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‐κB (p65)/IL‐6 signalling pathway and regulated the downstream extracellular matrix (ECM) genes such as α‐SMA and Col1a1. Therefore, we determined whether suppressing NF‐κB/p65 alleviated CP by treating mice with the NF‐κB/p65 inhibitor triptolide in the cerulein‐induced CP model and found that pancreatic fibrosis was alleviated by NF‐κB/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.
Highlights
Chronic pancreatitis (CP) is a recurrent, progressive and irreversible inflammatory disease of the pancreas with a long course and poor prognosis
We found that the expression levels of NF-κB/p65 and IL-6 were higher in the pancreas of the cerulein-treated wild-type mice compared with the untreated mice and that their expression levels were significantly decreased in the pancreas of the cerulein-treated hydrogen peroxide-inducible clone-5 (Hic-5) KO mice (Figure 4D,4)
The protein levels of NF-κB/p65 and IL-6 were significantly decreased in the Hic-5 KO pancreatic stellate cells (PSCs) compared with the wild-type PSCs (Figure 5F). These results indicated that the activation of PSCs was mediated through Hic-5 expression and that NF-κB/p65 may be involved in the development of CP in mice treated with cerulein
Summary
Chronic pancreatitis (CP) is a recurrent, progressive and irreversible inflammatory disease of the pancreas with a long course and poor prognosis. The few PSCs that are present in the connective tissue are quiescent In this state, the PSCs are rich in vitamin A-containing lipid droplets, and only a small amount of extracellular matrix (ECM) components are secreted.[8] during CP, PSCs are activated as demonstrated by their morphology resembling fibroblasts. Recent studies confirmed the role of EMT in fibrosis of organs such as the lungs and the liver.[13,14] Downregulation of epithelial markers such as E-cadherin and cytokeratin and changes in cell morphology and migration are important features of EMT.[12] Studies demonstrated that the processes underlying PSCs activation were similar to those observed during EMT,[15] suggesting that the inhibition of PSCs activation is a promising target for an optimal treatment approach in CP. We investigated the effect of NF-κB/p65 on CP development by inhibiting NF-κB/p65 with triptolide, an immunosuppressant diterpenoid epoxide
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