Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice

Sendler, Matthias; Dummer, A.; Weiss, Frank Ulrich; Krüger, Burkhard; Wartmann, Thomas; Scharffetter‐­Kochanek, Karin; Rooijen, Nico van; Malla, Sudarshan; Aghdassi, Ali; Halangk, Walter; Lerch, Markus M.; Mayerle, Julia

doi:10.1136/gutjnl-2011-300771

Cited by 187 publications

(194 citation statements)

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“…The two phenomena appear to be independent and mediated by different factors (62)(63)(64). Awla et al (61) use the pharmacologic inhibitor CsA to demonstrate the importance of calcineurin pathways.…”

Section: Discussionmentioning

confidence: 99%

Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Muili

Wang

Orabi

et al. 2013

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Muili

Wang

Orabi

et al. 2013

Journal of Biological Chemistry

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“…One is the observation that the autosomal dominant inherited form of pancreatitis is associated with germline mutations in the cationic trypsinogen (PRSS1) gene (4,5) and that most inherited risk factors for pancreatitis involve alterations in digestive proteases (6,7). The other is the fact that the mechanism of premature intracellular protease activation and its contributing biochemical and immunological factors are increasingly better understood (8,9) and have parallels in experimental models that mimic human pancreatitis (10 -12), allowing the conclusion that CTSB 3 is a critical intracellular player. CTSB is a lysosomal hydrolase that has long been shown to activate trypsinogen in vitro (13) but has also been found to be involved in the pathophysiology of experimental models of pancreatitis (14 -16).…”

mentioning

confidence: 99%

Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis

Sendler

Maertin

John

et al. 2016

Journal of Biological Chemistry

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Pancreatitis is associated with premature activation of digestive proteases in the pancreas. The lysosomal hydrolase cathepsin B (CTSB) is a known activator of trypsinogen, and its deletion reduces disease severity in experimental pancreatitis. Here we studied the activation mechanism and subcellular compartment in which CTSB regulates protease activation and cellular injury. Cholecystokinin (CCK) increased the activity of CTSB, cathepsin L, trypsin, chymotrypsin, and caspase 3 in vivo and in vitro and induced redistribution of CTSB to a secretory vesicleenriched fraction. Neither CTSB protein nor activity redistributed to the cytosol, where the CTSB inhibitors cystatin-B/C were abundantly present. Deletion of CTSB reduced and deletion of cathepsin L increased intracellular trypsin activation. CTSB deletion also abolished CCK-induced caspase 3 activation, apoptosis-inducing factor, as well as X-linked inhibitor of apoptosis protein degradation, but these depended on trypsinogen activation via CTSB. Raising the vesicular pH, but not trypsin inhibition, reduced CTSB activity. Trypsin inhibition did not affect apoptosis in hepatocytes. Deletion of CTSB affected apoptotic but not necrotic acinar cell death. In summary, CTSB in pancreatitis undergoes activation in a secretory, vesicular, and acidic compartment where it activates trypsinogen. Its deletion or inhibition regulates acinar cell apoptosis but not necrosis in two models of pancreatitis. Caspase 3-mediated apoptosis depends on intravesicular trypsinogen activation induced by CTSB, not CTSB activity directly, and this mechanism is pancreas-specific.Acute pancreatitis has long been regarded as a disease that is characterized by autodigestion of the pancreas by its own proteases (1). This hypothesis appears plausible because no other organ synthesizes and secretes such large amounts of serine and cysteine proteases as the exocrine pancreas (2, 3). However, under physiological conditions, serine proteases are discharged from the pancreas as inactive precursor zymogens, and, most prominently, trypsinogen only undergoes activation when in contact with the intestinal brush border and its enzyme enterokinase. Two discoveries have given new relevance to the autodigestion hypothesis. One is the observation that the autosomal dominant inherited form of pancreatitis is associated with germline mutations in the cationic trypsinogen (PRSS1) gene (4, 5) and that most inherited risk factors for pancreatitis involve alterations in digestive proteases (6, 7). The other is the fact that the mechanism of premature intracellular protease activation and its contributing biochemical and immunological factors are increasingly better understood (8, 9) and have parallels in experimental models that mimic human pancreatitis (10 -12), allowing the conclusion that CTSB 3 is a critical intracellular player. CTSB is a lysosomal hydrolase that has long been shown to activate trypsinogen in vitro (13) but has also been found to be involved in the pathophysiology of experimental models of pa...

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“…Therapies for AP currently under study aim to inhibit proinflammatory pathways, such as TNF-α, with neutralizing antibodies, or up-regulate anti-inflammatory cytokines such as IL-10 or IL-22 (Feng et al, 2012;Xue et al, 2012;Sendler et al, 2013). Elevation of anti-inflammatory cytokines as a therapy should be approached with caution though, as up-regulation of cytokines that reduce AP might also predispose to CP.…”

Section: Cytokines and Pancreatitismentioning

confidence: 99%

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

2015

Frontiers Research Topics

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Purpose of the review: Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer.Recent findings: Intracellular activation of both pancreatic enzymes and the transcription factor NF-κB are important mechanisms that induce acute pancreatitis (AP). Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogenic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16) can ultimately lead to development of pancreatic cancer.Summary: Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions.

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Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice

Cited by 187 publications

References 50 publications

Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Cathepsin B Activity Initiates Apoptosis via Digestive Protease Activation in Pancreatic Acinar Cells and Experimental Pancreatitis

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

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