Epithelial calcium-sensing receptor activation by eosinophil granule protein analog stimulates collagen matrix contraction

Peter D Ngo, Vince Mukkada, Razan Turki, Glenn T Furuta, John A A Macleod

Research output: Contribution to journalArticle (Academic Journal)peer-review

3 Citations (Scopus)

Abstract

BACKGROUND: Eosinophils reside in normal gastrointestinal tracts and increase during disease states. Receptors for eosinophil-derived granule proteins (EDGPs) have not been identified, but highly cationic molecules, similar to eosinophil proteins, bind extracellular calcium-sensing receptors (CaSRs). We hypothesized that stimulation of CaSRs by eosinophil proteins activates epithelial cells.

METHODS: Caco2 intestinal epithelial cells, AML14.3D10 eosinophils, wild-type (WT) human embryonic kidney 293 (HEK293) cells not expressing CaSRs (HEK-WT), and CaSR-transfected HEK293 cells (HEK-CaSR) were stimulated with an eosinophil protein analog poly-L-arginine (PA) and phosphorylated extracellular signal-regulated kinase (pERK)1 and pERK2 were measured. Functional activation was measured with collagen lattice contraction assays.

RESULTS: Coculture of Caco2 cells with AML14.3D10 eosinophils augmented lattice contraction as compared with lattices containing Caco2 cells alone. PA stimulation of Caco2 lattices augmented contraction. HEK-CaSR stimulation with PA or Ca(2+) resulted in greater pERK activation than that of stimulated HEK-WT cells. PA stimulated greater HEK-CaSR lattice contraction than unstimulated lattices. Contraction of PA-stimulated and PA-unstimulated HEK-WT lattices did not differ.

CONCLUSION: Exposure of intestinal epithelia to the EDGP analog PA stimulates CaSR-dependent ERK phosphorylation and epithelial-mediated collagen lattice contraction. We speculate that EDGP release within the epithelial layers activates the CaSR receptor, leading to matrix contraction and tissue fibrosis.

Original languageEnglish
Pages (from-to)414-9
Number of pages6
JournalPediatric Research
Volume73
Issue number4 Pt 1
DOIs
Publication statusPublished - Apr 2013

Keywords

  • Caco-2 Cells
  • Calcium
  • Collagen
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Eosinophil Granule Proteins
  • Epithelial Cells
  • Fibrosis
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Intestinal Mucosa
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Peptides
  • Phosphorylation
  • Receptors, Calcium-Sensing
  • Time Factors
  • Transfection

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