The numerous studies on Angiostatin (AST) mechanisms of angiogenesis inhibition have focused on the potential receptor-mediated interactions with endothelial cells. Although these studies have provided potential mechanisms, no single receptor system has been definitively shown to mediate AST activity. Recent studies have shown that inflammatory cells, in particular macrophages and neutrophils, are also targets of AST. These cells are part of a network that generates one of the most powerful anti-angiogenic cytokines: interleukin-12 (IL-12). We show that in in vivo preclinical studies, IL-12 is an essential mediator of AST antiangiogenic activity. Function blocking antibodies to IL-12 revert angiogenesis inhibition induced by AST. Further, AST is unable to exert angiogenesis inhibition in mice with gene targeted deletions of the IL-12 receptor IL-12R2, specific for IL-12, or in mice gene targeted for the IL- 12 p40 subunit. However, AST retains anti-angiogenic activity in IFNgene targeted mice, suggesting an IFNindependent angiogenesis inhibition mechanism as previously observed. We also identified a short synthetic peptide localized to the lysine binding domain that completely reproduces the IL-12 dependent anti-angiogenic properties of AST. Since endothelial cells do not express the IL-12 receptor, nor do they essentially change gene expression patterns when treated with AST in vitro, our data show that the immune system forms an integral part of the anti-angiogenic effects of AST, by both responding to AST and providing downstream signals to the endothelium. AST induced IL-12 synthesis by human macrophages polarized toward M1 phenotype in vitro. We also identified a short synthetic peptide with potential application in oncological therapy, that reproduced the IL-12 dependent anti-angiogenic properties of angiostatin.
The role of innate immunity in tumor angiogenesis: identification of downstream mediators in the IL-12 mediated anti-angiogenic activity of Angiostatin / Lorusso, Girieca. - (2008).
The role of innate immunity in tumor angiogenesis: identification of downstream mediators in the IL-12 mediated anti-angiogenic activity of Angiostatin.
Lorusso, Girieca
2008-01-01
Abstract
The numerous studies on Angiostatin (AST) mechanisms of angiogenesis inhibition have focused on the potential receptor-mediated interactions with endothelial cells. Although these studies have provided potential mechanisms, no single receptor system has been definitively shown to mediate AST activity. Recent studies have shown that inflammatory cells, in particular macrophages and neutrophils, are also targets of AST. These cells are part of a network that generates one of the most powerful anti-angiogenic cytokines: interleukin-12 (IL-12). We show that in in vivo preclinical studies, IL-12 is an essential mediator of AST antiangiogenic activity. Function blocking antibodies to IL-12 revert angiogenesis inhibition induced by AST. Further, AST is unable to exert angiogenesis inhibition in mice with gene targeted deletions of the IL-12 receptor IL-12R2, specific for IL-12, or in mice gene targeted for the IL- 12 p40 subunit. However, AST retains anti-angiogenic activity in IFNgene targeted mice, suggesting an IFNindependent angiogenesis inhibition mechanism as previously observed. We also identified a short synthetic peptide localized to the lysine binding domain that completely reproduces the IL-12 dependent anti-angiogenic properties of AST. Since endothelial cells do not express the IL-12 receptor, nor do they essentially change gene expression patterns when treated with AST in vitro, our data show that the immune system forms an integral part of the anti-angiogenic effects of AST, by both responding to AST and providing downstream signals to the endothelium. AST induced IL-12 synthesis by human macrophages polarized toward M1 phenotype in vitro. We also identified a short synthetic peptide with potential application in oncological therapy, that reproduced the IL-12 dependent anti-angiogenic properties of angiostatin.File | Dimensione | Formato | |
---|---|---|---|
PhD thesis lorusso completa.pdf
embargo fino al 31/12/2100
Descrizione: testo completo tesi
Tipologia:
Tesi di dottorato
Licenza:
Non specificato
Dimensione
1.95 MB
Formato
Adobe PDF
|
1.95 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.