poly(I:C) and LPS induce distinct IRF3 and NF-kappaB signaling during type-I IFN and TNF responses in human macrophages.
Macrophages play major roles in the onset of immune responses and inflammation by inducing a variety of cytokines such as TNF and IFN-beta. The pathogen-associated molecular pattern, polyinosinic-polycytidylic acid [poly(I:C)], and LPS were used to study type-I IFN and TNF responses in human macrophages. Additionally, activation of the key signaling pathways, IFN-regulatory factor 3 (IRF3) and NF-kappaB, were studied. We found that TNF production occurred rapidly after LPS stimulation. LPS induced a strong IFN-beta mRNA response within a short time-frame, which subsided at 8 h. The IFN-stimulated genes (ISGs), ISG56 and IFN-inducible protein 10, were strongly induced by LPS. These responses were associated with NF-kappaB and IRF3 activation, as shown by IRF3 dimerization and by nuclear translocation assays. poly(I:C), on the other hand, induced a strong and long-lasting (>12 h) IFN-beta mRNA and protein response, particularly when transfected, whereas only a protracted TNF response was observed when poly(I:C) was transfected. However, these responses were induced in the absence of detectable IRF3 and NF-kappaB signaling. Thus, in human macrophages, poly(I:C) treatment induces a distinct cytokine response when compared with murine macrophages. Additionally, a robust IFN-beta response can be induced in the absence of detectable IRF3 activation.
Reimer
Thornik
T
Institute of Veterinary Virology, University of Bern, Laenggassstrasse 122, Bern CH-3001, Switzerland. reimer@ivv.unibe.ch
Brcic
Marija
M
Schweizer
Matthias
M
Jungi
Thomas W
TW
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D007370:Interferon Type I / Q000235:genetics*; D016899:Interferon-beta / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D011070:Poly I-C / Q000494:pharmacology*; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D014157:Transcription Factors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C484290:IFIT1 protein, human; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D011070:Poly I-C