IFN regulatory factor 3-dependent induction of type I IFNs by intracellular bacteria is mediated by a TLR-and Nod2-independent mechanism

S Stockinger, B Reutterer, B Schaljo… - The Journal of …, 2004 - journals.aai.org
S Stockinger, B Reutterer, B Schaljo, C Schellack, S Brunner, T Materna, M Yamamoto…
The Journal of Immunology, 2004journals.aai.org
Like viruses, intracellular bacteria stimulate their host cells to produce type I IFNs (IFN-α and
IFN-β). In our study, we investigated the signals and molecules relevant for the synthesis of
and response to IFN by mouse macrophages infected with Listeria monocytogenes. We
report that IFN-β is the critical immediate-early IFN made during infection, because the
synthesis of all other type I IFN, expression of a subset of infection-induced genes, and the
biological response to type I IFN was lost upon IFN-β deficiency. The induction of IFN-β …
Abstract
Like viruses, intracellular bacteria stimulate their host cells to produce type I IFNs (IFN-α and IFN-β). In our study, we investigated the signals and molecules relevant for the synthesis of and response to IFN by mouse macrophages infected with Listeria monocytogenes. We report that IFN-β is the critical immediate-early IFN made during infection, because the synthesis of all other type I IFN, expression of a subset of infection-induced genes, and the biological response to type I IFN was lost upon IFN-β deficiency. The induction of IFN-β mRNA and the IFN-β-dependent sensitization of macrophages to bacteria-induced death, in turn, was absolutely dependent upon the presence of the transcription factor IFN regulatory factor 3 (IRF3). IFN-β synthesis and signal transduction occurred in macrophages deficient for TLR or their adaptors MyD88, TRIF, or TRAM. Expression of Nod2, a candidate receptor for intracellular bacteria, increased during infection, but the protein was not required for Listeria-induced signal transduction to the Ifn-β gene. Based on our data, we propose that IRF3 is a convergence point for signals derived from structurally unrelated intracellular pathogens, and that L. monocytogenes stimulates a novel TLR-and Nod2-independent pathway to target IRF3 and the type I IFN genes.
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