Abstract
The incidence of pancreatitis (AP) is increasing and there is no specific treatment available. Intracellular digestive enzyme activation is a key event in the pathogenesis of AP downstream of cytosolic calcium overload and impaired autophagy. Siraitia grosvenorii (Swingle) was used in Traditional Chinese Medicine to reduce inflammation and facilitate bowel movement. The bioactive components of this plant show hypolipedimic, antidiabetic, antifibrotic activity and have been used against pancreatic cancer. Here, we examined whether mogroside IIE, a major bioactive component of unripe S. grosvenorii fruit, can protect against AP. We found that mogroside IIE decreased the activity of trypsin and cathepsin B induced by cerulein plus lipopolysaccharide (LPS) in the pancreatic acinar cell line AR42J and primary acinar cells in a dose- and time-dependent manner. Mogroside IIE treatment decreased the levels of serum lipase and serum amylase in mice injected with cerulein plus LPS without influencing inflammation significantly. A multi-cytokine array revealed that mogroside IIE decreased the level of interleukin 9 (IL-9) in AP mice. Exogenous IL-9 eliminated the mogroside IIE induced reduction of trypsin and cathepsin B activity and reversed the inhibition of cytosolic calcium and modulation of autophagy mediated by mogroside IIE. An IL-9 receptor antibody neutralized the effect of IL-9, restoring mogroside IIE activity. The mogroside IIE targeted IL-9 may partially arise from Th9 cells. Taken together, we provide experimental evidence that mogroside IIE ameliorates AP in cell models and mice through downregulation of the IL-9/IL-9 receptor pathway.
Highlights
Acute pancreatitis (AP) is a common inflammatory disease without specific treatment (Moggia et al, 2017; Lee and Papachristou, 2019)
The signalling network in this manuscript is summarized as mogroside IIE inhibited the IL-9/IL-9R/calcium overload/cathepsin B activation/trypsinogen activation pathway
Wrote or contributed to the writing of the manuscript: JX, JJ
Summary
Acute pancreatitis (AP) is a common inflammatory disease without specific treatment (Moggia et al, 2017; Lee and Papachristou, 2019). Despite not being part of antiAP TCM decoctions, we decided to investigate if mogroside IIE, a major bitter taste bioactive component of unripe S. grosvenorii (Swingle) fruit (Wang et al, 2014) can protect against AP. Independent of trypsin, nuclear factor-k-gene binding (NFkB) pathway activation induce cytokine release which lead to local or systematic inflammation in the development of AP (Saluja et al, 2019). Platelet-activating factor directly causes pancreatitis (Jakkampudi et al, 2016). Chemokines, such as IL-8, MCP-1 and regulated upon activation, normal T cell expressed and presumably secreted (RANTES), are pro-inflammatory mediators (Bhatia, 2005). In our study we examined the effect of mogroside IIE on molecular markers of AP, focusing on pancreatic enzyme activity, cell calcium concentration, and systemic cytokine release. A large part of our work was dedicated to elucidate the effect of mogroside IIE on IL-9 pathway and its role in AP
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