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The anti-angiogenic activity of IL-12 is increased in iNOS−/− mice and involves NK cells

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Abstract

We have previously reported that the in vivo transfer of murine interleukin-12 (IL-12) gene using a Semliki Forest virus vector induced tumor regression through inhibition of tumor blood vessel formation. To examine whether IL-12 anti-angiogenic activity interferes with the NO pathway, we used inducible nitric oxide synthase-deficient mice (iNOS−/−) and demonstrated that the anti-tumor effect of IL-12 is more pronounced in these mice. In addition, despite the increased level of intratumoral VEGF in iNOS−/− mice, IL-12 induced a stronger inhibition of blood vessel formation. Histological analysis of SFV-IL-12-treated tumors showed an increase in natural killer (NK) perivascular infiltration in iNOS−/− as compared to control mice. In vitro IL-12-stimulated murine splenic NK cells displayed significant killing activity towards established murine endothelial cells used as targets. These studies indicate that the anti-angiogenic activity of IL-12 interferes with iNOS pathway and involves NK cell recruitment.

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Abbreviations

EC:

Endothelial cell

NOS:

Nitric oxide synthase

VEGF:

Vascular endothelial growth factor

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Acknowledgments

We thank P. Bouckaert for kindly providing the iNOS−/− mice.

Disclosures

The authors have no conflicting financial interests.

Author information

Authors and Affiliations

  1. INSERM U 753, Unité Immunologie des Tumeurs, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805, Villejuif, France

    Aleksandra Bielawska-Pohl, Séverine Blesson, Houssem Benlalam, Aurélie Trenado & Salem Chouaib

  2. UPR CNRS 4301, Centre de Biophysique Moléculaire, University of Orléans and to INSERM, Orléans, France

    Aleksandra Bielawska-Pohl, Claudine Kieda & Salem Chouaib

  3. UMR CNRS 8121, Laboratoire de Vectorologie et de Transfert de gènes, Institut Gustave Roussy, Villejuif, France

    Paule Opolon & Olivia Bawa

  4. Laboratoire d’Imagerie du Petit Animal, Institut Gustave Roussy, Villejuif, France

    Valérie Rouffiac

  5. Laboratory of Glycobiology and Cellular Interactions, Polish Academy of Sciences, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Wrocław, Poland

    Danuta Dus

Authors
  1. Aleksandra Bielawska-Pohl
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  2. Séverine Blesson
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  3. Houssem Benlalam
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  4. Aurélie Trenado
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  5. Paule Opolon
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  6. Olivia Bawa
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  7. Valérie Rouffiac
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  8. Danuta Dus
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  9. Claudine Kieda
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  10. Salem Chouaib
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Corresponding author

Correspondence to Salem Chouaib.

Additional information

Aleksandra Bielawska-Pohl and Séverine Blesson contributed equally to this work.

This work was supported in part by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), ARC association pour le Recherche sur le Cancer N°1025, Institut National du Cancer (INCa), Canceropole Ile de France and Canceropole Grand Ouest and the Polish Ministry of Science and Higher Education N401 149 32/2837.

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Bielawska-Pohl, A., Blesson, S., Benlalam, H. et al. The anti-angiogenic activity of IL-12 is increased in iNOS−/− mice and involves NK cells. J Mol Med 88, 775–784 (2010). https://doi.org/10.1007/s00109-010-0620-7

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  • DOI: https://doi.org/10.1007/s00109-010-0620-7

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