ATF6/p53 Signaling Plays a Distinct Role in Early and Late Stage During the Development of Chronic Pancreatitis
39 Pages Posted: 26 May 2019More...
Background: PRSS1 overaccumulation causes endoplasmic reticulum (ER) stress to regulate chronic pancreatitis (CP) progression. However, little is known about the downstream mechanisms. In this study, we investigated the pathogenic role of p53 expression in the ER stress response pathway and in CP pathogenesis.
Methods: CP progression was evaluated in human and mouse tissues by histological staining and inflammatory factor expression. The mouse CP model was established by caerulein in humanized PRSS1 transgenic mice. Collagen deposition was analyzed by Masson's trichrome staining. Gene expression in pancreatic tissues was detected by quantitative RT-PCR, western blotting, immunohistochemistry, and immunofluorescence. The Transferase-mediated d-UTP nick-end-labeling assay was used to assess cell apoptosis.
Findings: ER stress-response genes ATF6, XBP1s, and C/EBP-homologous protein (CHOP) were expressed significantly higher in the pancreatic tissues of CP patients. Caerulein treatment caused the progression of CP in transgenic mice overexpressing the human PRSS1 gene, shown by pathogenic alterations, collagen deposition, and elevated expression of inflammation factors IL-6, IL-1β, and TNF-α. The CP mouse model showed high expression of ER stress-response genes ATF4, ATF6, XBP1, and CHOP, which remarkably decreased at the late disease stage. ER stress enhanced p53 expression at the early stage in the CP model, which promotes pancreatic acinar cell apoptosis and represses CP progression. Notably, we found that ATF6 promotes p53 expression in pancreatic tissues in the early stage, which was suppressed in the late stage of CP progression. Inhibition of ATF6 or p53 resulted in enhanced inflammatory factor expression and CP progression four weeks after CP induction in the mouse model.
Interpretation: At the early disease stage, p53 mediates ER stress-induced suppression of CP, but its expression sustained by the ATF6/XBP1/CHOP axis promotes inflammation during late stage CP pathogenesis.
Funding: This study was supported by a grant from Southern Medical University.
Declaration of Interest: The authors declare no conflict of interest.
Ethical Approval: The research procedures were approved by the Ethics Committee of Southern Medical University and written informed consent was obtained from each patient before the study. The animal experimental operations were performed with approval from the Institutional Animal Care and Use Committee of Southern Medical University.
Keywords: Chronic pancreatitis; Endoplasmic reticulum stress; P53; PRSS1; Caerulein treatment
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