IL-4 suppresses the responses to TLR7 and TLR9 stimulation and increases the permissiveness to retroviral infection of murine conventional dendritic cells.
IL-4 suppresses the responses to TLR7 and TLR9 stimulation and increases the permissiveness to retroviral infection of murine conventional dendritic cells.
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DOI：
10.1371/journal.pone.0087668
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Gallucci S
中科院分区：
文献类型：
--
作者：
Sriram U;Xu J;Chain RW;Varghese L;Chakhtoura M;Bennett HL;Zoltick PW;Gallucci S
Th 2诱导的病理状况如寄生虫病通过尚不清楚的机制增加对病毒感染的易感性。我们以前曾报道，IL-4，一个关键的Th 2细胞因子，抑制小鼠骨髓来源的常规树突状细胞（cDCs）和脾DCs的反应，I型干扰素（IFN）。在此，我们分析了cDC分别对TLR 7和TLR 9配体R848和CpG的应答。我们发现，IL-4抑制IFNβ和IFN应答基因（IRGs）的基因表达后，TLR 7和TLR 9刺激。IL-4还抑制IFN依赖性MHC I类表达和TLR刺激后触发的IFN信号传导途径的扩增，如IRF 7和STAT 2的抑制所示。此外，IL-4通过抑制IFN依赖性和NFκ B依赖性反应抑制TLR 7和TLR 9诱导的cDC产生促炎细胞因子如TNFα、IL-12 p70和IL-6。IL-4同样抑制脾DC中的TLR应答。IL-4对IRG和TLR 7和TLR 9刺激后促炎细胞因子产生的抑制是STAT 6依赖性的，因为来自STAT 6-KO小鼠的DC对IL-4抑制具有抗性。对SOCS分子（SOCS 1、SOCS 2和SOCS 3）的分析表明，IL-4以STAT 6依赖的方式诱导SOCS 1和SOCS 2，并表明IL-4抑制可能由SOCS分子，特别是SOCS 2介导。IL-4还降低了IFN应答，并增加了暴露于基于HIV的慢病毒的cDC对病毒感染的容许性。我们的研究结果表明，IL-4调节和抵消TLR 7和TLR 9诱导的促炎刺激，它可能会对病毒和细胞内寄生虫的反应产生负面影响。
Th2-inducing pathological conditions such as parasitic diseases increase susceptibility to viral infections through yet unclear mechanisms. We have previously reported that IL-4, a pivotal Th2 cytokine, suppresses the response of murine bone-marrow-derived conventional dendritic cells (cDCs) and splenic DCs to Type I interferons (IFNs). Here, we analyzed cDC responses to TLR7 and TLR9 ligands, R848 and CpGs, respectively. We found that IL-4 suppressed the gene expression of IFNβ and IFN-responsive genes (IRGs) upon TLR7 and TLR9 stimulation. IL-4 also inhibited IFN-dependent MHC Class I expression and amplification of IFN signaling pathways triggered upon TLR stimulation, as indicated by the suppression of IRF7 and STAT2. Moreover, IL-4 suppressed TLR7- and TLR9-induced cDC production of pro-inflammatory cytokines such as TNFα, IL-12p70 and IL-6 by inhibiting IFN-dependent and NFκB-dependent responses. IL-4 similarly suppressed TLR responses in splenic DCs. IL-4 inhibition of IRGs and pro-inflammatory cytokine production upon TLR7 and TLR9 stimulation was STAT6-dependent, since DCs from STAT6-KO mice were resistant to the IL-4 suppression. Analysis of SOCS molecules (SOCS1, −2 and −3) showed that IL-4 induces SOCS1 and SOCS2 in a STAT6 dependent manner and suggest that IL-4 suppression could be mediated by SOCS molecules, in particular SOCS2. IL-4 also decreased the IFN response and increased permissiveness to viral infection of cDCs exposed to a HIV-based lentivirus. Our results indicate that IL-4 modulates and counteracts pro-inflammatory stimulation induced by TLR7 and TLR9 and it may negatively affect responses against viruses and intracellular parasites.
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