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

<p<Abstract</p< <p<Background</p< <p<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.</p< <p<Methods</p< <p<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.</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Morini Monica [verfasserIn] Pinter Marta [verfasserIn] Lorusso Girieca [verfasserIn] Ventura Agostina [verfasserIn] Brigati Claudio [verfasserIn] Albini Adriana [verfasserIn] Mancino Alessandra [verfasserIn] Sica Antonio [verfasserIn] Noonan Douglas M [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2009

Übergeordnetes Werk:	In: Journal of Translational Medicine - BMC, 2003, 7(2009), 1, p 5
Übergeordnetes Werk:	volume:7 ; year:2009 ; number:1, p 5

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/1479-5876-7-5

Katalog-ID:	DOAJ066209633

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allfields	10.1186/1479-5876-7-5 doi (DE-627)DOAJ066209633 (DE-599)DOAJ2e79996c53724eb9b576e2501f3e44d2 DE-627 ger DE-627 rakwb eng Morini Monica verfasserin aut Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target 2009 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<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.</p< <p<Methods</p< <p<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.</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Medicine R Pinter Marta verfasserin aut Lorusso Girieca verfasserin aut Ventura Agostina verfasserin aut Brigati Claudio verfasserin aut Albini Adriana verfasserin aut Mancino Alessandra verfasserin aut Sica Antonio verfasserin aut Noonan Douglas M verfasserin aut In Journal of Translational Medicine BMC, 2003 7(2009), 1, p 5 (DE-627)369084136 (DE-600)2118570-0 14795876 nnns volume:7 year:2009 number:1, p 5 https://doi.org/10.1186/1479-5876-7-5 kostenfrei https://doaj.org/article/2e79996c53724eb9b576e2501f3e44d2 kostenfrei http://www.translational-medicine.com/content/7/1/5 kostenfrei https://doaj.org/toc/1479-5876 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2009 1, p 5
spelling	10.1186/1479-5876-7-5 doi (DE-627)DOAJ066209633 (DE-599)DOAJ2e79996c53724eb9b576e2501f3e44d2 DE-627 ger DE-627 rakwb eng Morini Monica verfasserin aut Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target 2009 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<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.</p< <p<Methods</p< <p<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.</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Medicine R Pinter Marta verfasserin aut Lorusso Girieca verfasserin aut Ventura Agostina verfasserin aut Brigati Claudio verfasserin aut Albini Adriana verfasserin aut Mancino Alessandra verfasserin aut Sica Antonio verfasserin aut Noonan Douglas M verfasserin aut In Journal of Translational Medicine BMC, 2003 7(2009), 1, p 5 (DE-627)369084136 (DE-600)2118570-0 14795876 nnns volume:7 year:2009 number:1, p 5 https://doi.org/10.1186/1479-5876-7-5 kostenfrei https://doaj.org/article/2e79996c53724eb9b576e2501f3e44d2 kostenfrei http://www.translational-medicine.com/content/7/1/5 kostenfrei https://doaj.org/toc/1479-5876 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2009 1, p 5
allfields_unstemmed	10.1186/1479-5876-7-5 doi (DE-627)DOAJ066209633 (DE-599)DOAJ2e79996c53724eb9b576e2501f3e44d2 DE-627 ger DE-627 rakwb eng Morini Monica verfasserin aut Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target 2009 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<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.</p< <p<Methods</p< <p<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.</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Medicine R Pinter Marta verfasserin aut Lorusso Girieca verfasserin aut Ventura Agostina verfasserin aut Brigati Claudio verfasserin aut Albini Adriana verfasserin aut Mancino Alessandra verfasserin aut Sica Antonio verfasserin aut Noonan Douglas M verfasserin aut In Journal of Translational Medicine BMC, 2003 7(2009), 1, p 5 (DE-627)369084136 (DE-600)2118570-0 14795876 nnns volume:7 year:2009 number:1, p 5 https://doi.org/10.1186/1479-5876-7-5 kostenfrei https://doaj.org/article/2e79996c53724eb9b576e2501f3e44d2 kostenfrei http://www.translational-medicine.com/content/7/1/5 kostenfrei https://doaj.org/toc/1479-5876 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2009 1, p 5
