ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis

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.

Ambroxol Improves Neuronal Survival and Reduces White Matter Damage through Suppressing Endoplasmic Reticulum Stress in Microglia after Intracerebral Hemorrhage

“…Our data also indicated that TRAF2, one of the axis downstream molecules, was decreased with ambroxol administration, implying that IRE1α-TRAF2 axis was involved in ambroxol suppressing ER stress after ICH. Previous studies have demonstrated that the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) can induce transcriptional activation of genes that ultimately lead to cell death [31,32]. Moreover, recent study has proven that CHOP silencing attenuates acute brain injury in rats after subarachnoid hemorrhage (SAH) [33], which is in line with our data that the expression of CHOP among lesions was downregulated when using ambroxol, compared to the ICH group.…”

Identification of Potential Serum Exosomal microRNAs Involved in Acinar-Ductal Metaplasia That is A Precursor of Pancreatic Cancer Associated with Chronic Pancreatitis

“…Cyclin D1, an important regulator of the G1 phase of the cell cycle, increases in the pancreas of patients with CP, which may contribute to a hyperproliferative state in CP [35]. Inhibition of p53 expression decreased levels of in ammatory factors and suppressed progression of CP in the mouse model [36]. The chronic in ammatory process in CP markedly affects immune function in CP patients [37].…”

ATF6 aggravates acinar cell apoptosis and injury by regulating p53/AIFM2 transcription in Severe Acute Pancreatitis

“…ATF6-mediated signaling pathway of the UPR was involved in nonsteroidal anti-inflammatory drug-induced apoptosis 14 . Moreover, ATF6 promoted inflammation during chronic pancreatitis (CP) progression 15 . However, whether and how ATF6 participates in ER stress-mediated acinar apoptosis during SAP progression remains undiscovered.…”