A role for the interferon-inducible protein 10 in inhibition of angiogenesis by interleukin-12.
We have developed a nude mouse model in which tumor regression is reproducibly induced by coinjection with or intratumor inoculation of EBV-immortalized B cells. A wide spectrum of tumor-derived human cell lines can be established as subcutaneous tumors in sublethally irradiated athymic mice. Most of these tumors are induced to regress by human B cells immortalized with EBV. The tumor regression process is characterized by superficial necrosis and scarring that progressively extends itself to involve all or most of the tumor. Microscopically, tumor regression is characterized by tumor tissue necrosis, evidence of vascular damage with intimal thickening and capillary thrombosis, and macrophage, but not lymphocyte or neutrophil, infiltration. Profiles of cytokine expression differed between progressive and regressive Burkitt's tumors in that regressive tumors expressed larger levels of TNF-alpha, IL-6, IFN-gamma, IP-10, Mig, and IL-12 p35, but not other chemokines/cytokines. IP-10 and IL-12 were found to act as potent inhibitors of angiogenesis in vivo. IL-12 is an inducer of IFN-gamma and indirectly of IP-10, an IFN-gamma-inducible protein, raising the possibility that the antiangiogenic effect of IL-12 is mediated by IP-10. Previous studies have demonstrated that IL-12 has potent antitumor activity in vivo. Much of this activity was dependent on the presence of IFN-gamma and of immune T cells. The observation, made in our studies, that IP-10 is an inhibitor of angiogenesis raises the possibility that IP-10 might contribute to the antitumor effects of IL-12 by inhibiting angiogenesis. Inhibition of angiogenesis by IP-10 and IL-12 is T-cell independent, suggesting that IL-12 targets at least two compartments, T cells and capillaries, each capable of mediating antitumor effects.
Angiolillo
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AL
Children's National Medical Center, Washington, DC 20010, USA.
Sgadari
C
C
Tosato
G
G
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D002051:Burkitt Lymphoma / Q000473:pathology; D054357:Chemokine CXCL10; D018925:Chemokines / Q000494:pharmacology; D019743:Chemokines, CXC; D016207:Cytokines / Q000502:physiology*; D018664:Interleukin-12 / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D014183:Transplantation, Heterologous
D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D018664:Interleukin-12