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.
Paludan
S R
SR
Department of Medical Microbiology and Immunology, University of Aarhus, Denmark.
Ellermann-Eriksen
S
S
Malmgaard
L
L
Mogensen
S C
SC
D000818:Animals; D002460:Cell Line; D018258:Herpesvirus 2, Human / Q000502:physiology*; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000821:virology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D016328:NF-kappa B; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma