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Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice.

Chronic pancreatitis is an inflammatory disease that causes progressive destruction of pancreatic acinar cells and, ultimately, loss of pancreatic function. We investigated the role of IκB kinase α (IKKα) in pancreatic homeostasis. Pancreas-specific ablation of IKKα (Ikkα(Δpan)) caused spontaneous and progressive acinar cell vacuolization and death, interstitial fibrosis, inflammation, and circulatory release of pancreatic enzymes, clinical signs resembling those of human chronic pancreatitis. Loss of pancreatic IKKα causes defective autophagic protein degradation, leading to accumulation of p62-mediated protein aggregates and enhanced oxidative and ER stress in acinar cells, but none of these effects is related to NF-κB. Pancreas-specific p62 ablation prevented ER and oxidative stresses and attenuated pancreatitis in Ikkα(Δpan) mice, suggesting that cellular stress induced by p62 aggregates promotes development of pancreatitis. Importantly, downregulation of IKKα and accumulation of p62 aggregates were also observed in chronic human pancreatitis. Our studies demonstrate that IKKα, which may control autophagic protein degradation through its interaction with ATG16L2, plays a critical role in maintaining pancreatic acinar cell homeostasis, whose dysregulation promotes pancreatitis through p62 aggregate accumulation.

Pubmed ID: 23563314 RIS Download

Mesh terms: Acinar Cells | Animals | Autophagy | Carrier Proteins | Cell Proliferation | Down-Regulation | Endoplasmic Reticulum | Fibrosis | Gene Expression Regulation, Enzymologic | I-kappa B Kinase | Immunohistochemistry | Inflammation | Mice | Mice, Transgenic | NF-kappa B | Oxidative Stress | Pancreatitis | Transcription Factors

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Associated grants

  • Agency: NIDDK NIH HHS, Id: R01 DK088107
  • Agency: NIAID NIH HHS, Id: AI043477
  • Agency: NIAID NIH HHS, Id: R01 AI072581
  • Agency: NCI NIH HHS, Id: CA163798
  • Agency: NIAAA NIH HHS, Id: R01 AA019730
  • Agency: NCI NIH HHS, Id: R01 CA132847
  • Agency: NCI NIH HHS, Id: CA167120
  • Agency: NIAAA NIH HHS, Id: P50 AA011999
  • Agency: NCI NIH HHS, Id: R01 CA163798
  • Agency: NCI NIH HHS, Id: R03 CA167120
  • Agency: NIAID NIH HHS, Id: R01 AI043477
  • Agency: NCI NIH HHS, Id: R01 CA134530

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