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Journal of Translational Medicine

, 7:5

First Online: 14 January 2009Received: 16 December 2008Accepted: 14 January 2009DOI: 10.1186-1479-5876-7-5

Cite this article as: Albini, A., Brigati, C., Ventura, A. et al. J Transl Med 2009 7: 5. doi:10.1186-1479-5876-7-5

Abstract

BackgroundAngiostatin, an endogenous angiogenesis inhibitor, is a fragment of plasminogen. Its anti-angiogenic activity was discovered with functional assays in vivo, however, its direct action on endothelial cells is moderate and identification of definitive mechanisms of action has been elusive to date. We had previously demonstrated that innate immune cells are key targets of angiostatin, however the pathway involved in this immune-related angiogenesis inhibition was not known. Here we present evidence that IL-12, a principal TH1 cytokine with potent anti-angiogenic activity, is the mediator of angiostatin-s activity.

MethodsFunction blocking antibodies and gene-targeted animals were employed or in vivo studies using the subcutaneous matrigel model of angiogenesis. Quantitative real-time PCR were used to assess modulation of cytokine production in vitro.

ResultsAngiostatin inhibts angiogenesis induced by VEGF-TNFα or supernatants of Kaposi-s Sarcoma cells a highly angiogenic and inflammation-associated tumor. We found that function-blocking antibodies to IL-12 reverted angiostatin induced angiogenesis inhibition. The use of KO animal models revealed that angiostatin is unable to exert angiogenesis inhibition in mice with gene-targeted deletions of either the IL-12 specific receptor subunit IL-12Rβ2 or the IL-12 p40 subunit. Angiostatin induces IL-12 mRNA synthesis by human macrophages in vitro, suggesting that these innate immunity cells produce IL-12 upon angiostatin stimulation and could be a major cellular mediator.

ConclusionOur data demonstrate that an endogenous angiogenesis inhibitor such as angiostatin act on innate immune cells as key targets in inflammatory angiogenesis. Angiostatin proves to be anti-angiogenic as an immune modulator rather than a direct anti-vascular agent. This article is dedicated to the memory of Prof Judah Folkman for his leadership and for encouragement of these studies.

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-7-5 contains supplementary material, which is available to authorized users.

Adriana Albini, Claudio Brigati contributed equally to this work.

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Autor: Adriana Albini - Claudio Brigati - Agostina Ventura - Girieca Lorusso - Marta Pinter - Monica Morini - Alessandra Mancino -

Fuente: https://link.springer.com/







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