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Cellular and Molecular Life Sciences

, Volume 71, Issue 7, pp 1315–1326 | Cite as

Celiac disease patient IgA antibodies induce endothelial adhesion and cell polarization defects via extracellular transglutaminase 2

  • Cristina Antonella Nadalutti
  • Ilma Rita Korponay-Szabo
  • Katri Kaukinen
  • Martin Griffin
  • Markku Mäki
  • Katri LindforsEmail author
Research Article

Abstract

We have recently found that celiac disease patient serum-derived autoantibodies targeted against transglutaminase 2 interfere with several steps of angiogenesis, including endothelial sprouting and migration, though the mechanism involved remained to be fully characterized. This study now investigated the processes underlying the antiangiogenic effects exerted by celiac disease patient antibodies on endothelial cells, with particular regard to the adhesion, migration, and polarization signaling pathway. We observed that celiac IgA reduced endothelial cell numbers by affecting adhesion without increasing apoptosis. Endothelial cells in the presence of celiac IgA showed weak attachment, a high susceptibility to detach from fibronectin, and a disorganized extracellular matrix due to a reduction of protein cross-links. Furthermore, celiac patient IgA led to secretion of active transglutaminase 2 from endothelial cells into the culture supernatants. Additionally, cell surface transglutaminase 2 mediated integrin clustering in the presence of celiac IgA was coupled to augmented expression of β1-integrin. We also observed that celiac patient IgA-treated endothelial cells had migratory defects and a less polarized phenotype when compared to control groups, and this was associated with the RhoA signaling pathway. These biological effects mediated by celiac IgA on endothelial cells were partially influenced but not completely abolished by R281, an irreversible extracellular transglutaminase 2 enzymatic activity inhibitor. Taken together, our results imply that celiac patient IgA antibodies disturb the extracellular protein cross-linking function of transglutaminase 2, thus altering cell-extracellular matrix interactions and thereby affecting endothelial cell adhesion, polarization, and motility.

Keywords

Celiac disease antibodies Endothelial cells Transglutaminase 2 Integrins Adhesion Polarization 

Notes

Acknowledgments

We thank Kaisa Teittinen for comments on the manuscript. The Coeliac Disease Study Group was financially supported by the Academy of Finland, the Tampere Graduate Program in Biomedicine and Biotechnology, the Sigrid Juselius Foundation, the Research Fund of the Finnish Coeliac Society, the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital (grant numbers 9P020 and 9P033) and the Pediatric Research Foundation, Elna Kaarina Savolainen’s fund allocated for the development of cancer treatment and the European Commission IAPP grant TRANSCOM (Contract number PIA-GA-2010-251506). Further, the grants OTKA K101788, NK105046 and TÁMOP 4.2.2.11/1/KONV-2012-0023 are also acknowledged.

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Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Cristina Antonella Nadalutti
    • 1
  • Ilma Rita Korponay-Szabo
    • 2
    • 3
  • Katri Kaukinen
    • 4
    • 5
    • 6
  • Martin Griffin
    • 7
  • Markku Mäki
    • 1
  • Katri Lindfors
    • 1
    Email author
  1. 1.Tampere Center for Child Health ResearchUniversity of Tampere and Tampere University HospitalTampereFinland
  2. 2.Celiac Disease CenterHeim Pal Children’s HospitalBudapestHungary
  3. 3.Department of Pediatrics, Medical and Health Science CenterUniversity of DebrecenDebrecenHungary
  4. 4.School of MedicineUniversity of TampereTampereFinland
  5. 5.Department of Gastroenterology and Alimentary Tract SurgeryTampere University HospitalTampereFinland
  6. 6.Department of MedicineSeinäjoki Central HospitalSeinäjokiFinland
  7. 7.School of Life and Health SciencesAston UniversityBirminghamUK

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