Abstract
Dysregulated homeostasis of epithelial cells resulting in disruption of mucosal barrier function is an important pathogenic mechanism in inflammatory bowel diseases (IBD). We have characterized a novel gastric protein, Antrum Mucosal Protein (AMP)-18, that has pleiotropic properties; it is mitogenic, anti-apoptotic and can stimulate formation of tight junctions. A 21-mer synthetic peptide derived from AMP-18 exhibits the same biological functions as the full-length protein and is an effective therapeutic agent in mouse models of IBD. In this study we set out to characterize therapeutic mechanisms and identify molecular targets by which AMP-18 maintains and restores disrupted epithelial homeostasis in cultured intestinal epithelial cells and a mouse model of IBD. Tumor necrosis factor (TNF)-α, a pro-inflammatory cytokine known to mediate gastrointestinal (GI) mucosal injury in IBD, was used to induce intestinal epithelial cell injury, and study the effects of AMP-18 on apoptosis and the cell cycle. An apoptosis array used to search for targets of AMP-18 in cells exposed to TNF-α identified the cyclin-dependent kinase inhibitor p21WAF1/CIP1. Treatment with AMP-18 blunted increases in p21 expression and apoptosis, while reversing disturbed cell cycle kinetics induced by TNF-α. AMP-18 appears to act through PI3K/AKT pathways to increase p21 phosphorylation, thereby reducing its nuclear accumulation to overcome the antiproliferative effects of TNF-α. In vitamin D receptor-deficient mice with TNBS-induced IBD, the observed increase in p21 expression in colonic epithelial cells was suppressed by treatment with AMP peptide. The results indicate that AMP-18 can maintain and/or restore the homeostatic balance between proliferation and apoptosis in intestinal epithelial cells to protect and repair mucosal barrier homeostasis and function, suggesting a therapeutic role in IBD.
Highlights
An agent that maintains and/or restores the homeostatic balance between proliferation and apoptosis in epithelial cells is essential to regulate gastrointestinal (GI) epithelial morphology and function to protect the mucosal barrier, and speed its recovery after injury
Antrum Mucosal Protein (AMP)-18 appears to act through PI3K/AKT pathways to increase p21 phosphorylation, thereby reducing its nuclear accumulation to overcome the antiproliferative effects of Tumor necrosis factor (TNF)-α
Treatment with AMP-18 reduced p21 expression (Fig 1A), apoptosis (Fig 1B) [6], and disturbed cell cycle kinetics in epithelial cells induced by the cytokine TNF-α, a known mediator of GI mucosal barrier injury (Fig 2)
Summary
An agent that maintains and/or restores the homeostatic balance between proliferation and apoptosis in epithelial cells is essential to regulate gastrointestinal (GI) epithelial morphology and function to protect the mucosal barrier, and speed its recovery after injury. AMP-18 is synthesized in gastric antrum mucosal epithelial cells, stored in cytoplasmic granules, and secreted with mucus onto the apical cell surface. It appears to mediate its effects on intestinal and colonic epithelial cells by binding to the cholecystokinin-B/gastrin receptor (CCKBR) and activating its downstream pathways including Rho, ERK and p38 mitogen-activated protein kinases (MAPKs) [1,4,5]. The TJ consists of multiple proteins that bind epithelial cells together at their apical surface, and is essential to create and maintain mucosal barrier function. AMP-18 appears to be a promising new agent that could heal the injured intestinal epithelium
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