p53 up-regulated modulator of apoptosis (PUMA) activation contributes to pancreatic beta-cell apoptosis induced by proinflammatory cytokines and endoplasmic reticulum stress.
Type 1 diabetes is an autoimmune disorder characterized by chronic inflammation and pancreatic beta-cell loss. Here, we demonstrate that the proinflammatory cytokine interleukin-1beta, combined with interferon-gamma, induces the expression of the Bcl-2 homology 3 (BH3)-only activator PUMA (p53 up-regulated modulator of apoptosis) in beta-cells. Transcriptional activation of PUMA is regulated by nuclear factor-kappaB and endoplasmic reticulum stress but is independent of p53. PUMA activation leads to mitochondrial Bax translocation, cytochrome c release, and caspase-3 cleavage resulting in beta-cell demise. The antiapoptotic Bcl-XL protein is localized mainly at the mitochondria of the beta-cells and antagonizes PUMA action, but Bcl-XL is inactivated by the BH3-only sensitizer DP5/Hrk in cytokine-exposed beta-cells. Moreover, a pharmacological mimic of the BH3-only sensitizer Bad, which inhibits Bcl-XL and Bcl-2, induces PUMA-dependent beta-cell death and potentiates cytokine-induced apoptosis. Our data support a hierarchical activation of BH3-only proteins controlling the intrinsic pathway of beta-cell apoptosis in the context of inflammation and type 1 diabetes.
Gurzov
Esteban N
EN
Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808, CP-618, 1070 Brussels, Belgium. egurzov@ulb.ac.be
Germano
Carla M
CM
Cunha
Daniel A
DA
Ortis
Fernanda
F
Vanderwinden
Jean-Marie
JM
Marchetti
Piero
P
Zhang
Lin
L
Eizirik
Decio L
DL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C533952:Bbc3 protein, rat; D001713:Biphenyl Compounds; D016207:Cytokines; D053583:Interleukin-1beta; D016328:NF-kappa B; D009596:Nitrophenols; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D013449:Sulfonamides; D051020:bcl-X Protein; D007371:Interferon-gamma