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Sjögren’s syndrome pathological neovascularization is regulated by VEGF-A-stimulated TACE-dependent crosstalk between VEGFR2 and NF-κB

Genes & Immunity volume 13, pages 411–420 (2012)Cite this article

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Abstract

We explore the involvement of tumor necrosis factor α (TNF-α)-converting enzyme (TACE) in vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR2) (VEGF-A/VEGFR2)-mediated angiogenesis in Sjögren’s syndrome (SS), one of the most common autoimmune rheumatic diseases. To test the hypothesis that SS autoantibodies (Abs) regulate VEGF-A/VEGFR2 expression by a TACE-dependent nuclear factor-κB (NF-κB) activation pathway, their effects on the expression and activation of the VEGF-A/TACE/VEGFR2/NF-κB pathway were determined in human salivary gland epithelial cells (SGEC). An enhanced angiogenesis in SS salivary gland biopsies was observed, associated with an increased VEGF-A expression and activation of VEGF-A/VEGFR2 signaling. Human cytokine array analysis of the pro-inflammatory and pro-angiogenic protein response in SGEC treated with SS Abs revealed an overexpression of multiple pro-angiogenic factors. TACE RNA knockdown, the use of anti-VEGF-A monoclonal antibody and the inhibition of NF-κB activity significantly abrogated the release of pro-angiogenic factors, demonstrating that VEGF-A/TACE/VEGFR2/NF-κB axis dysfunction may be contributory to pathogenesis and exacerbation of this autoimmune condition.

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Acknowledgements

We are grateful to MVC Pragnell, BA, for their critical reading of the manuscript; we thank Dr P Bauerle, University of Munich and Dr M Lienhard Schmitz, Deutsches Krebsforschungszentrum, Germany, for providing IκBα dominant negative vector. We thank Dr C Filoni for the technical support. This study was supported by a grant (No.: 20216000056) from the Italian Ministry for Universities and Research.

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Author notes

  1. M Sisto and S Lisi: These authors contributed equally to this work and both are equally considered as first author.

Authors and Affiliations

  1. Department of Basic Medical Sciences, Section of Human Anatomy, Laboratory of Cell Biology, University of Bari Medical School, Bari, Italy

    M Sisto, S Lisi & D Ribatti

  2. Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy

    D D Lofrumento

  3. Department of Internal Medicine and Public Medicine, Section of Rheumatology, University of Bari Medical School, Bari, Italy

    M D'Amore

  4. Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy

    M A Frassanito

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  1. M Sisto
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  2. S Lisi
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  4. M D'Amore
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  5. M A Frassanito
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Correspondence to M Sisto.

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Sisto, M., Lisi, S., Lofrumento, D. et al. Sjögren’s syndrome pathological neovascularization is regulated by VEGF-A-stimulated TACE-dependent crosstalk between VEGFR2 and NF-κB. Genes Immun 13, 411–420 (2012). https://doi.org/10.1038/gene.2012.9

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