NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes.

Insulin-dependent diabetes mellitus (IDDM) is a disease characterized by the autoimmune destruction of the pancreatic beta-cells, which requires the expression of a number of immune-related genes including major histocompatibility complex proteins, cytokines, chemokines, and cytotoxic enzymes, many of which are regulated by the transcription factor, NFkappaB. Inhibition of the entire NFkappaB family of transcription factors may be harmful, as these factors are involved in many normal physiological processes. However, identifying and targeting specific NFkappaB subunits critical for the pathogenesis of disease may prove to be valuable in designing new therapeutic strategies. To assess the potential role of the NFkappaB subunit, p50, in the development of IDDM, mice with gene disruption for NFkappaB (p50) were investigated for susceptibility to IDDM. We found that p50-deficient mice were fully resistant against multiple low-dose streptozotocin-induced diabetes, a model of diabetes with a strong autoimmune component. The site of involvement of NFkappaB (p50) lies at an early, critical juncture of immune activation and proinflammatory mediator production, because: (1) isolated islets of Langerhans from NFkappaB (p50)-deficient mice were not protected from the islet dysfunction induced by in vitro application of proinflammatory cytokines; (2) p50-deficient mice were not resistant to diabetes induced by a single high dose of streptozotocin, a model with a large oxidant component and no autoimmune involvement; and (3) diabetes induced up-regulation of nitric oxide and interleukin-12 was blocked in the p50-deficient mice. Our data suggest that NFkappaB (p50) has an essential role in the development of autoimmune diabetes. Selective therapeutic blockade of this subunit may be beneficial in preventing IDDM.

[1]  N. Welsh,et al.  The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells , 1996, Diabetologia.

[2]  U. Förstermann,et al.  Nitric oxide synthase: expression and expressional control of the three isoforms , 1995, Naunyn-Schmiedeberg's Archives of Pharmacology.

[3]  J. Cunningham,et al.  Interleukin-1β effects on cyclic GMP and cyclic AMP in cultured rat islets of Langerhans — arginine — dependence and relationship to insulin secretion , 2004, Diabetologia.

[4]  T. Flotte,et al.  Adeno-associated virus vector-mediated IL-10 gene delivery prevents type 1 diabetes in NOD mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[5]  D. Eizirik,et al.  Inhibition of cytokine-induced NF-kappaB activation by adenovirus-mediated expression of a NF-kappaB super-repressor prevents beta-cell apoptosis. , 2001, Diabetes.

[6]  E. Ho,et al.  Administration of NF‐κB decoy inhibits pancreatic activation of NF‐κB and prevents diabetogenesis by alloxan in mice , 2001 .

[7]  C. Szabó,et al.  An inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite prevents diabetes development in NOD mice. , 2001, Journal of autoimmunity.

[8]  M. Kruhøffer,et al.  Identification of novel cytokine-induced genes in pancreatic beta-cells by high-density oligonucleotide arrays. , 2001, Diabetes.

[9]  A. Andersson,et al.  Cytokine-induced inhibition of insulin release from mouse pancreatic beta-cells deficient in inducible nitric oxide synthase. , 2001, Biochemical and biophysical research communications.

[10]  K. Murthy,et al.  Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation , 2001, Nature Medicine.

[11]  P. Tak,et al.  NF-κB: a key role in inflammatory diseases , 2001 .

[12]  R. Munday,et al.  Relative importance of transport and alkylation for pancreatic beta-cell toxicity of streptozotocin , 2000, Diabetologia.

[13]  M. Trucco,et al.  Protection of Human Islets from the Effects of Interleukin-1β by Adenoviral Gene Transfer of an IκB Repressor* , 2000, The Journal of Biological Chemistry.

[14]  I. Wicks,et al.  Distinct roles for the NF-kappaB1 (p50) and c-Rel transcription factors in inflammatory arthritis. , 2000, The Journal of clinical investigation.

[15]  P. Baeuerle,et al.  Recent advances torwards understanding redox mechanisms in the activation of nuclear factor κb , 2000 .

[16]  C. Berne,et al.  Beta-cell Activity and Destruction in Type 1 Diabetes , 2000, Upsala journal of medical sciences.

[17]  M. Karin,et al.  Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. , 2000, Annual review of immunology.

[18]  Y. Kaneda,et al.  Suppressed severity of collagen-induced arthritis by in vivo transfection of nuclear factor kappaB decoy oligodeoxynucleotides as a gene therapy. , 1999, Arthritis and rheumatism.

[19]  B. Hilliard,et al.  Experimental autoimmune encephalomyelitis in NF-kappa B-deficient mice:roles of NF-kappa B in the activation and differentiation of autoreactive T cells. , 1999, Journal of immunology.

[20]  G. Haskó,et al.  IL‐12 as a therapeutic target for pharmacological modulation in immune‐mediated and inflammatory diseases: regulation of T helper 1/T helper 2 responses , 1999, British journal of pharmacology.

[21]  B. Tyrberg,et al.  Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes. , 1999, Diabetes.

[22]  N. Sarvetnick,et al.  Islet-specific Th1, but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes. , 1999, Journal of immunology.

