimmune diabetes. Autoimmunity 14:[Suppl 1]12Google Scholar
  174. 174.
    Nicoletti F, Di Marco R, Barcellini W et al. (1994) Protection from experimental autoimmune diabetes in the non-obese diabetic mouse with soluble interleukin-1 receptor. Eur J Immunol 24: 1843–1847Google Scholar
  175. 175.
    Jacob CO, Aiso S, Schreiber RD, McDevitt HO (1992) Monoclonal anti-tumor necrosis factor antibody renders non-obese diabetic mice hypersensitive to irradiation and enhances insulitis development. Int Immunol 4: 611–614Google Scholar
  176. 176.
    Nicoletti F, Meroni P, Landolfo S et al. (1990) Prevention of diabetes in BB/Wor rats treated with monoclonal antibodies to interferon-gamma. Lancet 336: 319Google Scholar
  177. 177.
    Debray-Sachs M, Carnaud C, Boitard C et al. (1991) Prevention of diabetes in NOD mice treated with antibody to murine IFN-gamma. J Autoimmun 4: 237–248Google Scholar
  178. 178.
    Serreze DV, Leiter EH (1988) Defective activation of T suppressor cell function in nonobese diabetic mice: potential relation to cytokine deficiencies. J Immunol 140: 3801–3807Google Scholar
  179. 179.
    Tilg H, Atkins MB, Dinarello CA, Mier JW (1995) Induction of circulating interleukin 10 by interleukin 1 and interleukin 2, but not interleukin 6 immunotherapy. Cytokine 7: 734–739Google Scholar
  180. 180.
    Foulis AK, Farquharson MA, Meager A (1987) Immunoreactive α-interferon in insulin-secreting beta cells in type 1 diabetes mellitus. Lancet ii:1423–1427Google Scholar
  181. 181.
    Somoza N, Vargas F, Roura-Mir C et al. (1994) Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor VΒ usage, and cytokine profile. J Immunol 153: 1360–1377Google Scholar
  182. 182.
    Hussain MJ, Peakman M, Gallati H et al. (1996) Elevated serum levels of macrophage-derived cytokines precede and accompany the onset of IDDM. Diabetologia 39: 60–69Google Scholar
  183. 183.
    Cavallo MG, Pozzilli P, Bird C et al. (1991) Cytokines in sera from insulin-dependent diabetic patients at diagnosis. Clin Exp Immunol 86: 256–259Google Scholar
  184. 184.
    Lorini R, De Amici M, d'Annunzio G, Vitali L, Scaramuzza A (1995) Low serum levels of tumor necrosis factor-alpha in insulin-dependent diabetic children. Horm Res 43: 206–209Google Scholar
  185. 185.
    Ciampolillo A, Guastamacchia E, Caragiulo L et al. (1993) In vitro secretion of interleukin-1Β and interferon-gamma by peripheral blood lymphomononuclear cells in diabetic patients. Diabetes Res Clin Pract 21: 87–93Google Scholar
  186. 186.
    Sahdev I, Fort P, Herry A (1992) Macrophage-released interleukin-1 in patients with type 1 diabetes mellitus. Acta Paediatr Scand 81: 935–936Google Scholar
  187. 187.
    Giordano C, PantÒ F, Caruso C et al. (1989) Interleukin 2 and soluble interleukin 2-receptor secretion defect in vitro in newly diagnosed type 1 diabetic patients. Diabetes 38: 310–315Google Scholar
  188. 188.
    Luger A, Schernthaner G, Urbanski A, Luger TA (1988) Cytokine production in patients with newly diagnosed insulin-dependent (type 1) diabetes mellitus. Eur J Clin Invest 18: 233–236Google Scholar
  189. 189.
    MØlvig J, Pociot F, Baek L, et al. (1990) Monocyte function in IDDM patients and healthy individuals. Scand J Immunol 32: 297–311Google Scholar
  190. 190.
    Zier KS, Spielman RS, Baker L (1984) Decreased synthesis of interleukin-2 (IL-2) in insulin-dependent diabetes mellitus. Diabetes 33: 552–555Google Scholar
  191. 191.
    Lang F, Pogu S, Maurel C, Charbonnel B, Sai P (1987) Production of and response to interleukin 2 by blood mononuclear cells from some type 1 diabetic patients. Diabete Metabol 13: 37–43Google Scholar
  192. 192.
    Ohno Y, Aoki N, Nishimura A (1993) In vitro production of interleukin-1, interleukin-6 and tumor necrosis factor-α in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 77: 1072–1077Google Scholar
  193. 193.
