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¹ Division of Developmental Genetics, Institute of Molecular Embryology and Genetics, and ² Department of Gastroenterological Surgery, Kumamoto University, Kumamoto 860-0811, Japan
³ Department of Bioscience, Nagahama Institute of Bioscience and Technology, Nagahama, Shiga 526-0829, Japan
⁴ Department of Nutritional Physiology, Institute of Health Biosciences, and ⁵ Division of Enzyme Chemistry, Institute for Enzyme Research, University of Tokushima Graduate School, Tokushima 770-8503, Japan
⁶ Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
⁷ Solution-Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan

Correspondence to Ken-ichi Yamamura: yamamura{at}gpo.kumamoto-u.ac.jp

Autophagy is mostly a nonselective bulk degradation system within cells. Recent reports indicate that autophagy can act both as a protector and killer of the cell depending on the stage of the disease or the surrounding cellular environment (for review see Cuervo, A.M. 2004. Trends Cell Biol. 14:70–77). We found that cytoplasmic vacuoles induced in pancreatic acinar cells by experimental pancreatitis were autophagic in origin, as demonstrated by microtubule-associated protein 1 light chain 3 expression and electron microscopy experiments. To analyze the role of macroautophagy in acute pancreatitis, we produced conditional knockout mice lacking the autophagy-related 5 gene in acinar cells. Acute pancreatitis was not observed, except for very mild edema in a restricted area, in conditional knockout mice. Unexpectedly, trypsinogen activation was greatly reduced in the absence of autophagy. These results suggest that autophagy exerts devastating effects in pancreatic acinar cells by activation of trypsinogen to trypsin in the early stage of acute pancreatitis through delivering trypsinogen to the lysosome.

D. Hashimoto and M. Ohmuraya contributed equally to this paper.

Abbreviations used in this paper: Atg, autophagy related; CCK, cholecystokinin; H&E, hematoxylin and eosin; LC3, light chain 3; TAP, trypsinogen activation peptide.

© 2008 Hashimoto et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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