title: Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice.
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.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, UCSD, La Jolla, California 92093-0723, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Holzer
authors.forename: Jun-Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Jelena
authors.initials: J
authors.lastname: Todoric
authors.forename: Eek-Joong
authors.initials: EJ
authors.lastname: Park
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Ogata
authors.forename: Anna S
authors.initials: AS
authors.lastname: Gukovskaya
authors.forename: Ilya
authors.initials: I
authors.lastname: Gukovsky
authors.forename: Donald P
authors.initials: DP
authors.lastname: Pizzo
authors.forename: Scott
authors.initials: S
authors.lastname: VandenBerg
authors.forename: David
authors.initials: D
authors.lastname: Tarin
authors.forename: Ciǧdem
authors.initials: C
authors.lastname: Atay
authors.forename: Melek C
authors.initials: MC
authors.lastname: Arkan
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Deerinck
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Maria
authors.initials: M
authors.lastname: Diaz-Meco
authors.forename: David
authors.initials: D
authors.lastname: Dawson
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D061354:Acinar Cells / Q000166:cytology*; D000818:Animals; D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic; D051550:I-kappa B Kinase / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D010195:Pancreatitis / Q000378:metabolism*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C572696:Atg16L2 protein, mouse; D002352:Carrier Proteins; C490981:Gtf2h1 protein, mouse; D016328:NF-kappa B; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D051550:I-kappa B Kinase
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