Herpes simplex virus type 2 infection of macrophages impairs IL-4-mediatedinhibition of NO production through TNF-alpha-induced activation of NF-kappa B

Nitric oxide (NO) production in macrophages by the interferon (IFN)-gamma-i nducible NO synthase has been shown to play a role in clearance of viral in fections. We have previously shown that IFN-gamma-induced NO production is augmented by herpes simplex virus type 2 (HSV-2) infection through autocrin e tumour necrosis factor (TNF)-alpha secretion and is inhibited by interleu kin (IL)-4. Here we in investigated the effect of HSV-2 infection on the in hibitory function of IL-4. Virus infection of mouse J774A.1 macrophages str ongly reduced the ability of IL-4 to inhibit IFN-gamma-induced NO productio n, 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 reduc ed virus-induced TNF-alpha secretion and nuclear factor (NF)-kappa B activa tion significantly, but less in cells concomitantly treated with IFN-gamma. Furthermore, neutralisation of residual TNF-alpha activity or inhibition o f NF-kappa B activation largely restored the inhibitory effect of IL-4. The data show that inhibition of IFN-gamma-induced NO production by IL-4 is im paired by HSV-2 infection due to autocrine TNF-alpha-mediated NF-kappa B ac tivation. We suggest that the described phenomenon might be beneficial for the host by limiting high and sustained NO production to infectious foci.