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Published online before print February 5, 2008

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(Journal of Leukocyte Biology. 2008;83:1249-1257.)
© 2008 by Society for Leukocyte Biology

poly(I:C) and LPS induce distinct IRF3 and NF-B signaling during type-I IFN and TNF responses in human macrophages

Institute of Veterinary Virology, University of Bern, Bern, Switzerland

¹Correspondence: Institute of Veterinary Virology, University of Bern, Laenggassstrasse 122, Bern CH-3001, Switzerland. E-mail: reimer{at}ivv.unibe.ch

Macrophages play major roles in the onset of immune responses and inflammation by inducing a variety of cytokines such as TNF and IFN-β. 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-B, were studied. We found that TNF production occurred rapidly after LPS stimulation. LPS induced a strong IFN-β 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-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-β 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-B signaling. Thus, in human macrophages, poly(I:C) treatment induces a distinct cytokine response when compared with murine macrophages. Additionally, a robust IFN-β response can be induced in the absence of detectable IRF3 activation.

Key Words: signal transduction • interferon • transcription factors • gene regulation • cytokines • innate immunity