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Cancer Res ; 61(9): 3682-8, 2001 May 01.
Article in English | MEDLINE | ID: mdl-11325839

ABSTRACT

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.


Subject(s)
Apoptosis/physiology , DNA-Binding Proteins/physiology , Interferon-gamma/physiology , Macrophages/immunology , Nitric Oxide/physiology , Nuclear Proteins/physiology , Phosphoproteins/physiology , Signal Transduction/physiology , Animals , Binding Sites , Cell Hypoxia/physiology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Enzyme Induction , Female , Hypoxia-Inducible Factor 1 , Hypoxia-Inducible Factor 1, alpha Subunit , Interferon Regulatory Factor-1 , Interferon-gamma/pharmacology , Macrophage Activation/physiology , Macrophages/enzymology , Melanoma, Experimental/immunology , Mice , Mice, Inbred C57BL , Nitric Oxide Synthase/biosynthesis , Nitric Oxide Synthase/genetics , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolism , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Saccharomyces cerevisiae/genetics , Transcription Factors/physiology , Transcriptional Activation , Transfection
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