Signaling by IL-1beta+IFN-gamma and ER stress converge on DP5/Hrk activation: a novel mechanism for pancreatic beta-cell apoptosis.
Chronic inflammation and pro-inflammatory cytokines are important mediators of pancreatic beta-cell destruction in type 1 diabetes (T1D). We presently show that the cytokines IL-1beta+IFN-gamma and different ER stressors activate the Bcl-2 homology 3 (BH3)-only member death protein 5 (DP5)/harakiri (Hrk) resulting in beta-cell apoptosis. Chemical ER stress-induced DP5 upregulation is JNK/c-Jun-dependent. DP5 activation by cytokines also involves JNK/c-Jun phosphorylation and is antagonized by JunB. Interestingly, cytokine-inducted DP5 expression precedes ER stress: mitochondrial release of cytochrome c and ER stress are actually a consequence of enhanced DP5 activation by cytokine-mediated nitric oxide formation. Our findings show that DP5 is central for beta-cell apoptosis after different stimuli, and that it can act up- and downstream of ER stress. These observations contribute to solve two important questions, namely the mechanism by which IL-1beta+IFN-gamma induce beta-cell death and the nature of the downstream signals by which ER stress 'convinces' beta-cells to trigger apoptosis.
Gurzov
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EN
Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Brussels, Belgium. egurzov@ulb.ac.be
Ortis
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Cunha
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Gosset
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G
Li
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Cardozo
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Eizirik
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D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; C484585:Hrk protein, rat; D053583:Interleukin-1beta; D009479:Neuropeptides; D034741:RNA, Small Interfering; D007371:Interferon-gamma; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases