INHIBITION OF ANGIOGENESIS BY INTERLEUKIN-12 IS MEDIATED BY THE INTERFERON-INDUCIBLE PROTEIN-10

Interleukin 12 (IL-12), a multifunctional cytokine produced by macroph ages and B-cell lines, induces interferon-gamma (IFN-gamma) production , stimulates growth of both T and natural killer cells, promotes Th1-t ype helper T-cell responses, and inhibits neovascularization. Because the human interferon-inducible protein 10 (IP-10) can also inhibit neo vascularization, we tested whether IP-10, induced by IL-12 through the intermediate IFN-gamma, might be a mediator of IL-12 angiogenesis inh ibition. We report here that murine IL-12 profoundly inhibited basic f ibroblast growth factor (bFGF)-induced Matrigel neo-vascularization in vivo, and that this effect of IL-12 was neutralized by systemic admin istration of antibodies to either murine IFN-gamma or IP-10. Murine IL -12 induced murine IP-10 expression in mouse splenocytes, and human IF N-gamma induced human IP-10 expression in purified human endothelial c ells, suggesting that IL-12 can induce IP-10 expression in certain cel ls. These results document the important role of IP-10 as a mediator o f angiogenesis inhibition by IL-12, and raise the possibility that IP- 10 may also contribute to the antitumor effect of IL-12. This is a US government work. There are no restrictions on its use.