The anti-angiogenic activity of IL-12 is increased in iNOS-/- mice and involves NK cells.
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.
Bielawska-Pohl
Aleksandra
A
INSERM U 753, Unité Immunologie des Tumeurs, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805, Villejuif, France.
Blesson
Séverine
S
Benlalam
Houssem
H
Trenado
Aurélie
A
Opolon
Paule
P
Bawa
Olivia
O
Rouffiac
Valérie
V
Dus
Danuta
D
Kieda
Claudine
C
Chouaib
Salem
S
D000818:Animals; D042783:Endothelial Cells / Q000473:pathology; D055786:Gene Knockout Techniques; D018664:Interleukin-12 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000473:pathology; D009569:Nitric Oxide / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology
D042461:Vascular Endothelial Growth Factor A; D018664:Interleukin-12; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
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