Abstract
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that occurs in the lining of the rectum and colon. Apoptosis of the intestinal epithelial cells (IECs) is common in active UC patients. Ghrelin is reported to be downregulated in apoptosis of IECs induced by tumor necrosis factor-α (TNF-α). Therefore, we hypothesized that ghrelin might play an antiapoptotic role in UC progression, which was investigated using in vitro and in vivo studies. The TNF-α-treated Caco-2 cell model and mouse colitis model induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) were established and employed. We found that ghrelin could inhibit the apoptosis of Caco-2 cells induced by TNF-α, which could be disturbed by [D-lys3]-GHRP-6, the antagonist of ghrelin receptor GHS-R1a. Similarly, in the DSS- and TNBS-induced mouse colitis models, ghrelin could also protect intestinal tissues from apoptosis in DSS- and TNBS-induced colitis depending on GHS-R1a. Furthermore, ghrelin modulated the unfolded protein response (UPR) pathway and regulated the expressions of caspase-3, BAX, and Bcl-2, which contributed to the inhibition of cell apoptosis. In conclusion, ghrelin protects IECs from apoptosis during the pathogenesis of colitis by regulating the UPR pathway.
Highlights
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that occurs in the lining of the rectum and colon (Wang et al, 2020)
We found that ghrelin inhibited the apoptosis of Caco-2 cells induced by tumor necrosis factor-α (TNF-α), which could be disturbed by [D-lys3]-GHRP-6, the antagonist of GHS-R1a (Patel et al, 2012)
We hypothesized that ghrelin administration could inhibit the apoptosis of Caco-2 cells induced by TNF-α
Summary
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that occurs in the lining of the rectum and colon (Wang et al, 2020). The main pathological features of UC are weight loss, rectal bleeding, mucosal ulceration, and epithelial barrier disruption (Rapa et al, 2021). Due to the unclear pathogenesis of UC, there are no effective drugs adopted in the clinical treatment of this kind of disease. The intestinal epithelial barrier (IEB) separates the intestinal microorganism from the intestinal tissue, and its dysfunction is reported to be associated with UC (Maloy and Powrie, 2011). To keep the homeostasis of IEB, apoptosis and proliferation of the intestinal epithelial cells (IECs) should achieve a dynamic balance. It is reported that excessive apoptosis induced by endoplasmic reticulum (ER) stress is common in the development of UC (Luo and Cao, 2015; Zeng et al, 2015). ER stress activates the unfolded protein response (UPR) pathway and promotes the chaperone glucoseregulated protein 78 (GRP78, known as BIP and HSPA5) to dissociate from the ER transducer
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