Abstract
Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and progression of CP remains poorly understood. In the present study we aimed to elucidate the ER stress pathway involved in CP. We found high expression of the ER stress marker genes ATF6, XBP1, and CHOP in human clinical specimens. A humanized PRSS1 transgenic mouse was established and treated with caerulein to mimic the development of CP, as evidenced by pathogenic alterations, collagen deposition, and increased expression of the inflammatory factors IL-6, IL-1β, and TNF-α. ATF6, XBP1, and CHOP expression levels were also increased during CP development in this model. Acinar cell apoptosis was also significantly increased, accompanied by upregulated p53 expression. Inhibition of ATF6 or p53 suppressed the expression of inflammatory factors and progression of CP in the mouse model. Finally, we showed that p53 expression could be regulated by the ATF6/XBP1/CHOP axis to promote the development of CP. We therefore conclude that ATF6 signalling regulates CP progression by modulating pancreatic acinar cell apoptosis, which provides a target for ER stress-based diagnosis and treatment of CP.
Highlights
Chronic pancreatitis (CP) is characterized by persistent inflammation in the pancreas that usually causes irreversible structural damage and severely impairs digestive functions and pancreatic hormone secretion[1,2]
Compared with those in healthy volunteers, the protein levels of activating transcription factor 6 (ATF6), C/EBP-homologous protein (CHOP), and X-box-binding protein 1 (XBP1) were significantly increased in pancreatic tissues from patients with CP (Fig. 1b, c). These observations suggested that the endoplasmic reticulum (ER) stress-responsive ATF6/XBP1/CHOP axis might be involved in the development of CP
We found that levels of the inflammatory factors interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumour necrosis factor-α (TNF-α) were substantially increased in mouse pancreatic tissues after caerulein injection
Summary
Chronic pancreatitis (CP) is characterized by persistent inflammation in the pancreas that usually causes irreversible structural damage and severely impairs digestive functions and pancreatic hormone secretion[1,2]. Long-term CP is a critical risk factor for pancreatic cancer, which is one of the most lethal human malignancies[6]. Despite the clinical application of pancreatic enzyme replacement, Overaccumulation and misfolding of the serine protease 1 (PRSS1), known as trypsinogen, have been established as key driving factors for the development of some types of pancreatitis, such as hereditary or idiopathic CP8,9. PRSS1 is the principal isoform of trypsinogen secreted by the pancreas. In a transgenic murine model, wild-type or mutant human PRSS1 expression in acinar cells promoted cell apoptosis and spontaneous pancreatitis[10]. The pathogenic mechanisms underlying PRSS1 overaccumulation-induced CP, especially the downstream molecular events, are far from fully understood
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