Inhibition of NO production in macrophages by IL-13 is counteracted by Herpes simplex virus infection through tumor necrosis factor-alpha-induced activation of NK-kappa B
Paludan, S.R.; Ellermann-Eriksen, S.; Malmgaard, L.; Mogensen, S.C.
European Cytokine Network 11(2): 275-282
2000
ISSN/ISBN: 1148-5493 PMID: 10903807 Document Number: 513677
Interleukin (IL)-13 is known to antagonize many interferon (IFN)-gamma-activated functions in macrophages and among these, nitric oxide (NO) production. We have previously shown that this function of IL-13 is reduced in Herpes simplex virus type 2 (HSV-2)-infected macrophages. In the present study we show that IL-13 and IFN-gamma are indeed produced during infection of BALB/c mice with HSV-2. The lack of inhibitory function of IL-13 in infected macrophages, which was not overcome even at very high concentrations of IL-13, was not due to impaired IL-13 signalling, since virus infection did not affect IL-13-mediated activation of STAT6 (signal transducer and activator of transcription 6). Neutralizing tumour necrosis factor (TNF)-alpha antibodies, however, largely restored the effect of IL-13 on NO production in virus-infected macrophages. The same was observed after treatment of the cells with inhibitors of nuclear factor (NF)-kappa B activation, known to be involved in enhancement of IFN-gamma-induced NO production. Even though IL-13 reduced TNF-alpha secretion by 50%, this did not impair NF-kappa B activation in IFN-gamma-treated cells infected with HSV-2. The results indicate that TNF-alpha, secreted by virus-infected macrophages, activates NF-kappa B which impairs the IL-13-mediated inhibition of inducible NO synthase (iNOS) expression. This could imply that a sustained NO production would be focused to sites of active virus replication.