    Tomoda T, Kurashige T, Taniguchi T (1994) Imbalance of the interleukin 2 system in children with IDDM. Diabetologia 37: 476–482Google Scholar
  194. 194.
    Ilonen J, Salonen R, Mustonen A (1989) Low levels of mumps virus antigen induced interferon-alpha production in insulin-dependent diabetes. Diabetes Res 12: 75–78Google Scholar
  195. 195.
    Sachs JA, Whichelow CE, Hitman GA, Niven M, Thode H, Meager A (1990) The effect of HLA and insulin-dependent diabetes mellitus on the secretion levels of tumour necrosis factor alpha and beta and gamma interferon. Scand J Immunol 32: 703–708Google Scholar
  196. 196.
    Imagawa A, Itoh N, Hanafusa T, Waguri M, Kuwajima M, Matsuzawa Y (1996) Antibodies to glutamic acid decarboxylase induced by interferon-alpha therapy for chronic viral hepatitis. Diabetologia 39: 126Google Scholar
  197. 197.
    Waguri M, Hanafusa T, Itoh N et al. 1994) Occurrence of IDDM during interferon therapy for chronic viral hepatitis Diabetes Res Clin Pract 23: 33–36Google Scholar
  198. 198.
    Kyvik K, Green A, Beck-Nielsen H (1995) Concordance rates of insulin dependent diabetes mellitus: a population based study of young Danish twins. BMJ 311: 913–917Google Scholar
  199. 199.
    Thomson G, Robinson WP, Kuhner MK et al. (1988) Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. Am J Hum Genet 43: 799–816Google Scholar
  200. 200.
    Davies JL, Kawaguchi Y, Bennett ST et al. (1994) A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371: 130–136Google Scholar
  201. 201.
    Copeman JB, Cucca F, Hearne CM et al. (1995) Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31–q33. Nature Genet 9: 80–85Google Scholar
  202. 202.
    Cornall RJ, Prins J-B, Todd JA et al. (1991) Type 1 diabetes in mice is linked to the interleukin-1 receptor and Lsh/Ity/Bcg genes on chromosome 1. Nature 353: 262–265Google Scholar
  203. 203.
    Pociot F, MØlvig J, Wogensen LD, Worsaae H, Nerup J (1992) A Taql polymorphism in the human interleukin-1Β (IL-1Β) gene correlates with IL-1Β secretion in vitro. Eur J Clin Invest 22: 396–402Google Scholar
  204. 204.
    Pociot F, RØnningen KS, Bergholdt R et al. (1994) Genetic susceptibility markers in Danish patients with type 1 (insulin-dependent) diabetes — evidence for polygenecity in man. Autoimmunity 19: 169–178Google Scholar
  205. 205.
    Mandrup-Poulsen T, Pociot F, MØlvig J et al. (1994) Monokine antagonism is reduced in patients with IDDM. Diabetes 43: 1242–1247Google Scholar
  206. 206.
    Bergholdt R, Karlsen AE, Johannesen J et al. (1995) Characterization of polymorphisms of an interleukin 1 receptor type 1 gene (IL1R1) promotor region (P2) and their relation to insulin-dependent diabetes mellitus (IDDM). Cytokine 7: 727–733Google Scholar
  207. 207.
    Metcalfe KA, Hitman GA, Pociot F et al. (1995) A transracial study of association between IDDM and the interleukin-1 receptor type 1 gene. Diabetologia 38:[Suppl 1]A72 (Abstract)Google Scholar
  208. 208.
    Pociot F, Briant L, Jongeneel CV et al. (1993) Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-α and TNF-Β by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol 23: 224–231Google Scholar
  209. 209.
    Awata T, Matsumoto C, Urakami T, Hagura R, Amemiya S, Kanazawa Y (1994) Association of polymorphism in the interferon gamma gene with IDDM. Diabetologia 37: 1159–1162Google Scholar
  210. 210.
    Johannesen J, Vejijola R, Hansen PM et al. (1995) Analysis of polymorphism in the interferon-gamma gene in Danish and Finnish IDDM patients and control subjects. Diabetologia 38:[Suppl 1]A29 (Abstract)Google Scholar
  211. 211.
    Sandler S, Eizirik DL, Svensson C, Strandell E, Welsh M, Welsh N (1991) Biochemical and molecular actions of interleukin-1 on pancreatic Β-cells. Autoimmunity 10: 241–253Google Scholar
  212. 212.
    Corbett JA, McDaniel ML (1992) Does nitric oxide mediate autoimmune destruction of Β-cells? Diabetes 41: 897–903Google Scholar
  213. 213.
