Institute for Medical Immunology, Université Libre de Bruxelles, Brussels, Belgium.
J Immunol. 2010 Feb 15;184(4):1784-92. doi: 10.4049/jimmunol.0902005. Epub 2010 Jan 18.
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.
在髓样树突状细胞中，IL-27p28 基因的激活被 TLR4 或 TLR3 的配体选择性诱导，这两种受体都与 Toll/IL-1R 相关域包含的衔接子诱导 IFN/IFN 调节因子 (IRF)3 途径偶联。对于这两种配体，内源性的 1 型 IFN 产生对于最佳的 IL-27p28 表达是必需的。I 型 IFN 信号对于持续的 IRF1 激活和包含 IFN 刺激基因因子 3 复合物的 IRF9 的形成是必需的。事实上，我们证明了 IRF1 和 IRF9 是依次被激活并募集到 IL-27p28 IFN 刺激的调节元件位点。IRF1 和 IRF9 参与诱导 IL-27p28 在体外和体内暴露于 TLR 配体时得到了证实。因此，在 TLR4 或 TLR3 连接后，IL-27p28 基因的初始诱导取决于 IRF1 和 IRF3 的募集，而转录扩增需要募集 IFN 刺激基因因子 3 复合物。这些结果突出了 TLRs 和 I 型 IFNs 之间的复杂分子相互作用，用于控制 IL-27 合成。
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