EFFECTS OF DIFFERENT BIOLOGICAL RESPONSE MODIFIERS ON INTERFERON EXPRESSION IN BACTERIAL LIPOPOLYSACCHARIDE (LPS)-RESPONSIVE AND LPS-HYPORESPONSIVE MOUSE PERITONEAL-MACROPHAGES

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-c to PM resulted in a 100-fold inhibition of VSV yield. As antibodies to IFN-α/β inhibited only a portion of the IFN-α-induced antiviral state, such an antiviral state might reflet the synergism between IFN-α 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.