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Abstract
We have previously shown that the antiviral state of explanted mouse peritoneal macrophages (PM) decays during in vitro culture and that this decay is much more rapid in Lps d PM than it is in Lps n PM. Moreover, Lps n PM can transfer the antiviral state to other cells, whereas Lps d PM cannot. In vitro treatment of Lps n PM with different agents [i.e., bacterial lipopolysaccharide (LPS), interferon (IFN)-γ, tumour necrosis factor (TNF)-α, macrophage colony-stimulating factor (M-CSF) and antibody to Mac-1 antigen] induced an antiviral state to vesicular stomatitis virus (VSV) which was inhibited by antibodies to IFN-β. Treatment of Lps n PM with LPS or IFN-γ resulted in greater accumulation of IFN-β mRNA, whereas no change in the barely detectable levels of IFN-α mRNA was observed. Marked accumulation of IFN-β mRNA was also observed in PM after TNF-α treatment. M-CSF and IFN-γ (but not LPS) also induced an IFN-mediated antiviral state in Lps d PM. Low levels of spontaneous transcription of IFN-β mRNA were detected in nuclei from Lps d PM. Treatment of Lps d PM with IFN-γ for 3 h resulted in the accumulation of IFN-β mRNA without any concomitant increase in the transcription of the IFN-β gene, as determined by run-on transcription assays with isolated nuclei. The addition of as little as 1 international unit/ml of IFN-γ to PM resulted in a 100-fold inhibition of VSV yield. As antibodies to IFN-α/β inhibited only a portion of the IFN-γ-induced antiviral state, such an antiviral state might reflect the synergism between IFN-γ and endogenous IFN-β. In fact, the addition of low doses of both IFN-γ and IFN-β to either Lps n or Lps d PM resulted in synergistic antiviral effects. In vivo treatment of Lps d mice with granulocyte-macrophage (GM)-CSF, M-CSF, IFN-γ or Newcastle disease virus rendered peritoneal cells capable of transferring an antiviral state. These results indicate that (i) various stimuli can induce IFN-β production by PM, (ii) Lps d PM spontaneously transcribe low levels of IFN-β mRNA, even though they cannot transfer an antiviral state, (iii) different stimuli, but not LPS, induce a normal IFN response in Lps d PM, (iv) IFN-γ increases the accumulation of IFN-β mRNA in Lps d PM by post-transcriptional mechanisms and (v) IFN-γ may act synergistically with endogenous IFN-β in inducing a potent antiviral state to VSV in PM.
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