Severa Martina, Remoli Maria Elena, Giacomini Elena, Annibali Viviana, Gafa Valerie, Lande Roberto, Tomai Mark, Salvetti Marco, Coccia Eliana M
Department of Infectious, Parasitic, and Immuno-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
J Immunol. 2007 May 15;178(10):6208-16. doi: 10.4049/jimmunol.178.10.6208.
TLRs interact with a growing list of pathogen-derived products and these interactions drive the activation of innate and adaptive immune responses. Dendritic cells (DC) play a key role in these events expressing a heterogeneous repertoire of TLRs. We have previously demonstrated the production of type I IFNs in DC following bacterial infections and TLR triggering. In this study, we sought to characterize the transcriptome specifically induced in human DC by IFN-beta production stimulated upon LPS treatment. To this aim, by using cDNA microarrays, we compared the transcriptome of DC following LPS treatment in the absence or presence of neutralizing anti-type I IFN Abs. Interestingly, we found that the expression of TLR7 was induced during LPS-induced maturation of DC in a type I IFN-dependent manner. The induction of TLR7 in maturing DC was mainly a consequence of the transcriptional activity of IRF-1, whose binding site was located within TLR7 promoter. Moreover, we also demonstrated that "priming" of immature DC, that usually express TLR8 but not TLR7, with exogenous IFN-beta induced a functionally active TLR7. In fact, treatment with the TLR7-specific ligand 3M-001 up-regulated the expression of CD83, CD86, and CD38 in IFN-beta-primed DC but not in immature DC. Therefore, a robust enhancement in proinflammatory as well as regulatory cytokines was observed. These data suggest that TLR4-mediated type I IFN release activates specific transcription programs in DC amplifying the expression of pathogen sensors to correctly and combinatorially respond to a bacterial as well as viral infection.
Toll样受体（TLRs）可与越来越多的病原体衍生产物相互作用，这些相互作用驱动天然免疫和适应性免疫反应的激活。树突状细胞（DC）在这些事件中发挥关键作用，其表达多种不同的TLRs。我们之前已证明细菌感染和TLR触发后DC中I型干扰素的产生。在本研究中，我们试图表征在脂多糖（LPS）处理刺激下产生的IFN-β诱导的人DC中特异性诱导的转录组。为此，我们使用cDNA微阵列，比较了在不存在或存在中和性抗I型干扰素抗体的情况下LPS处理后DC的转录组。有趣的是，我们发现TLR7的表达在DC的LPS诱导成熟过程中以I型干扰素依赖性方式被诱导。成熟DC中TLR7的诱导主要是干扰素调节因子-1（IRF-1）转录活性的结果，其结合位点位于TLR7启动子内。此外，我们还证明，用外源性IFN-β对通常表达TLR8但不表达TLR7的未成熟DC进行“预刺激”可诱导出功能活跃的TLR7。事实上，用TLR7特异性配体3M-001处理可上调IFN-β预刺激的DC中CD83、CD86和CD38的表达，但在未成熟DC中则不然。因此，观察到促炎细胞因子和调节性细胞因子均有显著增强。这些数据表明，TLR4介导的I型干扰素释放激活DC中的特定转录程序，放大病原体传感器的表达，以正确且组合性地应对细菌和病毒感染。