    Dinarello CA (1994) The interleukin-1 family: 10 years of discovery. FASEB J 8: 1314–1325Google Scholar
  214. 214.
    Greenfelder SA, Nunes P, Kwee L, Labow M, Chizzonite RA (1995) Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J Biol Chem 270: 13757–13765Google Scholar
  215. 215.
    Brooks JW, Mizel SB (1994) Interleukin-1 signal transduction. Eur Cytokine Netw 5: 547–561Google Scholar
  216. 216.
    Hammonds P, Beggs M, Beresford G, Espinal J, Clarke J, Mertz RJ (1990) Insulin-secreting Β-cells possess specific receptors for interleukin-1Β. FEBS Lett 261: 97–100Google Scholar
  217. 217.
    Deyerle KL, Sims JE, Dower SK, Bothwell MA (1992) Pattern of IL-1 receptor gene expression suggests role in noninflammatory processes. J Immunol 149: 1657–1665Google Scholar
  218. 218.
    Eizirik DL, Björklund A, Welsh N (1993) Interleukin-1 induced expression of nitric oxide synthase in insulin-producing cells is preceded by c-fos induction and depends on gene transcription and protein synthesis. FEBS Lett 317: 62–66Google Scholar
  219. 219.
    Jafarian-Tehrani M, Amrani A, Homo-Delarche F, Marquette C, Dardenne M, Haour F (1995) Localization and characterization of interleukin-1 receptors in the islets of Langerhans from control and nonobese diabetic mice. Endocrinology 136: 609–613Google Scholar
  220. 220.
    Bristulf J, Gatti S, Malinowsky D, Bjork L, Sundgren AK, Bartfai T (1994) Interleukin-1 stimulates the expression of type I and type II interleukin-1 receptors in the rat insulinoma cell line Rinm5F; sequencing a rat type II interleukin-1 receptor cDNA. Eur Cytokine Netw 5: 319–330Google Scholar
  221. 221.
    Eizirik DL, Tracey DE, Bendtzen K, Sandler S (1991) An interleukin-1 receptor antagonist protein protects insulin-producing beta cells against suppressive effects of interleukin-1Β. Diabetologia 34: 445–448Google Scholar
  222. 222.
    Welsh N, Bendtzen K, Sandler S (1991) Influence of protease on inhibitory and stimulatory effects of interleukin 1Β on Β-cell function. Diabetes 40: 290–293Google Scholar
  223. 223.
    Rabuazzo AM, Buscema M, Caltabiano V, et al. (1995) Interleukin-1Β inhibition of insulin release in rat pancreatic islets: possible involvement of G-proteins in the signal transduction pathway. Diabetologia 38: 779–784Google Scholar
  224. 224.
    Sjöholm å (1991) Cytokines inhibit proliferation and insulin secretion by clonal rat insulinoma cells (RINm5F) non-synergistically and in a pertussis toxin-insensitive manner. Immunol Lett 30: 81–86Google Scholar
  225. 225.
    Helqvist S, Bouchelouche PN, Johannesen J, Nerup J (1990) Interleukin 1Β increases the cytosolic free sodium concentration in isolated rat islets of Langerhans. Scand J Immunol 32: 53–58Google Scholar
  226. 226.
    Corbett JA, Sweetland M, Lancaster JR Jr, McDaniel ML (1993) A 1-hour pulse with IL-1Β induces formation of nitric oxide and inhibits insulin secretion by rat islets of Langerhans: evidence for a tyrosine kinase signalling mechanism. FASEB J 7: 369–374Google Scholar
  227. 227.
    Corbett JA, Kwon G, Misko TP, Rodi CP, McDaniel ML (1994) Tyrosine kinase involvement in IL-1Β-induced expression of iNOS by Β-cells purified from islets of Langerhans. Am J Physiol 267:C48-C54Google Scholar
  228. 228.
    Zawalich WS, Zawalich KC (1989) Interleukin 1 is a potent stimulator of islet insulin secretion and phosphoinositide hydrolysis. Am J Physiol 256:[Endocrinol Metab 19]E19-E24Google Scholar
  229. 229.
    Hughes JH, Easom RA, Wolf BA, Turk J, McDaniel ML (1989) Interleukin 1-induced prostaglandin E2 accumulation by isolated pancreatic islets. Diabetes 38: 1251–1257Google Scholar
  230. 230.
    Bleich D, Chen S, Gu J-L, et al. (1995) Interleukin-1Β regulates the expression of a leukocyte type of 12-lipoxygenase in rat islets and RIN m5F cells. Endocrinology 136: 5736–5744Google Scholar
  231. 231.
