Critical role of the IFN-stimulated gene factor 3 complex in TLR-mediated IL-27p28 gene expression revealing a two-step activation process.
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.
Molle
Céline
C
Institute for Medical Immunology, Université Libre de Bruxelles, Brussels, Belgium.
Goldman
Michel
M
Goriely
Stanislas
S
D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007370:Interferon Type I / Q000502:physiology; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000502:physiology*; D015533:Transcriptional Activation / Q000276:immunology*
C486767:Il27 protein, mouse; D050856:Interferon Regulatory Factor-1; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007378:Interleukins; C494258:Irf1 protein, mouse; C494233:Irf3 protein, mouse; D021122:Protein Subunits; D051193:Toll-Like Receptors