Herpes simplex virus type 2 infection of macrophages impairs IL-4-mediated inhibition of NO production through TNF-alpha-induced activation of NF-kappaB.

Nitric oxide (NO) production in macrophages by the interferon (IFN)-gamma-inducible NO synthase has been shown to play a role in clearance of viral infections. We have previously shown that IFN-gamma-induced NO production is augmented by herpes simplex virus type 2 (HSV-2) infection through autocrine tumour necrosis factor (TNF)-alpha 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-gamma-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-alpha secretion and nuclear factor (NF)-kappaB activation significantly, but less in cells concomitantly treated with IFN-gamma. Furthermore, neutralisation of residual TNF-alpha activity or inhibition of NF-kappaB activation largely restored the inhibitory effect of IL-4. The data show that inhibition of IFN-gamma-induced NO production by IL-4 is impaired by HSV-2 infection due to autocrine TNF-alpha-mediated NF-kappaB activation. We suggest that the described phenomenon might be beneficial for the host by limiting high and sustained NO production to infectious foci.