SOCS-1 protects from virally-induced CD8 T cell mediated type 1 diabetes☆

Barral, Ana Marı́a; Thomas, Helen E.; Ling, Eleanor M.; Darwiche, Rima; Rodrigo, Evelyn; Christen, Urs; Ejrnæs, Mette; Wolfe, Tom; Kay, Thomas; Herrath, Matthias G. von

doi:10.1016/j.jaut.2006.08.002

Cited by 32 publications

(29 citation statements)

References 33 publications

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“…Several observations have led to the suggestion that pro-inflammatory cytokines secreted by macrophages and T lymphocytes infiltrating the pancreatic islets may contribute to the development of type 1 diabetes. Recent studies by us and others have provided further support for the hypothesis that cytokines contribute to type 1 diabetes by acting directly on the beta cells [3][4][5][6].…”

Section: Introductionmentioning

confidence: 77%

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

Zaitseva

Hultcrantz

Sharoyko

et al. 2009

Cell. Mol. Life Sci.

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Pancreatic beta cell damage caused by proinflammatory cytokines interleukin-1beta (IL-1beta), interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) is a key event in the pathogenesis of type 1 diabetes. The suppressor of cytokine signaling-1 (SOCS-1) blocks IFNgamma-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-1beta, IFNgamma, TNFalpha. 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 IFNgamma in beta cells. In summary, we show that interference with IFNgamma signal transduction pathways by SOCS-1 inhibits cytokine-stimulated pancreatic beta cell death.

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Section: Introductionmentioning

confidence: 77%

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

Zaitseva

Hultcrantz

Sharoyko

et al. 2009

Cell. Mol. Life Sci.

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“…38 Different studies demonstrated that inhibition of SOCS expression leading to sustained STAT activation contributes to the progression of chronic inflammatory diseases. 18,20,36,39 -41 By contrast, transgenic expression of SOCS1 in ␤ cells protects from T cellmediated damage in diabetic mice, 42 whereas adenovirus-mediated SOCS expression reduces arthritis 15,34,43 and innate immune responses. 44 Recently, a mimetic peptide containing the kinase inhibitory region of SOCS1 was proven to effectively protect against virus infection.…”

Section: Basic Research Wwwjasnorgmentioning

confidence: 99%

Suppressors of Cytokine Signaling Abrogate Diabetic Nephropathy

Ortiz-Muñoz¹,

López-Parra²,

López-Franco³

et al. 2010

Journal of the American Society of Nephrology

161

145

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Activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) is an important mechanism by which hyperglycemia contributes to renal damage, suggesting that modulation of this pathway may prevent renal and vascular complications of diabetes. Here, we investigated the involvement of suppressors of cytokine signaling (SOCS) as intracellular negative regulators of JAK/STAT activation in diabetic nephropathy. In a rat model, inducing diabetes resulted in JAK/STAT activation and increased expression of SOCS1 and SOCS3. In humans, we observed increased expression of glomerular and tubulointerstitial SOCS proteins in biopsies of patients with diabetic nephropathy. In vitro, high concentrations of glucose activated JAK/STAT/SOCS in human mesangial and tubular cells. Overexpression of SOCS reversed the glucose-induced activation of the JAK/STAT pathway, expression of STATdependent genes (chemokines, growth factors, and extracellular matrix proteins), and cell proliferation. In vivo, intrarenal delivery of adenovirus expressing SOCS1 and SOCS3 to diabetic rats significantly improved renal function and reduced renal lesions associated with diabetes, such as mesangial expansion, fibrosis, and influx of macrophages. SOCS gene delivery also decreased the activation of STAT1 and STAT3 and the expression of proinflammatory and profibrotic proteins in the diabetic kidney. In summary, these results provide direct evidence for a link between the JAK/STAT/SOCS axis and hyperglycemia-induced cell responses in the kidney. Suppression of the JAK/STAT pathway by increasing intracellular SOCS proteins may have therapeutic potential in diabetic nephropathy.

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“…Using a number of different model systems, the killing mechanisms used by diabetogenic CTL have been studied in vitro in conventional 51 Cr release assays. Overall the results suggest that when non-b-cell targets are used in vitro, CTL can effectively use either the perforin or Fas/FasL pathways to kill.…”

Section: Cells Recognize B-cells Through Class I Mhc-t Cell Receptor mentioning

confidence: 99%

“…However, perforin is not the only player, because LCMV-GP mice deficient in IFNg, lacking functional IFNg receptors on b-cells, or overexpressing SOCS-1 in b-cells also do not develop diabetes, suggesting an important role for IFNg. [51][52][53] In an effort to elucidate the killing pathways used by human CTL to kill human islets, we devised a model system using CTL specific for viral peptides and human islets loaded with specific peptide. We used HLA-A2-restricted CTL specific for the matrix peptide of influenza virus, and HLA-B8-restricted Epstein-Barr virus-specific CTL.…”

Section: Cells Recognize B-cells Through Class I Mhc-t Cell Receptor mentioning

confidence: 99%

The role of perforin and granzymes in diabetes

2009

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Type 1 diabetes results from autoimmune destruction of pancreatic b-cells by CD8 þ T cells. The requirement for CD8 þ T cells implicates perforin and granzymes as effectors of tissue destruction. Diabetogenic cytotoxic T cells kill b-cells by the perforin/ granzyme pathway in vitro. In the non-obese diabetic mouse model of type I diabetes, perforin deficiency results in a highly significant reduction in disease, indicating a direct role for perforin in b-cell death in vivo, although other cell death pathways must account for the residual diabetes in perforin-deficient mice. Perforin and granzyme B are also important in allogeneic destruction of islets. The dominant role of the perforin/granzyme pathway in b-cell destruction in type I diabetes and allogeneic islet graft rejection make this pathway an important target for blockade in future therapies for type I diabetes. In addition, granzymes have a newly recognized role in inflammation, a feature of both type I and II diabetes, suggesting their role should be further explored in both the common forms of diabetes.

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SOCS-1 protects from virally-induced CD8 T cell mediated type 1 diabetes☆

Cited by 32 publications

References 33 publications

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

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

Suppressors of Cytokine Signaling Abrogate Diabetic Nephropathy

The role of perforin and granzymes in diabetes

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