Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 83, Issue 5, Pages 1249-1257Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1189/jlb.0607412
Keywords
signal transduction; interferon; transcription factors; gene regulation; cytokines; innate immunity
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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-kappa B, 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-kappa B 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-kappa B 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.
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