[23]  L. Bouwens,et al.  Contribution of ductal cells to cytokine responses by human pancreatic islets. , 1999, Diabetes.

[24]  Xianglin Shi,et al.  New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. , 1999, Clinical chemistry.

[25]  W. Suarez-Pinzon,et al.  Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. , 1998, Biochemical pharmacology.

[26]  H. Jun,et al.  Cellular and molecular mechanisms for the initiation and progression of beta cell destruction resulting from the collaboration between macrophages and T cells. , 1998, Autoimmunity.

[27]  M J May,et al.  NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. , 1998, Annual review of immunology.

[28]  J. Mabley,et al.  Insulin‐like growth factor I reverses interleukin‐1β inhibition of insulin secretion, induction of nitric oxide synthase and cytokine‐mediated apoptosis in rat islets of Langerhans , 1997 .

[29]  H. Kolb,et al.  Suppression of cyclophosphamide induced diabetes development and pancreatic Th1 reactivity in NOD mice treated with the interleukin (IL)-12 antagonist IL-12(p40)2 , 1997, Diabetologia.

[30]  M. Karin,et al.  Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. , 1997, The New England journal of medicine.

[31]  K. Kröncke,et al.  Endothelial cells as cytotoxic effector cells: cytokine-activated rat islet endothelial cells lyse syngeneic islet cells via nitric oxide , 1997, Diabetologia.

[32]  M. Neurath,et al.  Local administration of antisense phosphorothiate olignucleotides to the p65 subunit of NF–κB abrogates established experimental colitis in mice , 1996, Nature Medicine.

[33]  J. Hiscott,et al.  Biological and biochemical inhibitors of the NF-κB/Rel proteins and cytokine synthesis , 1996 .

[34]  N. Welsh,et al.  Cytokines activate the nuclear factor κB (NF‐κB) and induce nitric oxide production in human pancreatic islets , 1996 .

[35]  J. Cunningham,et al.  Comparison of inhibition of glucose-stimulated insulin secretion in rat islets of Langerhans by streptozotocin and methyl and ethyl nitrosoureas and methanesulphonates. Lack of correlation with nitric oxide-releasing or O6-alkylating ability. , 1995, Biochemical pharmacology.

[36]  David Baltimore,et al.  Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses , 1995, Cell.

[37]  M. Modolell,et al.  Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone-marrow-derived macrophages. , 1995, Biochemical and biophysical research communications.

[38]  D. Carvajal,et al.  Mouse interleukin‐12 (IL‐12) p40 homodimer: a potent IL‐12 antagonist , 1995, European journal of immunology.

[39]  G. Trinchieri,et al.  Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. , 1994, Blood.

[40]  C. Newgard,et al.  STZ Transport and Cytotoxicity: Specific Enhancement in GLUT2-Expressing Cells , 1994, Diabetes.

[41]  N. Sarvetnick,et al.  Production of interleukin 10 by islet cells accelerates immune-mediated destruction of beta cells in nonobese diabetic mice , 1994, The Journal of experimental medicine.

[42]  M. Mcdaniel,et al.  Biochemical evidence for nitric oxide formation from streptozotocin in isolated pancreatic islets. , 1993, Biochemical and biophysical research communications.

[43]  Kentaro Yamada,et al.  Nitric Oxide and Nitric Oxide Synthase mRNA Induction in Mouse Islet Cells by Interferon-γ Plus Tumor Necrosis Factor-α , 1993 .

[44]  Susanne A. Fischer,et al.  The interleukin‐12 subunit p40 specifically inhibits effects of the interleukin‐12 heterodimer , 1993, European journal of immunology.

[45]  M. Mcdaniel,et al.  Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[46]  S. Moncada,et al.  Interleukin-10 (IL-10) inhibits the induction of nitric oxide synthase by interferon-gamma in murine macrophages. , 1992, Biochemical and biophysical research communications.

[47]  I. Green,et al.  Inhibition of insulin secretion by interleukin‐1β and tumour necrosis factor‐α via an L‐arginine‐dependent nitric oxide generating mechanism , 1990 .

[48]  H. Kolb,et al.  Mouse models of insulin dependent diabetes: low-dose streptozocin-induced diabetes and nonobese diabetic (NOD) mice. , 1987, Diabetes/metabolism reviews.

[49]  S. Tannenbaum,et al.  Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. , 1982, Analytical biochemistry.

[50]  S. Marklund,et al.  Superoxide dismutase is a prophylactic against alloxan diabetes , 1981, Nature.

[51]  A. Rossini,et al.  Complete protection from low-dose streptozotocin-induced diabetes in mice , 1978, Nature.

[52]  A. Rossini,et al.  Streptozotocin-induced pancreatic insulitis in mice. Morphologic and physiologic studies. , 1978, Laboratory investigation; a journal of technical methods and pathology.

[53]  A. Rossini,et al.  Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. , 1976, Science.

[54]  G. Gey,et al.  The Maintenance of Human Normal Cells and Tumor Cells in Continuous Culture: I. Preliminary Report: Cultivation of Mesoblastic Tumors and Normal Tissue and Notes on Methods of Cultivation , 1936 .