Berberine Ameliorates Pro-inflammatory Cytokine-Induced Endoplasmic Reticulum Stress in Human Intestinal Epithelial Cells In Vitro

Abstract

Endoplasmic reticulum stress (ER stress) in intestinal epithelial cells (IECs) plays an important role in the pathogenesis and perpetuation of inflammatory bowel disease (IBD). The aim of this study is to explore the potential of berberine (BBR) in regulating pro-inflammatory cytokine-induced ER stress and apoptosis in IECs. ER stress in cultured Caco-2 cells was induced by IFN-γ/TNF-α and tunicamycin, respectively. The experimental groups were pretreated with BBR. Cell viability was determined by MTT assay. In vitro apoptosis was examined by flow cytometry using annexin V-FITC labeling. The molecular markers of ER stress, including GRP-78, p-JNK, caspase-12, and cleaved caspase-3 were analyzed by Western blot. Xbp-1 mRNA splicing was detected by RT-PCR. Pretreatment of BBR helped to survive in cytokine-induced Caco-2 cells. BBR significantly attenuated cytokine-induced Caco-2 apoptosis. GRP78 expression and xbp-1 mRNA splicing were enhanced significantly in the presence of IFN-γ/TNF-α and tunicamycin, and they could be dampened by BBR. Further study revealed BBR could downregulate JNK phosphorylation, and the level of caspase-12 and cleaved caspase-3. Berberine can ameliorate pro-inflammatory cytokines induced ER stress in vitro, and it might be one of the targeted therapeutic agents for IBD.

Roles and regulation of the mucus barrier in the gut

“…Thus it is not surprising that IFNg and TNF-a were shown to increase ER stress in human intestinal epithelial cells in vitro. 164 It was also shown that similar to IL-10, dexamethasone enhanced MUC2 folding, reduced ER stress and up-regulated ERAD genes thereby enhancing degradation of misfolded proteins. 165 In summary, cytokines that induce ER stress in goblet cells inhibit proper mucin folding and reduce output of mucin while those that inhibit ER stress promote folding of mucins and hence enhance mucin biosynthesis and secretion to help maintain an intact and functional mucus barrier in the intestines.…”

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

“…[159] . Berberine has been reported to ameliorate proinflammatory cytokine-induced ERS in human intestinal epithelial cells [160] , reduce hypoxia/reoxygenation-induced human renal proximal tubular cell injury [161] , and inhibit the human immunodeficiency virus protease inhibitor-induced inflammatory response in murine macrophages [162] . Berberine has also been suggested to have an anti-hypertensive property [163] .…”

Arctigenin alleviates ER stress via activating AMPK

“…The most representative compounds are metformin and berberine, which exert anti-diabetic effects through activating AMPK [18,38] . Meanwhile, they are also reported to possess protective effect against ER stress [39][40][41] . Given the crucial role of ER stress in the development of pancreatic β-cell loss and insulin resistance in type 2 diabetes [6] , the alleviation of ER stress by AMPK may play an important role in treating type 2 diabetes.…”