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Am J Physiol Gastrointest Liver Physiol. 2016 Sep 1;311(3):G548-60. doi: 10.1152/ajpgi.00047.2016. Epub 2016 Aug 11.

Legumain is activated in macrophages during pancreatitis.

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Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia;
Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany;
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida;
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York;
Department of Pathology, Stanford University School of Medicine, Stanford, California;
Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud UMC, Nijmegen, The Netherlands;
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia;
Laboratory for Turbulence Research in Aerospace and Combustion, Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, Victoria, Australia;
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia;
Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany;
Department of Anatomy and Neuroscience, University of Melbourne and Florey Institute of Neuroscience and Mental Health, Parkville, Victoria Australia;
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia; and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Victoria, Australia.


Pancreatitis is an inflammatory disease of the pancreas characterized by dysregulated activity of digestive enzymes, necrosis, immune infiltration, and pain. Repeated incidence of pancreatitis is an important risk factor for pancreatic cancer. Legumain, a lysosomal cysteine protease, has been linked to inflammatory diseases such as atherosclerosis, stroke, and cancer. Until now, legumain activation has not been studied during pancreatitis. We used a fluorescently quenched activity-based probe to assess legumain activation during caerulein-induced pancreatitis in mice. We detected activated legumain by ex vivo imaging, confocal microscopy, and gel electrophoresis. Compared with healthy controls, legumain activity in the pancreas of caerulein-treated mice was increased in a time-dependent manner. Legumain was localized to CD68(+) macrophages and was not active in pancreatic acinar cells. Using a small-molecule inhibitor of legumain, we found that this protease is not essential for the initiation of pancreatitis. However, it may serve as a biomarker of disease, since patients with chronic pancreatitis show strongly increased legumain expression in macrophages. Moreover, the occurrence of legumain-expressing macrophages in regions of acinar-to-ductal metaplasia suggests that this protease may influence reprogramming events that lead to inflammation-induced pancreatic cancer.


activity-based probe; biomarker; cysteine cathepsin; inflammation; legumain; macrophage; pancreas; pancreatic cancer; pancreatitis

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