Stimulation of Inducible Nitric Oxide Synthase Expression by Beta Interferon Increases Necrotic Death of Macrophages upon Listeria monocytogenes Infection

Murine macrophage death upon infection with Listeria monocytogenes was previously shown to be increased by beta interferon, produced by the infected cells. We saw that interferon-upregulated caspase activation or other interferon-inducible, death-associated proteins, including TRAIL, protein kinase R, and p53, were not necessary for cell death. Macrophage death was reduced when inducible nitric oxide synthase (iNOS) was inhibited during infection, and iNOS-deficient macrophages were less susceptible to death upon infection than wild-type cells. The production of nitric oxide correlated with increased death, while no role was seen for iNOS in control of Listeria numbers during infection of resting macrophages. This indicates that the induction of iNOS by beta interferon in cells infected with L. monocytogenes contributes to cell death. Based on morphology, the maintenance of mitochondrial membrane potential, and a lack of dependence on caspase 1, we characterize the type of cell death occurring and show that infected macrophages die by interferon-upregulated necrosis.