Projects per year
Abstract
Pancre-atitis 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 caeruleintreated 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.
Original language | English |
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Pages (from-to) | G548-G560 |
Number of pages | 13 |
Journal | American Journal of Physiology: Gastrointestinal and Liver Physiology |
Volume | 311 |
Issue number | 3 |
DOIs | |
Publication status | Published - Sept 2016 |
Keywords
- Activity-based probe
- Biomarker
- Cysteine cathepsin
- Inflammation
- Legumain
- Macrophage
- Pancreas
- Pancreatic cancer
- Pancreatitis
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ARC Centre of Excellence in Convergent Bio-Nano Science and Technology
Davis, T., Boyd, B., Bunnett, N., Porter, C., Caruso, F., Kent, S., Thordarson, P., Kearnes, M., Gooding, J., Kavallaris, M., Thurecht, K., Whittaker, A. K., Parton, R., Corrie, S. R., Johnston, A., McGhee, J., Greguric, I. D., Stevens, M. M., Lewis, J. S., Lee, D. S., Alexander, C., Dawson, K., Hawker, C., Haddleton, D., Thierry, B., Prestidge, C. A., Meyer, A., Jones-Jayasinghe, N., Voelcker, N., Nann, T. & McLean, K.
Australian Research Council (ARC), Monash University, University of Melbourne, University of New South Wales (UNSW), University of Queensland , University of South Australia, Monash University – Internal Faculty Contribution, University of Wisconsin Madison, Memorial Sloan Kettering Cancer Center, University of California System, University College Dublin, Imperial College London, University of Warwick, SungKyunKwan University, Australian Nuclear Science and Technology Organisation (ANSTO) , University of Nottingham
30/06/14 → 29/06/21
Project: Research
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Contribution of MDSC-derived cysteine cathespins in breast cancer metastasis to bone
Edgington-Mitchell, L.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/15 → 31/12/17
Project: Research