期刊
CELL DEATH AND DIFFERENTIATION
卷 20, 期 12, 页码 1742-1752出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2013.134
关键词
gap junctions; Connexin36; cytokines; apoptosis; AMPK; pancreatic beta-cells
资金
- SNF [31003A-138528, 310030_141162, CR32I3_129987]
- JDRF [40-2011-11, 5-2012-281, 1-2011-589]
- EU [BETAIMAGE 222980]
- IMIDIA [C2008-T7]
- NIH [HL64232]
- Novartis Foundation
- Emma Muschamp Foundation, FNRS-MIS-Belgium [F.4521.11]
- [BETATRAIN 289932]
Cell-to-cell communication mediated by gap junctions made of Connexin36 (Cx36) contributes to pancreatic beta-cell function. We have recently demonstrated that Cx36 also supports b-cell survival by a still unclear mechanism. Using specific Cx36 siRNAs or adenoviral vectors, we now show that Cx36 downregulation promotes apoptosis in INS-1E cells exposed to the pro-inflammatory cytokines (IL-1 beta, TNF-alpha and IFN-gamma) involved at the onset of type 1 diabetes, whereas Cx36 overexpression protects against this effect. Cx36 overexpression also protects INS-1E cells against endoplasmic reticulum (ER) stress-mediated apoptosis, and alleviates the cytokine-induced production of reactive oxygen species, the depletion of the ER Ca2+ stores, the CHOP overexpression and the degradation of the anti-apoptotic protein Bcl-2 and Mcl-1. We further show that cytokines activate the AMP-dependent protein kinase (AMPK) in a NO-dependent and ER-stress-dependent manner and that AMPK inhibits Cx36 expression. Altogether, the data suggest that Cx36 is involved in Ca2+ homeostasis within the ER and that Cx36 expression is downregulated following ER stress and subsequent AMPK activation. As a result, cytokine-induced Cx36 downregulation elicits a positive feedback loop that amplifies ER stress and AMPK activation, leading to further Cx36 downregulation. The data reveal that Cx36 plays a central role in the oxidative stress and ER stress induced by cytokines and the subsequent regulation of AMPK activity, which in turn controls Cx36 expression and mitochondria-dependent apoptosis of insulin-producing cells.
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