Nitric Oxide, a Mediator of Inflammation, Suppresses Tumorigenesis

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Abstract
Inflammation influences the development of cancer. The nitric oxide synthase (NOS2) is induced by inflammatory cytokines, e.g., tumor necrosis factor α and interleukin 1β, and produces nitric oxide (NO·), a critical mediator of the inflammatory response. Because p53 governs NO· production by transcriptionally transrepressing NOS2, we used a genetic strategy to determine whether NO· and p53 cooperatively regulate tumorigenesis. Lymphomas developed more rapidly in p53−/−NOS2−/− or p53−/−NOS2+/− mice than in p53−/−NOS2+/+ mice that were cross-bred into a >95% C57BL6 background and maintained in a pathogen-free condition. Likewise, sarcomas and lymphomas developed faster in p53+/−NOS2−/− or p53+/−NOS2+/− than in p53+/−NOS2+/+ mice. When compared with the double knockout mice, p53−/−NOS2+/+ mice showed a higher apoptotic index and a decreased proliferation index with an increased expression of death receptor ligands, CD95-L and tumor necrosis factor-related apoptosis-inducing ligand, and the cell cycle checkpoint protein, p21waf1, in the spleen and thymus before tumor development. Furthermore, mice deficient in both p53 and NOS2 produced a high level of anti-inflammatory interleukin 10 when compared with p53-deficient mice. These studies provide genetic and mechanistic evidence that NO· can suppress tumorigenesis.