allfieldsGer	10.1186/1479-5876-7-5 doi (DE-627)DOAJ066209633 (DE-599)DOAJ2e79996c53724eb9b576e2501f3e44d2 DE-627 ger DE-627 rakwb eng Morini Monica verfasserin aut Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target 2009 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<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.</p< <p<Methods</p< <p<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.</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Medicine R Pinter Marta verfasserin aut Lorusso Girieca verfasserin aut Ventura Agostina verfasserin aut Brigati Claudio verfasserin aut Albini Adriana verfasserin aut Mancino Alessandra verfasserin aut Sica Antonio verfasserin aut Noonan Douglas M verfasserin aut In Journal of Translational Medicine BMC, 2003 7(2009), 1, p 5 (DE-627)369084136 (DE-600)2118570-0 14795876 nnns volume:7 year:2009 number:1, p 5 https://doi.org/10.1186/1479-5876-7-5 kostenfrei https://doaj.org/article/2e79996c53724eb9b576e2501f3e44d2 kostenfrei http://www.translational-medicine.com/content/7/1/5 kostenfrei https://doaj.org/toc/1479-5876 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2009 1, p 5
allfieldsSound	10.1186/1479-5876-7-5 doi (DE-627)DOAJ066209633 (DE-599)DOAJ2e79996c53724eb9b576e2501f3e44d2 DE-627 ger DE-627 rakwb eng Morini Monica verfasserin aut Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target 2009 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier <p<Abstract</p< <p<Background</p< <p<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.</p< <p<Methods</p< <p<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.</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p< Medicine R Pinter Marta verfasserin aut Lorusso Girieca verfasserin aut Ventura Agostina verfasserin aut Brigati Claudio verfasserin aut Albini Adriana verfasserin aut Mancino Alessandra verfasserin aut Sica Antonio verfasserin aut Noonan Douglas M verfasserin aut In Journal of Translational Medicine BMC, 2003 7(2009), 1, p 5 (DE-627)369084136 (DE-600)2118570-0 14795876 nnns volume:7 year:2009 number:1, p 5 https://doi.org/10.1186/1479-5876-7-5 kostenfrei https://doaj.org/article/2e79996c53724eb9b576e2501f3e44d2 kostenfrei http://www.translational-medicine.com/content/7/1/5 kostenfrei https://doaj.org/toc/1479-5876 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2009 1, p 5
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authorswithroles_txt_mv	Morini Monica @@aut@@ Pinter Marta @@aut@@ Lorusso Girieca @@aut@@ Ventura Agostina @@aut@@ Brigati Claudio @@aut@@ Albini Adriana @@aut@@ Mancino Alessandra @@aut@@ Sica Antonio @@aut@@ Noonan Douglas M @@aut@@
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title	Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target
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title_full	Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target
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author_browse	Morini Monica Pinter Marta Lorusso Girieca Ventura Agostina Brigati Claudio Albini Adriana Mancino Alessandra Sica Antonio Noonan Douglas M
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title_sort	angiostatin anti-angiogenesis requires il-12: the innate immune system as a key target
title_auth	Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target
abstract	<p<Abstract</p< <p<Background</p< <p<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.</p< <p<Methods</p< <p<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.</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p<
abstractGer	<p<Abstract</p< <p<Background</p< <p<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.</p< <p<Methods</p< <p<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.</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p<
abstract_unstemmed	<p<Abstract</p< <p<Background</p< <p<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.</p< <p<Methods</p< <p<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.</p< <p<Results</p< <p<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.</p< <p<Conclusion</p< <p<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.</p<
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title_short	Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target
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