    Wolf BA, Hughes JH, Florholmen J, Turk J, McDaniel ML (1989) Interleukin-1 inhibits glucose-induced Ca2+ uptake by islets of Langerhans. FEBS Lett 248: 35–38Google Scholar
  232. 232.
    Helqvist S, Bouchelouche PN, Andersen HU, Nerup J (1989) Modulation of calcium flux influences interleukin 1Β effects on insulin release from isolated islets of Langerhans. Acta Endocrinol 121: 447–455Google Scholar
  233. 233.
    Welsh N, Nilsson T, Hallberg A, Arkhammar P, Berggren P-O, Sandler S (1989) Human interleukin 1Β stimulates islet insulin release by a mechanism not dependent on changes in phospholipase C and protein kinase C activities or Ca2+ handling. Acta Endocrinol 121: 698–704Google Scholar
  234. 234.
    Sandler S, Bendtzen K, Eizirik DL, Strandell E, Welsh M, Welsh N (1990) Metabolism and Β-cell function of rat pancreatic islets exposed to human interleukin-1Β in the presence of a high glucose concentration. Immunol Lett 26: 245–252Google Scholar
  235. 235.
    Hughes JH, Watson MA, Easom RA, Turk J, McDaniel ML (1990) Interleukin-1 induces rapid and transient expression of the c-fos proto-oncogene in isolated pancreatic islets and in purified Β-cells. FEBS Lett 266: 33–36Google Scholar
  236. 236.
    Kwon G, Corbett JA, Rodi CP, Sullivan P, McDaniel ML (1995) Interleukin-1Β-induced nitric oxide synthase expression by rat pancreatic Β-cells: evidence for the involvement of nuclear factor kB in the signaling mechanism. Endocrinology 136: 4790–4795Google Scholar
  237. 237.
    Welsh N (1995) Interleukin-1Β induced ceramide and diacylglycerol generation does not lead to NF-kB activation in RINm5F cells. Diabetologia 38:[Suppl 1]A82 (Abstract)Google Scholar
  238. 238.
    Eizirik DL, Sandler S, Welsh N, Juntti-Berggren L, Berggren P-O (1995) Interleukin-1Β-induced stimulation of insulin release in mouse pancreatic islets is related to diacylglycerol production and protein kinase C activation. Mol Cell Endocrinol 111: 159–165Google Scholar
  239. 239.
    Zawalich WS, Diaz VA (1986) Interleukin 1 inhibits insulin secretion from isolated perifused rat islets. Diabetes 35: 1119–1123Google Scholar
  240. 240.
    Spinas GA, Hansen BS, Linde S et al. (1987) Interleukin 1 dose-dependently affects the biosynthesis of (pro)insulin in isolated rat islets of Langerhans. Diabetologia 30: 474–480Google Scholar
  241. 241.
    Comens PG, Wolf BA, Unanue ER, Lacy PE, McDaniel ML (1987) Interleukin 1 is potent modulator of insulin secretion from isolated rat islets of Langerhans. Diabetes 36: 963–970Google Scholar
  242. 242.
    Zawalich WS, Zawalich KC (1991) Influence of staurosporine, nitrendipine and monooleoylglycerol on interleukin-1-induced insulin secretion and phosphoinositide hydrolysis. Mol Cell Endocrinol 82: 303–311Google Scholar
  243. 243.
    Corbett JA, Kwon G, Turk J, McDaniel ML (1993) IL-1Β induces coexpression of both nitric oxide synthase and cyclooxygenase by islets of Langerhans: activation of cyclooxygenase by nitric oxide. Biochemistry 32: 13767–13770Google Scholar
  244. 244.
    Sjöholm å (1995) Ceramide inhibits pancreatic beta-cell insulin production and mitogenesis and mimics the actions of interleukin-1 beta. FEBS Lett 367: 283–286Google Scholar
  245. 245.
    Bigdeli N, Niemann A, Sandler S, Eizirik DL (1994) Dissociation between interleukin-1 beta induced expression of mRNA for superoxide dismutase and nitric oxide synthase in insulin-producing cells. Biochem Biophys Res Commun 203:1542–1547Google Scholar
  246. 246.
    Spinas GA, Palmer JP, Mandrup-Poulsen T, Andersen H, Nielsen JH, Nerup J (1988) The bimodal effect of interleukin 1 on rat pancreatic beta-cells — stimulation followed by inhibition — depends upon dose, duration of exposure, and ambient glucose concentration. Acta Endocrinol 119: 307–311Google Scholar
  247. 247.
