Pancreatitis

Journal: J Clin Invest

Volume: 123

Issue: 5

Pages: 2231-43

Date: May 1

Short Title: Loss of acinar cell IKKalpha triggers spontaneous pancreatitis in mice

Alternate Journal: The Journal of clinical investigation

ISSN: 1558-8238 (Electronic)

0021-9738 (Linking)

DOI: 10.1172/JCI64498

PMCID: 3635720

Accession Number: 23563314

Keywords: Acinar Cells/*cytology

Animals

Autophagy

Carrier Proteins/metabolism

Cell Proliferation

Down-Regulation

Endoplasmic Reticulum/metabolism

Fibrosis

*Gene Expression Regulation, Enzymologic

I-kappa B Kinase/*metabolism

Immunohistochemistry

Inflammation

Mice

Mice, Transgenic

NF-kappa B/metabolism

Oxidative Stress

Pancreatitis/*metabolism

Transcription Factors/metabolism

Abstract: 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 IkappaB kinase alpha (IKKalpha) in pancreatic homeostasis. Pancreas-specific ablation of IKKalpha (Ikkalpha(Deltapan)) 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 IKKalpha 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-kappaB. Pancreas-specific p62 ablation prevented ER and oxidative stresses and attenuated pancreatitis in Ikkalpha(Deltapan) mice, suggesting that cellular stress induced by p62 aggregates promotes development of pancreatitis. Importantly, downregulation of IKKalpha and accumulation of p62 aggregates were also observed in chronic human pancreatitis. Our studies demonstrate that IKKalpha, 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.

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