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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1612-1621
Contribution of Natural Killer Cells to Inhibition of
Angiogenesis by Interleukin-12
Lei Yao,
Cecilia Sgadari,
Keizo Furuke,
Eda T. Bloom,
Julie Teruya-Feldstein, and
Giovanna Tosato
From the Divisions of Hematologic Products and of Cellular and Gene
Therapies, Center for Biologics Evaluation and Research, Food and Drug
Administration; and the Hematopathology Section, Laboratory of
Pathology, National Cancer Institute, Bethesda, MD.
Interleukin-12 (IL-12) inhibits angiogenesis in vivo by inducing
interferon- (IFN-) and other downstream mediators. Here, we
report that neutralization of natural killer (NK) cell function with
antibodies to either asialo GM1 or NK 1.1 reversed IL-12 inhibition of
basic fibroblast growth factor (bFGF)-induced angiogenesis in athymic
mice. By immunohistochemistry, those sites where bFGF-induced neovascularization was inhibited by IL-12 displayed accumulation of NK cells and the presence of IP-10-positive cells. Based on expression of the cytolytic mediators perforin and granzyme B, the NK
cells were locally activated. Experimental Burkitt lymphomas treated
locally with IL-12 displayed tumor tissue necrosis, vascular damage,
and NK-cell infiltration surrounding small vessels. After activation in
vitro with IL-12, NK cells from nude mice became strongly cytotoxic for
primary cultures of syngeneic aortic endothelial cells. Cytotoxicity
was neutralized by antibodies to IFN-. These results document that
NK cells are required mediators of angiogenesis inhibition by IL-12,
and provide evidence that NK-cell cytotoxicity of endothelial cells is
a potential mechanism by which IL-12 can suppress neovascularization.
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