IL-2 Induced Nitric Oxide Synthesis by Tumor Cells in Corultures of Lymphocytes and Tumor Cells / 대한암학회지

ABSTRACT

PURPOSE: Nitric oxide (NO) synthesis has been known to be induced during interleukin-2 (IL-2) therapy. The present study was designed to elucidate mechanisms and roles of IL-2-induced NO synthesis in tumor cells. MATERIALS AND METHODS: Mechanisms of IL-2-induced NO synthesis were evaluated using in vitro culture systems of BALB/c mouse splenic lymphocytes and Meth-A tumor cells. Effects of IL-2-induced NO synthesis by Meth-A tumor cells on the tumor cell proliferation were also evaluated using an NO synthase inhibitor, N -monomethyl- L-arginine (MLA). RESULTS: Cultures of both lymphocytes alone and Meth-A tumor cells alone did not produce any significant amounts of nitrite, a stable metabolite of NO during IL-2 stimulation. In contrast, cocultures of lymphocytes and Meth-A tumor cells produced a large amount of nitrite during IL-2 stimulation. Addition of culture supernatants of lymphocytes incubated with IL-2 induced nitrite production in Meth-A tumor cell cultures. However, addition of culture supernatants of Meth-A tumor cells incubated with IL-2 did not induce nitrite production in lymphocyte cultures. Nitrite accumulation was markedly inhibited by addition of anti-interferon-y antibody, confirming the role of the cytokine in mediating tumor cell NO synthesis. MLA inhibited nitrite production by Meth-A tumor cells in a dose-dependent manner in the presence of culture supernatants of lymphocytes incubated with IL-2. Meth-A tumor cell nitrite production in the presence of increasing concentrations of MLA correlated inversely with tumor cell proliferation. CONCLUSION: NO synthesis can be induced by tumor cells by the secondarily released cytokines from lymphocytes during IL-2 stimulation. Autologous NO synthesized by tumor cells during IL-2 stimulation inhibits proliferation of tumor cells themselves.