IL-2 AND IP-10 AND IL-15 ARE POTENT REGULATORS OF ANGIOGENESIS

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IL-12 is a multifunctional cytokine produced by macrophages, B cell lines and other cells that stimulates the proliferation of T cells and NK cells, enhances non-specific cytolytic functions, induces Interferon-gamma production, and promotes the development of Th1-type T cell responses. In murine models IL-12 has demonstrated antitumor , antimicrobial and antifungal activities. Because the mechanisms responsible for the antitumor activity of IL-12 are largely unknown, we explored the possibility that IL-12 may act as an inhibitor of angiogenesis. Tumor cells need to attract new vessels to grow locally and to induce distant metastasis, and a number of inhibitors of angiogenesis have antitumor activity. In the present studies we have shown that IL-12 is a potent inhibitor of angiogenesis in vivo. We have further shown that this effect is indirectly mediated through interferon gamma and, secondarily IP-10, a member of the alpha chemokine family that functions as a potent inhibitor of angiogenesis in vivo. By contrast, IL-15 potently stimulates neovascularization in vivo, acting directly on endothelial cells. IL-12 is presently being tested in initial clinical trials to assess its potential as a cancer therapeutic. Preclinical studies have documented that IL-12 can exert potent antitumor activity against a variery of experimental tumors, as well as anti-microbial and anti-fungal activity against a variety of infectious agents. Although IL-12 is known to exibit a variety of effects on the immune system that explain its anti-microbial functions, our understanding of its antitumor effects is conjectural. It would be very important to know how IL-12 is tumoricydal, and this information may be critical in designing product development. In particular, this information may help in predicting its toxicity. Our studies have confirmed i that IL-12 is an inhibitor of angiogenesis in vivo, and have further established that this activity is indirecly mediated through interferon-gamma and, secondarily, IP-10. In the course of these studies, we have developed improved biological tests for IL-12, established novel in vitro and in vivo models in which to study effects on angiogenesis.