Objective: Chronic pancreatitis is a progressive inflammatory disorder of the pancreas characterized by permanent destruction of acinar cells. Mutations in the chymotrypsinogen C (CTRC) gene have been linked to the development of chronic pancreatitis. The aim of the present study was to explore whether CTRC mutants induce endoplasmic reticulum (ER) stress in pancreatic acinar cells.
Design: Dexamethasone-differentiated AR42J rat acinar cells and freshly isolated mouse acini were transfected with recombinant adenovirus carrying wild type CTRC or the p.A73T pancreatitis-associated mutant. ER stress markers were assessed by reverse transcription-PCR and western blotting. Apoptosis was characterized by caspase-3/7 activity and the TUNEL assay.
Results: Acinar cells transfected with the p.A73T mutant, but not those with wild-type CTRC, developed significant ER stress, as judged by elevated mRNA and protein levels of the ER chaperone immunoglobulin-binding protein (BiP), increased splicing of the X-box binding protein-1 (XBP1) mRNA and marked induction of the transcription factor C/EBP-homologous protein (CHOP), a mediator of ER stress-associated apoptosis. Consistent with higher CHOP expression, AR42J cells expressing the p.A73T mutant became detached over time and showed considerably increased caspase-3/7 activity and TUNEL staining.
Conclusions: Pancreatitis-associated CTRC mutations can markedly increase the propensity of chymotrypsinogen C to elicit ER stress in pancreatic acinar cells. Thus, carriers of CTRC mutations may be at a higher risk of developing ER stress in the exocrine pancreas, which may contribute to parenchymal damage through acinar cell apoptosis.
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