Nitric oxide (NO) production in macrophages by the interferon (IFN)-γ-inducible NO synthase has been shown to play a role in clearance of viral infections. We have previously shown that IFN-γ-induced NO production is augmented by herpes simplex virus type 2 (HSV-2) infection through autocrine tumour necrosis factor (TNF)-α secretion and is inhibited by interleukin (IL)-4. Here we investigated the effect of HSV-2 infection on the inhibitory function of IL-4. Virus infection of mouse J774A.1 macrophages strongly reduced the ability of IL-4 to inhibit IFN-γ-induced NO production, even at very high IL-4 concentrations. The effect of HSV-2 infection did not involve the IL-4 signal transduction pathway through STAT6. IL-4 reduced virus-induced TNF-α secretion and nuclear factor (NF)-κB activation significantly, but less in cells concomitantly treated with IFN-γ. Furthermore, neutralisation of residual TNF-α activity or inhibition of NF-κB activation largely restored the inhibitory effect of IL-4. The data show that inhibition of IFN-γ-induced NO production by IL-4 is impaired by HSV-2 infection due to autocrine TNF-α-mediated NF-κB activation. We suggest that the described phenomenon might be beneficial for the host by limiting high and sustained NO production to infectious foci.
Archives of Virology – Springer Journals
Published: Mar 1, 2000
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