Cerulein-induced in vitro activation of trypsinogen in rat pancreatic acini is mediated by cathepsin B

Saluja, Ashok K.; Donovan, Erin A.; Yamanaka, Kazushi; Yamaguchi, Yoshikazu; Hofbauer, B.; Steer, Michael L.

doi:10.1016/s0016-5085(97)70108-2

Cited by 184 publications

(155 citation statements)

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“…This observation is in line with earlier reports using either lysosomal enzyme inhibitors (24) or knockout strains of mice in which the cathepsin B gene was deleted (4). Although our present experiments cannot exclude that nonlysosomal cysteine proteases (such as calpain) or lysosomal hydrolases other than cathepsin B (e.g., cathepsin L, K, and H) account for some of the E-64d effect reported here and elsewhere, our studies using cathepsin B-deleted animals have firmly established the role of this particular cysteine protease in triggering trypsinogen activation (4).…”

Section: Discussionsupporting

confidence: 94%

“…With the use of E-64d as a cellpermeant cysteine protease inhibitor, which has been shown not to interact with trypsin activity (24), together with S124 to inhibit trypsin activity and degradation, we found that the cysteine protease inhibitor significantly reduced the generation of free trypsin activity and confirmed that S124 induced a dramatic increase in intracellular trypsin activity (Fig. 5).…”

Section: Characterization Of Trypsin Inhibition By N␣-(2-naphthylsusupporting

confidence: 59%

“…The first predicts that cathepsin B, a lysosomal enzyme that has been found to colocalize with digestive zymogens in the pancreas during early pancreatitis, accounts for the initial activation of trypsinogen (25,26,29). We and others have already confirmed that a significant proportion of intrapancreatic trypsinogen activation depends on the presence of cathepsin B in the pancreas (4,24). The second hypothesis predicts that trypsinogen autoactivates (31) and, therefore, a trypsin-induced trypsinogen activation represents the triggering event for acute pancreatitis.…”

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confidence: 80%

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Trypsin activity is not involved in premature, intrapancreatic trypsinogen activation

Halangk

Krüger

Ruthenbürger

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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Halangk, Walter, Burkhard Krü ger, Manuel Ruthenbü rger, Jö rg Stü rzebecher, Elke Albrecht, Hans Lippert, and Markus M. Lerch. Trypsin activity is not involved in premature, intrapancreatic trypsinogen activation. Am J Physiol Gastrointest Liver Physiol 282: G367-G374, 2002. First published September 21, 2001 10.1152/ajpgi.00315.2001.-A premature and intracellular activation of digestive zymogens is thought to be responsible for the onset of pancreatitis. Because trypsin has a critical role in initiating the activation cascade of digestive enzymes in the gut, it has been assumed that trypsin also initiates intracellular zymogen activation in the pancreas. We have tested this hypothesis in isolated acini and lobules from rat pancreas. Intracellular trypsinogen activation was induced by supramaximal secretagogue stimulation and measured using either specific trypsin substrates or immunoreactivity of the trypsinogen activation peptide (TAP). To prevent a trypsin-induced trypsinogen activation, we used the cell-permeant, highly specific, and reversible inhibitor N␣-(2-naphthylsulfonyl)-3-amidinophenylalanine-carboxymethylpiperazide (S124), and to prevent cathepsin-induced trypsinogen activation, we used the cysteine protease inhibitor E-64d. Incubation of acini or lobules in the presence of S124 completely prevented the generation of trypsin activity in response to supramaximal caerulein but had no effect whatsoever on the generation of TAP. Conversely, when trypsin activity was recovered at the end of the experiment by either washout of S124 from acini or extensive dilution of lobule homogenates, it was up to 400% higher than after caerulein alone and corresponded, in molar terms, to the generation of TAP. Both trypsin activity and TAP release were inhibited in parallel by E-64d. We conclude that caerulein-induced trypsinogen activation in the pancreas is caused by an E-64d-inhibitable mechanism such as cathepsin-induced trypsinogen activation, and neither involves nor requires intracellular trypsin activity. Specific trypsin inhibition, on the other hand, prevents 80% of trypsin inactivation or autodegradation in the pancreas. autoactivation; cathepsin B; acute pancreatitis ACUTE PANCREATITIS HAS LONG been thought to represent an autodigestion of the pancreas by its own digestive proteases (1). Recent evidence suggests that a premature activation of digestive proteases does indeed occur within pancreatic acinar cells (6, 10, 13) and has been closely associated with the proteolytic damage to the organ (3, 23). What have remained controversial are the triggering events that initiate the premature and intrapancreatic activation of these proteolytic enzymes that are physiologically synthetized, stored, and secreted from the pancreas as inactive precursor zymogens.In a series of elegant studies from the first half of the last century, Kunitz and Northrop (11) have firmly established that highly purified trypsin cannot only activate other serine protease precursors, such as chymotrypsinogen, but can also convert itsel...