    Mandrup-Poulsen T, Nerup J, Reimers JI et al. (1996) Cytokines and the endocrine system. II. Roles in substrate metabolism, modulation of thyroidal and pancreatic endocrine cell functions and autoimmune endocrine diseases. Eur J Endocrinol 134: 21–30Google Scholar
  248. 248.
    Eizirik DL, Sandler S, Hallberg A, Bendtzen K, Sener A, Malaisse WJ (1989) Differential sensitivity of Β-cell secretagogues in cultured rat pancreatic islets exposed to human interleukin-1Β. Endocrinology 125: 752–759Google Scholar
  249. 249.
    Southern C, Schulster D, Green IC (1990) Inhibition of insulin secretion by interleukin-1Β and tumour necrosis factor-α via an l-arginine-dependent nitric oxide generating mechanism. FEBS Lett 276: 42–44Google Scholar
  250. 250.
    Welsh N, Eizirik DL, Bendtzen K, Sandler S (1991) Interleukin-1Β-induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme aconitase. Endocrinology 129: 3167–3173Google Scholar
  251. 251.
    Corbett JA, Lancaster JR Jr, Sweetland MA, McDaniel ML (1991) Interleukin-1Β-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans. J Biol Chem 266: 21351–21354Google Scholar
  252. 252.
    Eizirik DL, Cagliero E, Björklund A, Welsh N (1992) Interleukin-1Β induces the expression of an isoform of nitric oxide synthase in insulin-producing cells, which is similar to that observed in activated macrophages. FEBS Lett 308: 249–252Google Scholar
  253. 253.
    Karlsen AE, Andersen HU, Vissing H et al. (1995) Cloning and expression of cytokine-inducible nitric oxide synthase cDNA from rat islets of Langerhans. Diabetes 44: 753–758Google Scholar
  254. 254.
    Strandell E, Buschard K, Saldeen J, Welsh N (1995) Interleukin-1Β induces the expression of HSP70, heme oxygenase and Mn-SOD in FACS-purified rat islet Β-cells, but not in α-cells. Immunol Lett 48: 145–148Google Scholar
  255. 255.
    Lancaster JR Jr (1994) Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc Natl Acad Sci 91: 8137–8141Google Scholar
  256. 256.
    Kallmann B, Burkart V, Kröncke K-D, Kolb-Bachofen V, Kolb H (1992) Inflammatory damage of pancreatic islet cells by nitric oxide: protection by nicotinamide but not by radical scavengers. Life Sci 51: 671–678Google Scholar
  257. 257.
    Cunningham JM, Mabley JG, Delaney CA, Green IC (1994) The effect of nitric oxide donors on insulin secretion, cyclic GMP and cyclic AMP in rat islets of Langerhans and the insulin-secreting cell lines HIT-T15 and RINm5F. Mol Cell Endocrinol 102: 23–29Google Scholar
  258. 258.
    Fehsel K, Jalowy A, Qi S, Burkart V, Hartmann B, Kolb H (1993) Islet cell DNA is a target of inflammatory attack by nitric oxide. Diabetes 42: 496–500Google Scholar
  259. 259.
    Heller B, Wang Z-Q, Wagner EF et al. (1995) Inactivation of the poly (ADP-ribose) polymerase gene affects oxygen radical and nitric oxide toxicity in islet cells. J Biol Chem 270: 11176–11180Google Scholar
  260. 260.
    Xie K, Huang S, Zhongyun D, Fidler IJ (1993) Cytokine-induced apoptosis in transformed murine fibroblasts involves synthesis of endogenous nitric oxide. Int J Oncol 3: 1043–1048Google Scholar
  261. 261.
    Scaglia L, Smith FE, Bonner-Weir S (1995) Apoptosis contributes to the involution of Β-cell mass in the post partum rat pancreas. Endocrinology 136: 5461–5468Google Scholar
  262. 262.
    Sánchez-Margalet V, Lucas M, Solano F, Goberna R (1993) Sensitivity of insulin-secreting RIN m5F cells to undergoing apoptosis by the protein kinase C inhibitor staurosporine. Exp Cell Res 209: 160–163Google Scholar
  263. 263.
    Loweth AC, Scarpello JHB, Williams GT, Morgan NG (1995) Effects of modulators of G-protein function on apoptosis in RINm5F cells and rat islets. Diabetologia 38:[Suppl 1]A45 (Abstract)Google Scholar
  264. 264.
