A celiac cellular phenotype, with altered LPP sub-cellular distribution, is inducible in controls by the toxic gliadin peptide P31-43

PLoS One. 2013 Nov 22;8(11):e79763. doi: 10.1371/journal.pone.0079763. eCollection 2013.

Abstract

Celiac disease (CD) is a frequent inflammatory intestinal disease, with a genetic background, caused by gliadin-containing food. Undigested gliadin peptides P31-43 and P57-68 induce innate and adaptive T cell-mediated immune responses, respectively. Alterations in the cell shape and actin cytoskeleton are present in celiac enterocytes, and gliadin peptides induce actin rearrangements in both the CD mucosa and cell lines. Cell shape is maintained by the actin cytoskeleton and focal adhesions, sites of membrane attachment to the extracellular matrix. The locus of the human Lipoma Preferred Partner (LPP) gene was identified as strongly associated with CD using genome-wide association studies (GWAS). The LPP protein plays an important role in focal adhesion architecture and acts as a transcription factor in the nucleus. In this study, we examined the hypothesis that a constitutive alteration of the cell shape and the cytoskeleton, involving LPP, occurs in a cell compartment far from the main inflammation site in CD fibroblasts from skin explants. We analyzed the cell shape, actin organization, focal adhesion number, focal adhesion proteins, LPP sub-cellular distribution and adhesion to fibronectin of fibroblasts obtained from CD patients on a Gluten-Free Diet (GFD) and controls, without and with treatment with A-gliadin peptide P31-43. We observed a "CD cellular phenotype" in these fibroblasts, characterized by an altered cell shape and actin organization, increased number of focal adhesions, and altered intracellular LPP protein distribution. The treatment of controls fibroblasts with gliadin peptide P31-43 mimics the CD cellular phenotype regarding the cell shape, adhesion capacity, focal adhesion number and LPP sub-cellular distribution, suggesting a close association between these alterations and CD pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Celiac Disease / metabolism*
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism*
  • Diet, Gluten-Free / adverse effects
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Genome-Wide Association Study
  • Gliadin / toxicity*
  • Humans
  • LIM Domain Proteins / metabolism*
  • Male
  • Peptide Fragments / toxicity*

Substances

  • Cytoskeletal Proteins
  • LIM Domain Proteins
  • LPP protein, human
  • Peptide Fragments
  • gliadin p31-43
  • Gliadin

Grants and funding

This study was supported by PRIN 2009 (Research Programs of National Interest), code CUP E61J11000300001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.