Abstract
Nuclear receptor subfamily 5 group A member 2 (Nr5a2) is widely involved in the physiological and pathological processes of the pancreas. However, the cytological and molecular evidence regarding how Nr5a2 implicated in acute pancreatitis (AP) remains insufficient. Here, we explored this problem by using cellular AP model in both normal and Nr5a2 silenced AR42J pancreatic acinar cells. An in vitro cellular model of AP was established by stimulating AR42J cells with caerulein (CAE) for 24 h. Reduced Nr5a2 expression was observed in the CAE-treated cells. Nr5a2 silencing led to AP-like inflammation, with increased interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α mRNA levels. In the cellular AP model, Nr5a2 silencing further increased IL-1β, IL-6, and TNF-α mRNA levels, as well as amylase activity. In addition, we found that Nr5a2 silencing did not affect IL-10 level under physiological conditions but inhibited the anti-inflammatory response of IL-10 in AP model. Moreover, in CAE-induced pancreatic inflammation, Nr5a2 silencing increased the apoptosis and necrosis of acinar cells and inhibited the proliferation of acinar cells, which has not been shown previously. Further experiments showed, for the first time, that Nr5a2 silencing downregulated the expression of β-catenin and its downstream target gene T-cell factor (TCF)-4 in the cellular AP model but increased the expression of nuclear factor (NF)-κB. In conclusion, in CAE-induced pancreatic inflammation, lower Nr5a2 level leads to downregulation of β-catenin and its downstream target gene TCF-4 and upregulation of NF-κB, which exacerbates the inflammatory response and cell damage and inhibits the proliferation and regeneration of acinar cells.
Highlights
Acute pancreatitis (AP) refers to acute inflammation of the pancreas initiated in pancreatic acinar cells, it is one of the most frequent gastrointestinal causes of hospital admission, with an increased annual incidence of 13–45/100,000 people (Yadav and Lowenfels, 2013)
The proinflammatory and anti-inflammatory responses of the cellular acute pancreatitis (AP) model were assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR), and the amylase activity in AP model was assessed by a colorimetric assay
The average mRNA levels of IL-1β, IL-6, tumor necrosis factor (TNF)-α in the CAE-treated cells were significantly higher than in the control cells treated with phosphate buffered saline (PBS) (Figures 1A–C); the average mRNA level of IL-10 was significantly lower in CAE-treated cells than in the control cells (Figure 1D)
Summary
Acute pancreatitis (AP) refers to acute inflammation of the pancreas initiated in pancreatic acinar cells, it is one of the most frequent gastrointestinal causes of hospital admission, with an increased annual incidence of 13–45/100,000 people (Yadav and Lowenfels, 2013). Uncovering the cellular damage-repair mechanisms of the acinar cells involved in mild/severe AP development may have important therapeutic implications. Nr5a2 regulates especially the development of acinar cells in pancreatic exocrine structures without affecting pancreatic endocrine structures (von Figura et al, 2014; Nissim et al, 2016). Nr5a2 was reported to affect inflammatory response of AP (Flandez et al, 2014). These reports suggest that Nr5a2 is widely involved in the physiological and pathological processes of the pancreas. Cytological and molecular evidence on whether and how Nr5a2 is involved in the occurrence and development of AP is still insufficient
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