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Published online before print February 5, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0607412

Received for publication June 19, 2007.
Revised November 16, 2007.
Accepted for publication November 30, 2007.

Article

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

^@ To whom correspondence should be addressed. E-mail: reimer{at}ivv.unibe.ch.

	Abstract

Macrophages play major roles in the onset of immune responses and inflammation by inducing a variety of cytokines such as TNF and IFN-. 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- 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- 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- response can be induced in the absence of detectable IRF3 activation.

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

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