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RhoB is associated with the anti-angiogenic effects of celiac patient transglutaminase 2-targeted autoantibodies

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An Erratum to this article was published on 18 February 2012

Abstract

Celiac patient-derived anti-transglutaminase 2 (TG2) antibodies disturb several steps in angiogenesis, but the detailed molecular basis is not known. Therefore, we here analyzed by microarray technology the expression of a set of genes related to angiogenesis and endothelial cell biology in order to identify factors that could explain our previous data related to vascular biology in the context of celiac disease. To this end, in vitro models using human umbilical vein endothelial cells (HUVECs) or in vivo models of angiogenesis were used. A total of 116 genes were analyzed after treatment with celiac patient autoantibodies against TG2. Compared to treatment with control IgA celiac patient, total IgA induced a consistent expression change of 10 genes, the up-regulation of four and down-regulation of six. Of these genes the up-regulated RhoB was selected for further studies. RhoB expression was found to be up-regulated at both messenger RNA and protein level in response to celiac patient total IgA as well as anti-TG2-specific antibody derived from a celiac patient. Interestingly, down-regulation of RhoB by specific small interfering RNA treatment in endothelial cells could rescue the deranged endothelial length and tubule formation caused by celiac disease autoantibodies. RhoB function is controlled by its post-translational modification by farnesylation. This modification of RhoB required for its correct function can be prevented by the cholesterol lowering drug simvastatin, which was also able to abolish the anti-angiogenic effects of celiac anti-TG2 autoantibodies. Taken together, our results would suggest that RhoB plays a key role in the response of endothelial cells to celiac disease-specific anti-TG2 autoantibodies.

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Acknowledgments

The Celiac Disease Study Group has been financially supported by the Academy of Finland, the Sigrid Juselius Foundation, the Pediatric Research Foundation, the Competitive Research Funding of the Tampere University Hospital, the Research Fund of the Finnish Coeliac Society, the Hungarian Scientific Research Fund (OTKA K61868), Compagnia Sanpaolo, and the European Commission (contract numbers PIA-GA-2010-251506 and PERG08-GA-2010-277049).

Disclosure of potential conflict of interests

The authors declare no conflict of interests related to this study.

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Authors and Affiliations

  1. Pediatric Research Center, University of Tampere and Tampere University Hospital, Finn-Medi 3, School of Medicine, 33014, University of Tampere, Finland

    Stefania Martucciello, Ilma Korponay-Szabo, Cristina Nadalutti, Essi Myrsky, Tiina Rauhavirta, Ana-Marija Sulic, Markku Mäki, Katri Lindfors & Sergio Caja

  2. Department of Chemistry, University of Salerno, Fisciano, Italy

    Stefania Martucciello & Carla Esposito

  3. Department of Life Sciences, University of Trieste, Trieste, Italy

    Miha Lavric & Roberto Marzari

  4. Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Toth Boglarka

  5. Heim Pal Children’s Hospital, Budapest and Department of Pediatrics, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary

    Ilma Korponay-Szabo

  6. Department Medical Sciences and IRCAD, University of Eastern Piedmont, Novara, Italy

    Daniele Sblattero

  7. School of Medicine, University of Tampere, Finn-Medi 3, School of Medicine, 33014, University of Tampere, Finland

    Katri Kaukinen

  8. Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland

    Katri Kaukinen

Authors
  1. Stefania Martucciello
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  2. Miha Lavric
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  3. Toth Boglarka
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  4. Ilma Korponay-Szabo
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  5. Cristina Nadalutti
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  6. Essi Myrsky
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  7. Tiina Rauhavirta
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  8. Carla Esposito
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  9. Ana-Marija Sulic
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  10. Daniele Sblattero
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  11. Roberto Marzari
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  12. Markku Mäki
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  13. Katri Kaukinen
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  14. Katri Lindfors
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  15. Sergio Caja
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Corresponding author

Correspondence to Katri Lindfors.

Additional information

S. Martucciello and M. Lavric contributed equally to the work.

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Martucciello, S., Lavric, M., Boglarka, T. et al. RhoB is associated with the anti-angiogenic effects of celiac patient transglutaminase 2-targeted autoantibodies. J Mol Med 90, 817–826 (2012). https://doi.org/10.1007/s00109-011-0853-0

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  • DOI: https://doi.org/10.1007/s00109-011-0853-0

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