TLR7 and TLR8 agonists trigger different signaling pathways for human dendritic cell maturation
TLR7 and TLR8 agonists trigger different signaling pathways for human dendritic cell maturation
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DOI：
10.1189/jlb.0808504
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发表时间：
2009-04-01
影响因子：
5.5
通讯作者：
Kerdine-Roemer, Saadia
中科院分区：
文献类型：
--
作者：
Larange, Alexandre;Antonios, Diane;Kerdine-Roemer, Saadia
树突状细胞(DC)在连接天然免疫和获得性免疫中起着重要作用。这些APC具有通过TLRs识别病原体的特定分子特征的能力。尤其是细胞内的TLR7和TLR8，介导了DC对单链RNA的识别，在病毒感染时的免疫应答中发挥了重要作用。尽管TLR7和TLR8在细胞表达和功能方面存在差异，但TLR7或TLR8参与后导致DC成熟的信号通路在很大程度上尚不清楚。我们比较了选择性TLR7(咪喹莫特)和TLR8(3M002)激动剂诱导人CD34-DC成熟的信号通路。TLR7和TLR8激活可上调CCR7、CD40、CD86和CD83的表达以及IL-6和IL-12p40的产生。但只有TLR8激活才能诱导IL-12p70的产生和IL-12p35mRNA的表达。我们发现，在TLR7和TLR8激活后，JNK和NF-kappa B正向调节CCR7、CD86、CD83和CD40的表达以及IL-6和IL-12p40的产生。然而，尽管p38MAPK参与了TLR7激活后成熟标志物的上调，但该激酶对TLR8刺激的DC的CD40表达和IL-12的产生具有抑制作用。我们还发现，Jak/STAT信号通路参与了TLR7刺激的DC中CD40的表达和细胞因子的产生，但对TLR8激活的DC中CD83的表达和细胞因子的分泌起负性调节作用。本研究表明，TLR7和TLR8激活了相似的信号通路，在DC成熟过程中发挥不同的作用，这取决于TLR被触发的方式。J.Leukoc。比奥尔。85：673-683；2009。
Dendritic cells (DCs) play an important role in bridging innate and adaptive immunity. These APCs have the ability to recognize specific molecular signatures of pathogens through TLRs. In particular, the intracellular TLR7 and TLR8, mediating the recognition of ssRNA by DCs, play a major role in the immune response during viral infection. Although differences have been identified between TLR7 and TLR8, in terms of cellular expression and functions, the signaling pathways that lead to DC maturation following TLR7 or TLR8 engagement are largely unknown. We compared the signaling pathways involved in human CD34-DC maturation induced by agonists selective for TLR7 (imiquimod) or TLR8 (3M002). TLR7 and TLR8 activation up-regulated CCR7, CD40, CD86, and CD83 expression and IL-6 and IL-12p40 production. However, only TLR8 activation led to IL-12p70 production and il-12p35 mRNA expression. We found that upon TLR7 and TLR8 activation, JNK and NF-kappa B positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. However, although p38MAPK participated in the up-regulation of maturation markers in response to TLR7 activation, this kinase exerted an inhibitory effect on CD40 expression and IL-12 production in TLR8-stimulated DCs. We also showed that the Jak/STAT signaling pathway was involved in CD40 expression and cytokine production in TLR7-stimulated DCs but negatively regulated CD83 expression and cytokine secretion in DCs activated through TLR8. This study showed that TLR7 and TLR8 activate similar signaling pathways that play different roles in DC maturation, depending on which TLR is triggered. J. Leukoc. Biol. 85: 673-683; 2009.