Pancreas-Specific ARID1A Deficiency Promotes Acinar-to-Ductal Metaplasia and Elevates Interleukin-6 Expression in Experimental Pancreatitis Model

Abstract Background: Although role of ARID1A in pancreatic homeostasis and tumorigenesis has been recently described using genetically engineered mouse (GEM) models, whether ARID1A plays a role in pancreatic inflammation and regeneration remains to be explored.Methods: Pancreas-specific Arid1a-deficient GEM model (Arid1adef) was generated by Ela1-Cre/ERT2 mice crossing with Arid1afl/fl mice and characterized histologically. In physiological and inflammatory conditions, serum amylase and lipase activity were measured to investigate effects of Arid1a deficiency on pancreatic secretion function. Histology analysis of pancreas was used to evaluate pancreatic lesions and recovery. Ex vivo primary acinar cell culture was employed to study acinar-to-ductal metaplasia (ADM) process. In HPNE cells, ARID1A knockdown and histone acetyltransferases inhibitors were used to explore epigenetic regulation on interleukin-6 (IL6) expression. Chromatin immunoprecipitation (ChIP) and quantitative real-time PCR were performed to analyze on IL6 promoters.Results: Arid1a deficiency promoted formation of ductal cysts characterized as silenced acinar genes and activated duct genes. Arid1a-deficient acinar cells were more inclined to trans-differentiation to ductal cells in cerulein-induced acute pancreatitis (AP) model. Expression analysis of proinflammatory cytokines reveals that ARID1A deficiency led to increased IL-6 expression in mice acinar cells and HPNE cells. ARID1A-associated histone acetylation partially involved in epigenetic regulation of IL-6. Conclusion: These results demonstrate ARID1A is involved in cerulein-induced AP development by mediating pro-inflammatory cytokines IL-6 and suggest that ARID1A-containing SWI/SNF complex is an epigenetic regulator of acute pancreatitis.