Interleukin-1 Beta Induces Autophagy By Affecting Calcium Homeostasis And Trypsinogen Activation In Pancreatic Acinar Cells

The strong up-regulation of inflammatory mediators has been reported to play a key role in acute pancreatitis (AP). Elevated serum levels of interleukin-1 beta (IL-1 beta) are associated with the development of AP. However, the precise effect and mechanism of IL-1 beta in AP remains obscure. In this study, we investigated the potential role and mechanism of IL-1 beta in AP. We measured autophagy activation in response to IL-1 beta in AR42J cells. The disrupting effects of IL-1 beta on cellular Ca2+ were observed. To determine whether the disruption of Ca2+ signaling has protective effects in vivo during AP, male C57BL/6 mice were treated with cerulein to induce AP. We found that the treatment of AR42J cells with IL-1 beta triggered autophagy and that the autophagic flux was impaired. In addition, IL-1 beta induced Ca2+ release from the ER. Furthermore, the expression of the ER stress markers GRP78 and IRE1 also increased. 2APB, an antagonist of the InsP(3) receptor, inhibited increased expression of autophagy markers. Subsequent biochemical assays revealed that co-culture with IL-1 beta could induce the activation of trypsinogen to trypsin and reduce the viability of acinar cells. Pathological changes of the pancreas were also observed in vivo. We found that the pathological injuries of the pancreas were significantly alleviated in mice co-treated with 2APB. Taken together, our results indicate that IL-1 beta can induce trypsin activation and decrease cellular viability in pancreatic acinar cells. These effects depend on impaired autophagy via intracellular calcium changes. Ca2+ signaling may become a promising therapeutic target in the treatment of pancreatitis.