    Ankarcrona M, Dypbukt JM, Brüne B, Nicotera P (1994) Interleukin-1Β-induced nitric oxide production activates apoptosis in pancreatic RINm5F cells. Exp Cell Res 213: 172–177Google Scholar
  265. 265.
    Morgan NG, Cable HC, Newcombe NR, Williams GT (1994) Treatment of cultured pancreatic B-cells with streptozotocin induces cell death by apoptosis. Biosci Rep 14: 243–250Google Scholar
  266. 266.
    Kaneto H, Fujii J, Seo HG et al. (1995) Apoptotic cell death triggered by nitric oxide in pancreatic Β-cells. Diabetes 44: 733–738Google Scholar
  267. 267.
    Dunger A, Schlosser M, Ziegler B, Schmidt S (1995) Interleukin 1-beta induces apoptosis in insulin-producing cells. Diabetologia 38:[Suppl 1]A38 (Abstract)Google Scholar
  268. 268.
    Flodström M, Niemann A, Bedoya FJ, Morris SM, Eizirik DL (1995) Expression of the citrulline-nitric oxide cycle in rodent and human pancreatic Β-cells: induction of argininosuccinate synthetase by cytokines. Endocrinology 136: 3200–3206Google Scholar
  269. 269.
    Kleemann R, Rothe H, Kolb-Bachofen V et al. (1993) Transcription and translocation of inducible nitric oxide synthase in the pancreas of prediabetic BB rats. FEBS Lett 328: 9–12Google Scholar
  270. 270.
    Rothe H, Faust A, Schade U et al. (1994) Cyclophosphamide treatment of female non-obese diabetic mice causes enhanced expression of inducible nitric oxide synthase and interferon-gamma, but not of interleukin-4. Diabetologia 37: 1154–1158Google Scholar
  271. 271.
    Lukic ML, Stosic-Grujicic S, Ostojic N, Chan WL, Liew FY (1991) Inhibition of nitric oxide generation affects the induction of diabetes by streptozocin in mice. Biochem Biophys Res Commun 178: 913–920Google Scholar
  272. 272.
    Corbett JA, Mikhael A, Shimizu J et al. (1993) Nitric oxide production in islets from nonobese diabetic mice: Aminoguanidine-sensitive and -resistant stages in the immunological diabetic process. Proc Natl Acad Sci 90: 8992–8995Google Scholar
  273. 273.
    Lindsay RM, Smith W, Rossiter SP, McIntyre MA, Williams BC, Baird JD (1995) NG-Nitro-l-Arginine methyl ester reduces the incidence of IDDM in BB/E rats. Diabetes 44: 365–368Google Scholar
  274. 274.
    Suarez-Pinzon WL, Strynadka K, Schulz R, Rabinovitch A (1994) Mechanisms of cytokine-induced destruction of rat insulinoma cells: the role of nitric oxide. Endocrinology 134: 1006–1010Google Scholar
  275. 275.
    Cetkovic-Cvrlje M, Sandler S, Eizirik DL (1993) Nicotinamide and dexamethasone inhibit interleukin-1-induced nitric oxide production by RINm5F cells without decreasing messenger ribonucleic acid expression for nitric oxide synthase. Endocrinology 133: 1739–1743Google Scholar
  276. 276.
    Andersen HU, JØrgensen KH, Egeberg J, Mandrup-Poulsen T, Nerup J (1994) Nicotinamide prevents interleukin-1 effects on accumulated insulin release and nitric oxide production in rat islets of Langerhans. Diabetes 43: 770–777Google Scholar
  277. 277.
    Corbett JA, Sweetland M, Wang JL, Lancaster JR Jr, McDaniel ML (1993) Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. Proc Natl Acad Sci 90: 1731–1735Google Scholar
  278. 278.
    Eizirik DL, Sandler S, Welsh N, et al. (1994) Cytokines suppress human islet function irrespective of their effects on nitric oxide generation. J Clin Invest 93: 1968–1974Google Scholar
  279. 279.
    Delaney CA, Eizirik DL, Lowe JE et al. (1995) Effects of nitric oxide on DNA damage and ultrastructure in islets of Langerhans — a comparison of human and rodent. Diabetologia 38:[Suppl 1]A17 (Abstract)Google Scholar
  280. 280.
    Sumoski W, Baquerizo H, Rabinovitch A (1989) Oxygen free radical scavengers protect rat islet cells from damage by cytokines. Diabetologia 32: 792–796Google Scholar
  281. 281.
    Takane N, Yamada K, Inada C, Nonaka K (1994) Cytokine-induced Fas antigen mRNA expression and DNA fragmentation in islet cells. 15th International Diabetes Federation Congress, Kobe, Japan, 1994Google Scholar
  282. 282.
