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Cytokines downregul...
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
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Cardozo, AK (författare)
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Ortis, F (författare)
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Storling, J (författare)
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Feng, YM (författare)
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Rasschaert, J (författare)
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Tonnesen, M (författare)
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Van Eylen, F (författare)
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Mandrup-Poulsen, T (författare)
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Herchuez, A (författare)
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Eizirik, DL (författare)
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- American Diabetes Association, 2005
- 2005
- Engelska.
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 54:2, s. 452-461
- Relaterad länk:
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http://diabetes.diab...
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http://kipublication...
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https://doi.org/10.2...
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Abstract
Ämnesord
Stäng
- 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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- art (ämneskategori)
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Diabetes
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- Av författaren/redakt...
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Cardozo, AK
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Ortis, F
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Storling, J
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Feng, YM
-
Rasschaert, J
-
Tonnesen, M
-
visa fler...
-
Van Eylen, F
-
Mandrup-Poulsen, ...
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Herchuez, A
-
Eizirik, DL
-
visa färre...
- Artiklar i publikationen
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Diabetes
- Av lärosätet
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Karolinska Institutet