背景:尽管最近的研究已经表征了树突状细胞(DC)诱导T(H)1/T(H)17反应的机制,使DC能够极化T(H)2响应的功能专业化仍未定义。因为IL-4在T(H)2应答期间是必需的,不仅通过激活GATA-3作用于CD4(+)T细胞,而且还通过调节IgE类别转换,上皮细胞通透性,和肌肉收缩力,我们假设IL-4也可能在T(H)2反应过程中对DCs的调节中起作用。
目的:我们试图分析IL-4是否在DCs分化过程中发挥免疫调节功能,导致它们诱导T(H)2反应的功能专业化。
方法:分析在其分化期间由IL-4调节的单核细胞来源的DC(moDC)(IL-4调节的moDC[IL-4-moDC])响应于Toll样受体刺激的T(H)1-极化/炎性细胞因子产生。通过使用染色质免疫沉淀分析编码这些细胞因子的基因的启动子的乙酰化水平。通过使用小鼠基因组微阵列定义IL-4-moDC的基因表达谱。测试IL-4-moDC诱导屋尘螨介导的过敏反应的能力。
结果:我们的数据表明,IL-4通过这些基因启动子的去乙酰化抑制IL-4-moDC上的T(H)1极化/炎性细胞因子基因表达,导致它们的转录抑制。微阵列分析证实IL-4上调T(H)2相关基因作为嗜酸性粒细胞相关核糖核酸酶,嗜酸性粒细胞/嗜碱性粒细胞趋化因子,和M2基因。IL-4许可的moDCs诱导T(H)2反应,引起屋尘螨介导的过敏性气道炎症。
结论:本研究描述了IL-4的新作用,证明了moDC受IL-4调节,通过组蛋白次乙酰化和上调T(H)2相关基因阻断T(H)1极化/炎性细胞因子的产生来诱导T(H)2反应。
BACKGROUND: Whereas recent research has characterized the mechanism by which dendritic cells (DCs) induce T(H)1/T(H)17 responses, the functional specialization enabling DCs to polarize T(H)2 responses remains undefined. Because IL-4 is essential during T(H)2 responses not only by acting on CD4(+) T cells through the activation of GATA-3 but also by regulating IgE class-switching, epithelial cell permeability, and muscle contractility, we hypothesized that IL-4 could also have a role in the conditioning of DCs during T(H)2 responses.
OBJECTIVE: We sought to analyze whether IL-4 exerts an immunomodulatory function on DCs during their differentiation, leading to their functional specialization for the induction of T(H)2 responses.
METHODS: Monocyte-derived DCs (moDCs) conditioned by IL-4 during their differentiation (IL-4-conditioned moDCs [IL-4-moDCs]) were analyzed for T(H)1-polarizing/inflammatory cytokine production in response to Toll-like receptor stimulation. The acetylation level of the promoters of the genes encoding these cytokines was analyzed by using chromatin immunoprecipitation. Gene expression profiling of IL-4-moDCs was defined by using mouse genome microarrays. IL-4-moDCs were tested for their capacity to induce house dust mite-mediated allergic reactions.
RESULTS: Our data suggest that IL-4 inhibits T(H)1-polarizing/inflammatory cytokine gene expression on IL-4-moDCs through the deacetylation of the promoters of these genes, leading to their transcriptional repression. Microarray analyses confirmed that IL-4 upregulated T(H)2-related genes as eosinophil-associated ribonucleases, eosinophil/basophil chemokines, and M2 genes. IL-4 licensed moDCs for the induction of T(H)2 responses, causing house dust mite-mediated allergic airway inflammation.
CONCLUSIONS: This study describes a new role for IL-4 by demonstrating that moDCs are conditioned by IL-4 for the induction of T(H)2 responses by blocking T(H)1-polarizing/inflammatory cytokine production through histone hypoacetylation and upregulating T(H)2-related genes.