Abstract
In myeloid dendritic cells, activation of the IL-27p28 gene is selectively induced by ligands of TLR4 or TLR3, both coupled to the Toll/IL-1R-related domain-containing adaptor-inducing IFN/IFN regulatory factor (IRF)3 pathway. In response to both ligands, autocrine type 1 IFN production was required for optimal IL-27p28 expression. Type I IFN signaling was necessary for sustained IRF1 activation and formation of the IRF9-containing IFN-stimulated gene factor 3 complex. Indeed, we demonstrated that IRF1 and IRF9 are sequentially activated and recruited to the IL-27p28 IFN-stimulated regulatory element site. Involvement of IRF1 and IRF9 in the induction of IL-27p28 was confirmed in vitro and upon in vivo exposure to TLR ligands. Thus, in response to TLR4 or TLR3 ligation, the initial induction of the IL-27p28 gene depends on the recruitment of IRF1 and IRF3, whereas transcriptional amplification requires recruitment of the IFN-stimulated gene factor 3 complex. These results highlight the complex molecular interplay between TLRs and type I IFNs for the control of IL-27 synthesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Humans
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Interferon Regulatory Factor-1 / deficiency
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Interferon Regulatory Factor-1 / genetics
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Interferon Regulatory Factor-1 / physiology
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Interferon Regulatory Factor-3 / deficiency
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Interferon Regulatory Factor-3 / genetics
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Interferon Regulatory Factor-3 / physiology*
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Interferon Type I / physiology
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Interferon-Stimulated Gene Factor 3, gamma Subunit / deficiency
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Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics
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Interferon-Stimulated Gene Factor 3, gamma Subunit / physiology
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Interleukins / biosynthesis
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Interleukins / genetics*
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Interleukins / metabolism
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Mice
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Protein Subunits / genetics*
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Protein Subunits / metabolism
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Receptor Cross-Talk / immunology
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Signal Transduction / genetics
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Signal Transduction / immunology
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Toll-Like Receptors / physiology*
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Transcriptional Activation / immunology*
Substances
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Il27 protein, mouse
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Interferon Regulatory Factor-1
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Interferon Regulatory Factor-3
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Interferon Type I
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Interferon-Stimulated Gene Factor 3, gamma Subunit
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Interleukins
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Irf1 protein, mouse
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Irf3 protein, mouse
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Protein Subunits
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Toll-Like Receptors