    Hughes JH, Colca JR, Easom RA, Turk J, McDaniel ML (1990) Interleukin 1 inhibits insulin secretion from isolated rat pancreatic islets by a process that requires gene transcription and mRNA translation. J Clin Invest 86: 856–863Google Scholar
  283. 283.
    Eizirik DL, Bendtzen K, Sandler S (1991) Short exposure of rat pancreatic islets to interleukin-1Β induces a sustained but reversible impairment in Β-cell function: influence of protease activation, gene transcription, and protein synthesis. Endocrinology 128: 1611–1616Google Scholar
  284. 284.
    Andersen HU, Larsen PM, Fey SJ, Karlsen AE, Mandrup-Poulsen T, Nerup J (1995) Two-dimensional gel electrophoresis of rat islet proteins. Interleukin 1Β-induced changes in protein expression are reduced by l-Arginine depletion and nicotinamide. Diabetes 44: 400–407Google Scholar
  285. 285.
    Helqvist S, Polla BS, Johannesen J, Nerup J (1991) Heat shock protein induction in rat pancreatic islets by recombinant human interleukin 1Β. Diabetologia 34: 150–156Google Scholar
  286. 286.
    Borg LAH, Cagliero E, Sandler S, Welsh N, Eizirik DL (1992) Interleukin-1Β increases the activity of Superoxide dismutase in rat pancreatic islets. Endocrinology 130: 2851–2857Google Scholar
  287. 287.
    Eizirik DL, Strandell E, Bendtzen K, Sandler S (1988) Functional characteristics of rat pancreatic islets maintained in culture after exposure to human interleukin 1. Diabetes 37: 916–919Google Scholar
  288. 288.
    Cetkovic-Cvrlje M, Eizirik DL (1994) TNF-α and IFN-gamma potentiate the deleterious effects of IL-1Β on mouse pancreatic islets mainly via generation of nitric oxide. Cytokine 6: 399–406Google Scholar
  289. 289.
    Yamada K, Otabe S, Inada C, Takane N, Nonaka K (1993) Nitric oxide and nitric oxide synthase mRNA induction in mouse islet cells by interferon-gamma plus tumor necrosis factor-α. Biochem Biophys Res Commun 197: 22–27Google Scholar
  290. 290.
    Sternesjö J, Bendtzen K, Sandler S (1995) Effects of prolonged exposure in vitro to interferon-gamma and tumour necrosis factor-α on nitric oxide and insulin production of rat pancreatic islets. Autoimmunity 20: 185–190Google Scholar
  291. 291.
    Nerup J, Mandrup-Poulsen T, MØlvig J, Helqvist S, Wogensen LD, Egeberg J (1988) Mechanisms of pancreatic Β-cell destruction in type I diabetes. Diabetes Care 11:[Suppl 1]16–23Google Scholar
  292. 292.
    Dahlquist G (1995) Environmental risk factors in human type 1 diabetes — an epidemiological perspective. Diab Metab Rev 11: 37–46Google Scholar
  293. 293.
    Leiter E (1987) Murine macrophages and pancreatic beta-cells. Chemotactic properties of insulin and beta-cytostatic action of interleukin-1. J Exp Med 166: 1174–1179Google Scholar
  294. 294.
    Cavallo MG, Baroni MG, Toto A et al. (1992) Viral infection induces cytokine release by beta islet cells. Immunology 75: 664–668Google Scholar
  295. 295.
    Bach LW (1996) Interleukin-1Β-mediated beta-cell inhibition in vivo. A role of circulating interleukin-1Β in the pathogenesis of insulin dependent diabetes mellitus? Dan Med Bull 43: 39–57Google Scholar
  296. 296.
    Tsumara H, Wang JZ, Ogawa S, Ohota H, Komada H, Ito Y et al. (1994) IL-1 induces intracisternal type A virus and retrovirus type C in pancreatic beta-cells of NOD mice. J Exp Anim Sci 36: 141–150Google Scholar
  297. 297.
    Takane N, Yamada K, Otabe S, Inoue M, Nonaka K (1993) Interleukin-1 induction of tumor necrosis factor-α mRNA and bioactive tumor necrosis factor-α in a pancreatic Β-cell line by a mechanism requiring no de novo protein synthesis. Biochem Biophys Res Commun 194: 163–169Google Scholar
  298. 298.
    Campbell IL, Cutri A, Wilson A, Harrison LC (1989) Evidence for IL-6 production by and effects on the pancreatic Β-cell. J Immunol 143: 1188–1191Google Scholar
  299. 299.
