1887

Abstract

Nitric oxide (NO), produced in interferon (IFN)-- activated murine macrophages by the enzyme inducible nitric oxide synthase (iNOS), has been found to have antiviral properties. We have previously shown that herpes simplex virus type 2 (HSV-2) infection of macrophages synergistically enhances IFN--induced NO production, and we now extend these findings by providing evidence that virus- induced tumour necrosis factor (TNF)-α mediates activation of the transcription factor nuclear factor (NF)-B, which in turn is responsible for the synergistic effect. HSV-2 infection and IFN- stimulation of macrophages synergistically induced TNF-α secretion and nuclear translocation of NF-B, which bound to a sequence corresponding to a B site in the iNOS promoter. The effect of HSV-2 on NF-B and NO production was eliminated when cells were treated with antibodies to TNF-α, and direct inhibition of NF-B activation with pyrrolidinedithio- carbamate (PDTC) also blocked the effect of HSV-2 infection on NO production. The effect of the NF-B activation inhibitor was not mediated through inhibition of the production of interferon regulatory factor (IRF)-1 or of TNF-α itself, and a possible alternative mechanism of activation of NF-B through virus-induced activation of the kinase PKR was also ruled out. Thus, our data indicate that NF-B activation, through virus-induced autocrine TNF-α secretion, is responsible for the synergistic effect of HSV-2 infection on IFN--induced NO production, and that such activation might constitute a mechanism by which high-output NO production is targeted to infectious foci.

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1998-11-01
2022-05-29
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