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Intersection of Interferon and Hypoxia Signal Transduction Pathways in Nitric Oxide-induced Tumor Apoptosis¹

Division of Cardiology, Department of Medicine [D. S. T., C. B., C. J. L.], and Departments of Oncology [T. W., D. A. P.], and Dermatology [E. A. R.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and Division of Hematology and Oncology [E. L. H.], Brigham and Women‘s Hospital, Boston, Massachusetts 02115

Activated macrophages play a central role in antitumor immunity. However, the stimuli that activate macrophages to kill tumor cells are not completely understood. Because the center of solid tumors can be hypoxic, we hypothesized that hypoxia may be an important signal in activating macrophages to kill tumor cells. Hypoxia stimulates IFN-primed macrophages to express the inducible nitric oxide synthase (NOS2) and to synthesize nitric oxide (NO). We show that this synergy between IFN and hypoxia is mediated by the direct interaction of the hypoxia inducible factor-1 (HIF-1) and IFN regulatory factor-1 (IRF-1), which are both required for the hypoxic transcription of NOS2. This interaction between HIF-1 and IRF-1 may explain the mechanism by which macrophages infiltrating into tumors are activated to express NOS2 and to produce NO, a mediator of tumor apoptosis.

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