| First Author | Li N | Year | 2013 |
| Journal | J Clin Invest | Volume | 123 |
| Issue | 5 | Pages | 2231-43 |
| PubMed ID | 23563314 | Mgi Jnum | J:201459 |
| Mgi Id | MGI:5514127 | Doi | 10.1172/JCI64498 |
| Citation | Li N, et al. (2013) Loss of acinar cell IKKalpha triggers spontaneous pancreatitis in mice. J Clin Invest 123(5):2231-43 |
| abstractText | 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. |
