Hic-5 deficiency protects cerulein-induced chronic pancreatitis via down-regulation of the NF-?B (p65)/IL-6 signalling pathway.

ABSTRACT: Chronic pancreatitis (CP), characterized by pancreatic fibrosis, is a recurrent, progressive and irreversible disease. Activation of the pancreatic stellate cells (PSCs) is considered a core event in pancreatic fibrosis. In this study, we investigated the role of hydrogen peroxide-inducible clone-5 (Hic-5) in CP. Analysis of the human pancreatic tissue samples revealed that Hic-5 was overexpressed in patients with CP and was extremely low in healthy pancreas. Hic-5 was significant up-regulated in the activated primary PSCs independently from transforming growth factor beta stimulation. CP induced by cerulein injection was ameliorated in Hic-5 knockout (KO) mice, as shown by staining of tissue level. Simultaneously, the activation ability of the primary PSCs from Hic-5 KO mice was significantly attenuated. We also found that the Hic-5 up-regulation by cerulein activated the NF-?B (p65)/IL-6 signalling pathway and regulated the downstream extracellular matrix (ECM) genes such as ?-SMA and Col1a1. Therefore, we determined whether suppressing NF-?B/p65 alleviated CP by treating mice with the NF-?B/p65 inhibitor triptolide in the cerulein-induced CP model and found that pancreatic fibrosis was alleviated by NF-?B/p65 inhibition. These findings provide evidence for Hic-5 as a therapeutic target that plays a crucial role in regulating PSCs activation and pancreatic fibrosis.

SUBMITTER: Chen H 

PROVIDER: S-EPMC6991662 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature