AMP-18 Targets p21 to Maintain Epithelial Homeostasis

PLoS One. 2015 Apr 28;10(4):e0125490. doi: 10.1371/journal.pone.0125490. eCollection 2015.


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 p21 WAF1/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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Cycle / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Colitis / chemically induced
  • Colitis / metabolism
  • Colitis / pathology
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Homeostasis / drug effects*
  • Humans
  • Mice
  • Peptide Hormones / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Signal Transduction / drug effects
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / metabolism
  • Trinitrobenzenesulfonic Acid
  • Tumor Necrosis Factor-alpha / pharmacology


  • Cyclin-Dependent Kinase Inhibitor p21
  • GKN1 protein, human
  • Peptide Hormones
  • Tumor Necrosis Factor-alpha
  • Trinitrobenzenesulfonic Acid
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspase 3