Inhibition of angiogenesis by interleukin-12 is mediated by the interferon-inducible protein 10.
Interleukin 12 (IL-12), a multifunctional cytokine produced by macrophages and B-cell lines, induces interferon-gamma (IFN-gamma) production, stimulates growth of both T and natural killer cells, promotes Th1-type helper T-cell responses, and inhibits neovascularization. Because the human interferon-inducible protein 10 (IP-10) can also inhibit neovascularization, we tested whether IP-10, induced by IL-12 through the intermediate IFN-gamma, might be a mediator of IL-12 angiogenesis inhibition. We report here that murine IL-12 profoundly inhibited basic fibroblast growth factor (bFGF)-induced Matrigel neovascularization in vivo, and that this effect of IL-12 was neutralized by systemic administration of antibodies to either murine IFN-gamma or IP-10. Murine IL-12 induced murine IP-10 expression in mouse splenocytes, and human IFN-gamma induced human IP-10 expression in purified human endothelial cells, suggesting that IL-12 can induce IP-10 expression in certain cells. These results document the important role of IP-10 as a mediator of angiogenesis inhibition by IL-12, and raise the possibility that IP-10 may also contribute to the antitumor effect of IL-12.
Sgadari
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C
Division of Hematologic Products, Food and Drug Administration, Bethesda, MD 20892, USA.
Angiolillo
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AL
Tosato
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D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D016222:Fibroblast Growth Factor 2; D018664:Interleukin-12