Interferon Regulatory Factor (IRF)-1 Is a Master Regulator of the Cross Talk between Macrophages and L929 Fibrosarcoma Cells for Nitric Oxide Dependent Tumoricidal Activity

Macrophage tumoricidal activity relies, mainly, on the release of Tumor NecrosisFactor alpha (TNFα) and/or on reactive oxygen or nitrogen intermediates. Inthe present work, we investigated the cytotoxic activity of resident peritonealmacrophages against L929 fibrosarcoma cell line in vitro andin vivo. Resident macrophages lysed L929 cells in a mechanismindependent of TNFα and cell-to-cell contact. The cytotoxic activity waslargely dependent on nitric oxide (NO) release since treatment with L-NAME (NOSinhibitor) inhibited L929 cells killing. Macrophages from mice with targeted deletionof inducible NO synthase (iNOS) together with L929 cells produced less NO anddisplayed lower, but still significant, tumoricidal activity. Notably, NO productionand tumor lysis were abolished in co-cultures with macrophages deficient inInterferon Regulatory Factor, IRF-1. Importantly, the in vitrofindings were reproduced in vivo as IRF-1 deficient animalsinoculated i.p with L929 cells were extremely susceptible to tumor growth and theirmacrophages did not produce NO, while WT mice killed L929 tumor cells and theirmacrophages produced high levels of NO. Our results indicate that IRF-1 is a masterregulator of bi-directional interaction between macrophages and tumor cells. Overall,IRF-1 was essential for NO production by co-cultures and macrophage tumoricidalactivity in vitro as well as for the control of tumor growthin vivo.