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.
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.
Paludan
S R
SR
Department of Medical Microbiology and Immunology, The Bartholin Building, University of Aarhus, DK-8000 Aarhus C, Denmark. srp@microbiology.au.dk
Ellermann-Eriksen
S
S
Malmgaard
L
L
Mogensen
S C
SC
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006558:Herpes Genitalis / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D018258:Herpesvirus 2, Human / Q000472:pathogenicity* / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*; D014779:Virus Replication
D017931:DNA Primers; D018793:Interleukin-13; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma