IL-18/IL-18R1 Involved in Pancreatic Fibrosis via Activating Pancreatic Stellate Cells

Abstract

Introduction: Chronic pancreatitis (CP) is a fibro-inflammatory syndrome characterized by irreversible tissue damage leading to exocrine and endocrine insufficiency, persistent pain, and an increased risk of pancreatic cancer. This study investigates the role of IL-18 in the activation process of pancreatic stellate cells (PSCs) and the progression of pancreatic fibrosis in CP. Methods: A total of 69 CP and 32 normal pancreatic tissue samples were analyzed using qRT-PCR and IHC to assess IL-18R1 expression. Primary PSCs were isolated from murine pancreata and cultured. Effects of recombinant IL-18 on PSC activation were evaluated using qRT-PCR and flow cytometry. Additionally, the impact of IL-18 binding protein (IL-18BP) and IL-18R1 antibody on PSC activation was examined. Results: IL-18R1 expression was significantly upregulated in CP tissues compared to normal pancreatic tissues, correlating with fibrosis severity. Cultured PSCs showed increased alpha-SMA and IL-18R1 expression over time, indicating activation. Treatment with recombinant IL-18 induced a dose-dependent increase in alpha-SMA expression, confirming PSC activation. Furthermore, cultured PSCs secreted IL-18, suggesting an autocrine activation mechanism. IL-18BP and IL-18R1 antibody treatments reduced PSC activation, underscoring IL-18's regulatory role. Conclusion: Upregulation of IL-18R1 and its correlation with fibrosis severity in CP highlights the significant role of IL-18 in PSC activation and pancreatic fibrosis. These findings suggest that targeting the IL-18/IL-18R1 axis could be a promising therapeutic strategy to mitigate pancreatic fibrosis in CP, offering potential new avenues for treatment.