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Disruption of the gamma-interferon signaling pathway at the level of signal transducer and activator of transcription-1 prevents immune destruction of beta-cells

(2005) DIABETES. 54(8). p.2396-2403
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Abstract
beta-Cells under immune attack are destroyed by the aberrant activation of key intracellular signaling cascades. The aim of the present study was to evaluate the contribution of the signal transducer and activator of transcription (STAT)-1 pathway for R-cell apoptosis by studying the sensitivity of beta-cells from STAT-1 knockout (-/-) mice to immune-mediated cell death in vitro and in vivo. Whole islets from STAT-1(-/-) mice were completely resistant to interferon (IFN)-gamma (studied in combination with interleukin [IL]-1 beta)-mediated cell death (92 +/- 4 % viable cells in STAT-1(-/-) mice vs. 56 +/- 3 % viable cells in wild-type controls, P <= 0.001) and had preserved insulin release after exposure to IL-1 beta and IFN-gamma. Moreover, analysis of cell death in cytokine-exposed purified beta-cells confirmed that protection was due to absence of STAT-1 in the beta-cells themselves. Deficiency of STAT-1 in islets completely prevented cytokine-induced upregulation of IL-15, interferon inducible protein 10, and inducible nitric oxide synthase transcription but did not interfere with monocyte chemoattractant protein I and macrophage inflammatory protein 3 alpha expression. In vivo, STAT-1(-/-) mice were partially resistant to development of diabetes after multiple low-dose streptozotocin injections as reflected by mean blood glucose at 12 days after first injection (159 +/- 28 vs. 283 +/- 81 mg1dI in wild-type controls, P <= 0.05) and diabetes incidence at the end of the follow-up period (39 vs. 73 % in wild-type controls, P <= 0.05). In conclusion, the present results indicate that STAT-1 is a crucial transcription factor in the process of IFN-gamma-mediated beta-cell death and the subsequent development of immune-mediated diabetes.
Keywords
PREDIABETIC NOD MICE, REGULATORY FACTOR-I, NF-KAPPA-B, IFN-GAMMA, ISLET CELLS, CYTOKINE SIGNALING-1, GENE-TRANSCRIPTION, PANCREATIC-ISLETS, MESSENGER-RNA, EXPRESSION

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MLA
Gysemans, Conny A et al. “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 54.8 (2005): 2396–2403. Print.
APA
Gysemans, C. A., Ladrière, L., Callewaert, H., Rasschaert, J., Flamez, D., Levy, D. E., Matthys, P., et al. (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(8), 2396–2403.
Chicago author-date
Gysemans, Conny A, Laurence Ladrière, Hanne Callewaert, Joanne Rasschaert, Daisy Flamez, David E Levy, Patrick Matthys, Décio L Eizirik, and Chantal Mathieu. 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 (8): 2396–2403.
Chicago author-date (all authors)
Gysemans, Conny A, Laurence Ladrière, Hanne Callewaert, Joanne Rasschaert, Daisy Flamez, David E Levy, Patrick Matthys, Décio L Eizirik, and Chantal Mathieu. 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 (8): 2396–2403.
Vancouver
1.
Gysemans CA, Ladrière L, Callewaert H, Rasschaert J, Flamez D, Levy DE, et al. 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. 2005;54(8):2396–403.
IEEE
[1]
C. A. Gysemans et al., “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, vol. 54, no. 8, pp. 2396–2403, 2005.
@article{847194,
  abstract     = {beta-Cells under immune attack are destroyed by the aberrant activation of key intracellular signaling cascades. The aim of the present study was to evaluate the contribution of the signal transducer and activator of transcription (STAT)-1 pathway for R-cell apoptosis by studying the sensitivity of beta-cells from STAT-1 knockout (-/-) mice to immune-mediated cell death in vitro and in vivo. Whole islets from STAT-1(-/-) mice were completely resistant to interferon (IFN)-gamma (studied in combination with interleukin [IL]-1 beta)-mediated cell death (92 +/- 4 % viable cells in STAT-1(-/-) mice vs. 56 +/- 3 % viable cells in wild-type controls, P <= 0.001) and had preserved insulin release after exposure to IL-1 beta and IFN-gamma. Moreover, analysis of cell death in cytokine-exposed purified beta-cells confirmed that protection was due to absence of STAT-1 in the beta-cells themselves. Deficiency of STAT-1 in islets completely prevented cytokine-induced upregulation of IL-15, interferon inducible protein 10, and inducible nitric oxide synthase transcription but did not interfere with monocyte chemoattractant protein I and macrophage inflammatory protein 3 alpha expression. In vivo, STAT-1(-/-) mice were partially resistant to development of diabetes after multiple low-dose streptozotocin injections as reflected by mean blood glucose at 12 days after first injection (159 +/- 28 vs. 283 +/- 81 mg1dI in wild-type controls, P <= 0.05) and diabetes incidence at the end of the follow-up period (39 vs. 73 % in wild-type controls, P <= 0.05). In conclusion, the present results indicate that STAT-1 is a crucial transcription factor in the process of IFN-gamma-mediated beta-cell death and the subsequent development of immune-mediated diabetes.},
  author       = {Gysemans, Conny A and Ladrière, Laurence and Callewaert, Hanne and Rasschaert, Joanne and Flamez, Daisy and Levy, David E and Matthys, Patrick and Eizirik, Décio L and Mathieu, Chantal},
  issn         = {0012-1797},
  journal      = {DIABETES},
  keywords     = {PREDIABETIC NOD MICE,REGULATORY FACTOR-I,NF-KAPPA-B,IFN-GAMMA,ISLET CELLS,CYTOKINE SIGNALING-1,GENE-TRANSCRIPTION,PANCREATIC-ISLETS,MESSENGER-RNA,EXPRESSION},
  language     = {eng},
  number       = {8},
  pages        = {2396--2403},
  title        = {Disruption of the gamma-interferon signaling pathway at the level of signal transducer and activator of transcription-1 prevents immune destruction of beta-cells},
  url          = {http://dx.doi.org/10.2337/diabetes.54.8.2396},
  volume       = {54},
  year         = {2005},
}

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