Viral Infection of Macrophages Profoundly Alters Requirements for Induction of Nitric Oxide Synthesis

AbstractActivated mouse macrophages can produce high levels of nitric oxide, an antimicrobial effector molecule recently also implicated in antiviral defense. As viral infection may alter macrophage functions, nitric oxide production was investigated in murine macrophages infected with a Flavivirus, tick-borne encephalitis virus. Infected macrophages produced high levels of nitric oxide upon stimulation with lipopolysaccharide without priming, while in control macrophages induction of nitric oxide production by lipopolysaccharide required priming with interferon-γ. Addition of interferon-γ to infected macrophages further increased lipopolysaccharide-stimulated nitric oxide production. In contrast, nitric oxide production upon stimulation with interferon-γ plus tumor necrosis factor-α was markedly reduced in infected macrophages. Downregulation of interferon-γ plus tumor necrosis factor-α-induced nitric oxide synthesis by viral infection could be attributed to endogenous interferon-αβ produced by infected macrophages. Addition of interferon-αβ to uninfected macrophages inhibited interferon-γ plus tumor necrosis factor-α-induced nitric oxide production, and addition of interferon-αβ antibodies to infected macrophages increased identically stimulated nitric oxide production to normal levels. Thus, interferon-αβ mimicked the effect of viral infection on macrophage nitric oxide production. These findings indicate that viral infection profoundly alters requirements of mouse macrophages for induction of nitric oxide synthesis, depending on the activating signal applied. The described effects of viral infection of macrophages on the regulation of nitric oxide production add new complexity to the role of nitric oxide in host defense against viruses