    Campbell IL, Cutri A, Wilkinson D, Boyd AW, Harrison LC (1989) Intercellular adhesion molecule 1 is induced on isolated endocrine islet cells by cytokines but not by reovirus infection. Proc Natl Acad Sci 86: 4282–4286Google Scholar
  300. 300.
    Kjaer TW, Rygaard J, Bendtzen K, Josefsen K, Bock T, Buschard K (1992) Interleukins increase surface ganglioside expression of pancreatic islet cells in vitro. APMIS 100: 509–514Google Scholar
  301. 301.
    Eizirik DL, Welsh N, Niemann A, Velloso LA, Malaisse WJ (1994) Succinic acid monomethyl ester protects rat pancreatic islet secretory potential against interleukin-1Β (IL-1Β) without affecting glutamate decarboxylase expression or nitric oxide production. FEBS Lett 337: 298–302Google Scholar
  302. 302.
    Feutren G, Papoz L, Assan R et al. (1986) Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset. Results of a multicentre double-blind trial. Lancet ii:119–123Google Scholar
  303. 303.
    The Canadian-European randomized control trial group (1988) Cyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion. Diabetes 37: 1574–1582Google Scholar
  304. 304.
    Mori Y, Suko M, Okudaira H et al. (1986) Preventive effects of cyclosporin on diabetes in NOD mice. Diabetologia 29: 244–247Google Scholar
  305. 305.
    Laupacis A, Stiller CR, Gardell C et al. (1983) Cyclosporin prevents diabetes in BB Wistar rats. Lancet i:10–12Google Scholar
  306. 306.
    Lukic M, Stosic S, Ostojic N (1993) Effector mechanisms in low-dose streptozotocin induced diabetes in mice. EOS 13: 91–92Google Scholar
  307. 307.
    Welsh N, Bendtzen K, Welsh M (1995) Expression of an insulin/interleukin-1 receptor antagonist hybrid gene in insulin-producing cell lines (HIT-T15 and NIT-1) confers resistance against interleukin-1-induced nitric oxide production. J Clin Invest 95: 1717–1722Google Scholar
  308. 308.
    Welsh N (1994) A role for tyrosine kinase activation in interleukin-1 beta induced nitric oxide production in the insulin producing cell line RINm-5F. Biosci Rep 14: 43–50Google Scholar
  309. 309.
    Saldeen J, Welsh N (1994) Interleukin-1Β induced activation of NF-kB in insulin producing RINm5F cells is prevented by the protease inhibitor Nα-p-tosyl-1-lysine chromethylketone. Biochem Biophys Res Commun 203: 149–155Google Scholar
  310. 310.
    Bedoya FJ, Flodström M, Eizirik DL (1995) Pyrrolidine dithiocarbamate prevents IL-1-induced nitric oxide synthase mRNA, but not Superoxide dismutase mRNA, in insulin producing cells. Biochem Biophys Res Commun 210: 816–822Google Scholar
  311. 311.
    Kolb H, Kiesel U, Kröncke K-D, Kolb-Bachofen V (1991) Suppression of low dose streptozotocin induced diabetes in mice by administration of a nitric oxide synthase inhibitor. Life Sci 49:PL 213-PL 217Google Scholar
  312. 312.
    Wu G (1995) Nitric oxide synthesis and the effect of aminoguanidine and NG-Monomethyl-l-Arginine on the onset of diabetes in the spontaneously diabetic BB rat. Diabetes 44: 360–364Google Scholar
  313. 313.
    Yamada K, Inada C, Otabe S, Takane N, Hayashi H, Nonaka K (1993) Effects of free radical scavengers on cytokine actions on islet cells. Acta Endocrinol 128: 379–384Google Scholar
  314. 314.
    Drash AL, Rudert WA, Borquaye S, Wang R, Lieberman I (1988) Effect of probucol on development of diabetes mellitus in BB rats. Am J Cardiol 62: 27B-30BGoogle Scholar
  315. 315.
    Mendola J, Wright JR, Lacy PE (1989) Oxygen free-radical scavengers and immune destruction of murine islets in allograft rejection and multiple low-dose streptozocin-induced insulitis. Diabetes 38: 379–385Google Scholar
  316. 316.
    Mandrup-Poulsen T, Reimers JI, Andersen HU, et al. (1993) Nicotinamide treatment in the prevention of insulin-dependent diabetes mellitus. Diab Metab Rev 9: 295–309Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • T. Mandrup-Poulsen
    • 1
  1. 1.Steno Diabetes CenterGentofteDenmark

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