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

Autor(es)

Nascimento, Flavia R. F. ^[1] ; Gomes, Eliane A. ^[2] ; Russo, Momtchilo ^[2] ; Lepique, Ana P. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Fed Maranhao, Ctr Biol Sci & Hlth, Dept Pathol, Sao Luis - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Dept Imunol, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 10, n. 2 FEB 6 2015.
• Citações Web of Science: 9

Resumo

Macrophage tumoricidal activity relies, mainly, on the release of Tumor Necrosis Factor alpha (TNF alpha) and/or on reactive oxygen or nitrogen intermediates. In the present work, we investigated the cytotoxic activity of resident peritoneal macrophages against L929 fibrosarcoma cell line in vitro and in vivo. Resident macrophages lysed L929 cells in a mechanism independent of TNF alpha and cell-to-cell contact. The cytotoxic activity was largely dependent on nitric oxide (NO) release since treatment with L-NAME (NOS inhibitor) inhibited L929 cells killing. Macrophages from mice with targeted deletion of inducible NO synthase (iNOS) together with L929 cells produced less NO and displayed lower, but still significant, tumoricidal activity. Notably, NO production and tumor lysis were abolished in co-cultures with macrophages deficient in Interferon Regulatory Factor, IRF-1. Importantly, the in vitro findings were reproduced in vivo as IRF-1 deficient animals inoculated i.p with L929 cells were extremely susceptible to tumor growth and their macrophages did not produce NO, while WT mice killed L929 tumor cells and their macrophages produced high levels of NO. Our results indicate that IRF-1 is a master regulator of bi-directional interaction between macrophages and tumor cells. Overall, IRF-1 was essential for NO production by co-cultures and macrophage tumoricidal activity in vitro as well as for the control of tumor growth in vivo. (AU)

• Processo FAPESP: 13/24694-1 - Imunoterapia na asma experimental por agonistas de receptores toll-like, infecção ou tolerância
• Beneficiário: Momtchilo Russo
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 10/20010-2 - Modulação da resposta imune por células tumorais
• Beneficiário: Ana Paula Lepique
• Modalidade de apoio: Auxílio à Pesquisa - Regular