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Section: Discussionsupporting

confidence: 94%

Section: Characterization Of Trypsin Inhibition By N␣-(2-naphthylsusupporting

confidence: 59%

mentioning

confidence: 80%

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Trypsin activity is not involved in premature, intrapancreatic trypsinogen activation

Halangk

Krüger

Ruthenbürger

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The administration of potent lysosomal enzyme inhibitors in vivo does not prevent the onset of acute experimental pancreatitis in some studies [4]. Both increases and decreases in the rate of intracellular trypsinogen activation have been reported in experiments that used lysosomal protease inhibitors in vitro [48,49]. Even a protective role against premature zymogen activation has been considered for cathepsin B [50,51].…”

Section: Cathepsin B In Premature Digestive Protease Activationmentioning

confidence: 99%

Early events in acute pancreatitis

Halangk¹,

Lerch²

2004

Gastroenterology Clinics of North America

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“…3e5 AP arises with local inflammation on activation of proteolytic pancreatic enzymes within the acinar tissue and may lead to systemic inflammatory response and complications. 6,7 Specific therapy for AP is lacking, and understanding the molecular mechanisms underlying its pathogenesis is fundamental for management and therapy of the disease at early and late stages.…”

mentioning

confidence: 99%

Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice

Bettaieb

Koike

Chahed

et al. 2016

The American Journal of Pathology

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Acute pancreatitis (AP) is a common and devastating gastrointestinal disorder that causes significant morbidity. The disease starts as local inflammation in the pancreas that may progress to systemic inflammation and complications. Protein tyrosine phosphatase 1B (PTP1B) is implicated in inflammatory signaling, but its significance in AP remains unclear. To investigate whether PTP1B may have a role in AP, we used pancreas PTP1B knockout (panc-PTP1B KO) mice and determined the effects of pancreatic PTP1B deficiency on cerulein-and arginine-induced acute pancreatitis. We report that PTP1B protein expression was increased in the early phase of AP in mice and rats. In addition, histological analyses of pancreas samples revealed enhanced features of AP in cerulein-treated panc-PTP1B KO mice compared with controls. Moreover, cerulein-and arginine-induced serum amylase and lipase were significantly higher in panc-PTP1B KO mice compared with controls. Similarly, pancreatic mRNA and serum concentrations of the inflammatory cytokines IL-1B, IL-6, and tumor necrosis factor-a were increased in panc-PTP1B KO mice compared with controls. Furthermore, panc-PTP1B KO mice exhibited enhanced cerulein-and arginine-induced NF-kB inflammatory response accompanied with increased mitogen-activated protein kinases activation and elevated endoplasmic reticulum stress. Notably, these effects were recapitulated in acinar cells treated with a pharmacological inhibitor of PTP1B. These findings reveal a novel role for pancreatic PTP1B in cerulein-and arginine-induced acute pancreatitis. (Am J Pathol 2016 http://dx

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Cerulein-induced in vitro activation of trypsinogen in rat pancreatic acini is mediated by cathepsin B

Cited by 184 publications

References 1 publication

Trypsin activity is not involved in premature, intrapancreatic trypsinogen activation

Trypsin activity is not involved in premature, intrapancreatic trypsinogen activation

Early events in acute pancreatitis

Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice

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