Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target

Adriana Albini, Claudio Brigati, Agostina Ventura, Girieca Lorusso, Marta Pinter, Monica Morini, Alessandra Mancino, Antonio Sica, Douglas M. Noonan

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background: Angiostatin, 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. Methods: Function 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. Results: Angiostatin 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. Conclusion: Our 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.

Original languageEnglish
Article number5
JournalJournal of Translational Medicine
Volume7
DOIs
Publication statusPublished - Jan 14 2009

Fingerprint

Angiostatins
Immune system
Interleukin-12
Immune System
Blocking Antibodies
Angiogenesis Inhibitors
Animals
Interleukin-12 Receptors
Genes
Cytokines
Macrophages
Kaposi's Sarcoma
Plasminogen
Endothelial cells
Gene Deletion
Innate Immunity
Modulators
Vascular Endothelial Growth Factor A
Blood Vessels
Tumors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Angiostatin anti-angiogenesis requires IL-12 : The innate immune system as a key target. / Albini, Adriana; Brigati, Claudio; Ventura, Agostina; Lorusso, Girieca; Pinter, Marta; Morini, Monica; Mancino, Alessandra; Sica, Antonio; Noonan, Douglas M.

In: Journal of Translational Medicine, Vol. 7, 5, 14.01.2009.

Research output: Contribution to journalArticle

@article{d17f7ed79e20447686f0de61a31f6846,
title = "Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target",
abstract = "Background: Angiostatin, 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. Methods: Function 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. Results: Angiostatin 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. Conclusion: Our 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.",
author = "Adriana Albini and Claudio Brigati and Agostina Ventura and Girieca Lorusso and Marta Pinter and Monica Morini and Alessandra Mancino and Antonio Sica and Noonan, {Douglas M.}",
year = "2009",
month = "1",
day = "14",
doi = "10.1186/1479-5876-7-5",
language = "English",
volume = "7",
journal = "Journal of Translational Medicine",
issn = "1479-5876",
publisher = "BioMed Central Ltd.",

}

TY - JOUR

T1 - Angiostatin anti-angiogenesis requires IL-12

T2 - The innate immune system as a key target

AU - Albini, Adriana

AU - Brigati, Claudio

AU - Ventura, Agostina

AU - Lorusso, Girieca

AU - Pinter, Marta

AU - Morini, Monica

AU - Mancino, Alessandra

AU - Sica, Antonio

AU - Noonan, Douglas M.

PY - 2009/1/14

Y1 - 2009/1/14

N2 - Background: Angiostatin, 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. Methods: Function 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. Results: Angiostatin 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. Conclusion: Our 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.

AB - Background: Angiostatin, 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. Methods: Function 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. Results: Angiostatin 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. Conclusion: Our 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.

UR - http://www.scopus.com/inward/record.url?scp=59349113775&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=59349113775&partnerID=8YFLogxK

U2 - 10.1186/1479-5876-7-5

DO - 10.1186/1479-5876-7-5

M3 - Article

C2 - 19144161

AN - SCOPUS:59349113775

VL - 7

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

SN - 1479-5876

M1 - 5

ER -