Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice.

TitleLoss of acinar cell IKKα triggers spontaneous pancreatitis in mice.
Publication TypeJournal Article
Year of Publication2013
AuthorsLi N, Wu X, Holzer RG, Lee J-H, Todoric J, Park E-J, Ogata H, Gukovskaya AS, Gukovsky I, Pizzo DP, VandenBerg S, Tarin D, Atay C, Arkan MC, Deerinck TJ, Moscat J, Diaz-Meco M, Dawson D, Erkan M, Kleeff J, Karin M
JournalJ Clin Invest
Volume123
Issue5
Pagination2231-43
Date Published2013 May
ISSN1558-8238
KeywordsAcinar 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 Factor TFIIH, Transcription Factors
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 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.

DOI10.1172/JCI64498
Alternate JournalJ Clin Invest
PubMed ID23563314
Grant ListAI043477 / AI / NIAID NIH HHS / United States
CA163798 / CA / NCI NIH HHS / United States
CA167120 / CA / NCI NIH HHS / United States
Related Faculty: 
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.

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