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2016 ; 311
(3
): G548-60
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Legumain is activated in macrophages during pancreatitis
#MMPMID27514475
Edgington-Mitchell LE
; Wartmann T
; Fleming AK
; Gocheva V
; van der Linden WA
; Withana NP
; Verdoes M
; Aurelio L
; Edgington-Mitchell D
; Lieu T
; Parker BS
; Graham B
; Reinheckel T
; Furness JB
; Joyce JA
; Storz P
; Halangk W
; Bogyo M
; Bunnett NW
Am J Physiol Gastrointest Liver Physiol
2016[Sep]; 311
(3
): G548-60
PMID27514475
show ga
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.