Krüppel-like Factor 5 Plays an Important Role in the Pathogenesis of Chronic Pancreatitis

Chronic pancreatitis results in the formation of pancreatic intraepithelial neoplasia (PanIN) and poses a risk of developing pancreatic cancer. Our previous study demonstrated that Krüppel-like factor 5 (KLF5) is necessary for forming acinar-to-ductal metaplasia (ADM) in acute pancreatitis. Here, we investigated the role of KLF5 in response to chronic injury in the pancreas. Human tissues originating from chronic pancreatitis patients showed increased levels of epithelial KLF5. An inducible genetic model combining the deletion of and the activation of mutant expression in pancreatic acinar cells together with chemically induced chronic pancreatitis was used. The chronic injury resulted in increased levels of KLF5 in both control and mutant mice. Furthermore, it led to numerous ADM and PanIN lesions and extensive fibrosis in the KRAS mutant mice. In contrast, pancreata with loss (with or without ) failed to develop ADM, PanIN, or significant fibrosis. Furthermore, the deletion of reduced the expression level of cytokines and fibrotic components such as , , , , , and . Notably, using ChIP-PCR, we showed that KLF5 binds directly to the promoters of , , and genes. In summary, the inactivation of inhibits ADM and PanIN formation and the development of pancreatic fibrosis.