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- Cardozo, AK, et al.
(författare)
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Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells
- 2005
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 54:2, s. 452-461
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Tidskriftsartikel (refereegranskat)abstract
- Cytokines and free radicals are mediators of β-cell death in type 1 diabetes. Under in vitro conditions, interleukin-1β (IL-1β) + γ-interferon (IFN-γ) induce nitric oxide (NO) production and apoptosis in rodent and human pancreatic β-cells. We have previously shown, by microarray analysis of primary β-cells, that IL-1β + IFN-γ decrease expression of the mRNA encoding for the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b (SERCA2b) while inducing expression of the endoplasmic reticulum stress–related and proapoptotic gene CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein). In the present study we show that cytokine-induced apoptosis and necrosis in primary rat β-cells and INS-1E cells largely depends on NO production. IL-1β + IFN-γ, via NO synthesis, markedly decreased SERCA2b protein expression and depleted ER Ca2+ stores. Of note, β-cells showed marked sensitivity to apoptosis induced by SERCA blockers, as compared with fibroblasts. Cytokine-induced ER Ca2+ depletion was paralleled by an NO-dependent induction of CHOP protein and activation of diverse components of the ER stress response, including activation of inositol-requiring ER-to-nucleus signal kinase 1α (IRE1α) and PRK (RNA-dependent protein kinase)-like ER kinase (PERK)/activating transcription factor 4 (ATF4), but not ATF6. In contrast, the ER stress–inducing agent thapsigargin triggered these four pathways in parallel. In conclusion, our results suggest that the IL-1β + IFN-γ–induced decrease in SERCA2b expression, with subsequent depletion of ER Ca2+ and activation of the ER stress pathway, is a potential contributory mechanism to β-cell death.
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| 2. |
- Rønn, SG, et al.
(författare)
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Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:10, s. 1873-1882
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis The pro-inflammatory cytokines IL-1 and IFN gamma are critical molecules in immune-mediated beta cell destruction leading to type 1 diabetes mellitus. Suppressor of cytokine signalling (SOCS)-3 inhibits the cytokine-mediated destruction of insulinoma-1 cells. Here we investigate the effect of SOCS3 in primary rodent beta cells and diabetic animal models. Methods Using mice with beta cell-specific Socs3 expression and a Socs3-encoding adenovirus construct, we characterised the protective effect of SOCS3 in mouse and rat islets subjected to cytokine stimulation. In transplantation studies of NOD mice and alloxan-treated mice the survival of Socs3 transgenic islets was investigated. Results Socs3 transgenic islets showed significant resistance to cytokine-induced apoptosis and impaired insulin release. Neither glucose-stimulated insulin release, insulin content or glucose oxidation were affected by SOCS3. Rat islet cultures transduced with Socs3-adenovirus displayed reduced cytokine-induced nitric oxide and apoptosis associated with inhibition of the IL-1-induced nuclear factor-kappa B and mitogen-activated protein kinase (MAPK) pathways. Transplanted Socs3 transgenic islets were not protected in diabetic NOD mice, but showed a prolonged graft survival when transplanted into diabetic allogenic BALB/c mice. Conclusions/interpretation SOCS3 inhibits IL-1-induced signalling through the nuclear factor-kappa B and MAPK pathways and apoptosis induced by cytokines in primary beta cells. Moreover, Socs3 transgenic islets are protected in an allogenic transplantation model. SOCS3 may represent a target for pharmacological or genetic engineering in islet transplantation for treatment of type 1 diabetes mellitus.
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