Cytokines Tumor Necrosis Factor-α and Interferon-γ Induce Pancreatic β-Cell Apoptosis through STAT1-mediated Bim Protein Activation

被引：97

作者：

Barthson, Jenny ^{[1
]}

Germano, Carla M. ^{[1
]}

Moore, Fabrice ^{[1
]}

Maida, Adriano ^{[2
]}

Drucker, Daniel J. ^{[2
]}

Marchetti, Piero ^{[4
]}

Gysemans, Conny ^{[5
]}

Mathieu, Chantal ^{[5
]}

Nunez, Gabriel ^{[6
]}

Jurisicova, Andrea ^{[3
]}

Eizirik, Decio L.

Gurzov, Esteban N. ^{[1
]}

机构：

[1] Univ Libre Bruxelles, Expt Med Lab, B-1070 Brussels, Belgium

[2] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Med, Toronto, ON M5G 1X5, Canada

[3] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Obstet & Gynecol, Toronto, ON M5G 1X5, Canada

[4] Univ Pisa, Dept Endocrinol & Metab, Metab Unit, I-56126 Pisa, Italy

[5] Katholieke Univ Leuven, Dept Expt Med Endocrinol, Fac Med, B-3000 Louvain, Belgium

[6] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2011年 / 286卷 / 45期

关键词：

ENDOPLASMIC-RETICULUM STRESS; SIGNAL TRANSDUCER; FAMILY-MEMBER; ER STRESS; DEATH; BCL-2; ISLETS; PUMA; GENE; BAX;

D O I：

10.1074/jbc.M111.253591

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Type 1 diabetes is characterized by local inflammation (insulitis) in the pancreatic islets causing beta-cell loss. The mitochondrial pathway of apoptosis is regulated by the balance and interaction between Bcl-2 members. Here we clarify the molecular mechanism of beta-cell death triggered by the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. The combination of TNF-alpha + IFN-gamma induced DP5, p53 up-regulated modulator of apoptosis (PUMA), and Bim expression in human islets and rodent beta-cells. DP5 and PUMA inactivation by RNA interference partially protected against TNF-alpha + IFN-gamma-induced beta-cell apoptosis. DP5 knock-out mice had increased beta-cell area, and isolated islets from these mice were resistant to cytokine exposure. Bim expression was transcriptionally regulated by STAT1, and its activation triggered cleavage of caspases. Silencing of Bim protected rodent and human beta-cells to a large extent against TNF-alpha + IFN-gamma, indicating a major role of this BH3-only activator protein in the mechanism of apoptosis. Our data support a highly regulated and context-dependent modulation of specific Bcl-2 members controlling the mitochondrial pathway of beta-cell apoptosis during insulitis.

引用

页码：39632 / 39643

页数：12

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