The Inverse Agonist DG172 Triggers a PPARβ/δ-Independent Myeloid Lineage Shift and Promotes GM-CSF/IL-4-Induced Dendritic Cell Differentiation
The Inverse Agonist DG172 Triggers a PPARβ/δ-Independent Myeloid Lineage Shift and Promotes GM-CSF/IL-4-Induced Dendritic Cell Differentiation
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DOI：
10.1124/mol.114.094672
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发表时间：
2015-02-01
影响因子：
3.6
通讯作者：
Mueller, Rolf
中科院分区：
文献类型：
--
作者：
Lieber, Sonja;Scheer, Frithjof;Mueller, Rolf
二苯乙烯衍生物（Z）-2-（2-溴苯基）-3-{[4-（1-甲基哌嗪）氨基]苯基}丙烯腈（DG 172）是一种高选择性抑制过氧化物酶体增殖物激活受体（PPAR）β/δ配体。在这里，我们描述了一种新的PPAR β/δ独立的，但高度特异性，DG 172对骨髓细胞（BMC）分化的影响。DG 172强烈增强粒细胞-巨噬细胞-集落刺激因子（GM-CSF）诱导的来自Ppard敲除小鼠的原代BMCs分化为两个特定群体，其特征在于成熟（CD 11 c（hi）MHCII（hi））和未成熟（CD 11 c（hi）MHCII（lo））树突状细胞（DCs）。IL-4与DG 172协同作用，使MHCIIlo细胞在体外向成熟DC分化。DC分化的促进是以向粒细胞Gr 1（+）Ly 6 B（+）细胞分化为代价的。与这些发现一致，转录组分析显示，在分化的野生型和Ppard缺失细胞中，DG 172介导的编码嗜酸性标志物的基因的强烈抑制，而巨噬细胞/DC标志物基因被上调。DG 172还抑制驱动粒细胞分化的转录因子（Cebpe、Gfi 1和Klf 5）的表达，并增加促进巨噬细胞/DC分化的转录因子（Irf 4、Irf 8、Spib和Spic）的水平。DG 172仅在由GM-CSF诱导的BMC分化的早期阶段发挥这些作用，不影响巨噬细胞集落刺激因子触发的向巨噬细胞的分化，并且对测试的其他细胞类型没有可检测到的PPAR β/δ非依赖性作用。结构-功能分析表明，DG 172中的4-甲基哌嗪部分是其对DC分化的作用所必需的，但对于PPAR β/δ结合是不必要的。基于这些数据，我们开发了一种新的化合物（Z）-2-（4-氯苯基）-3-[4（4-甲基哌嗪-1-基）苯基]丙烯腈（DG 228），其在不存在显著的PPAR β/δ结合的情况下增强DC分化。
The stilbene derivative (Z)-2-(2-bromophenyl)-3-{[4-(1-methylpiperazine) amino] phenyl} acrylonitrile (DG172) was developed as a highly selective inhibitory peroxisome proliferator-activated receptor (PPAR)beta/delta ligand. Here, we describe a novel PPAR beta/delta-independent, yet highly specific, effect of DG172 on the differentiation of bone marrow cells (BMCs). DG172 strongly augmented granulocyte-macrophage- colony-stimulating factor (GM-CSF)-induced differentiation of primary BMCs from Ppard null mice into two specific populations, characterized as mature (CD11c(hi)MHCII(hi)) and immature (CD11c(hi)MHCII(lo)) dendritic cells (DCs). IL-4 synergized with DG172 to shift the differentiation from MHCIIlo cells to mature DCs in vitro. The promotion of DC differentiation occurred at the expense of differentiation to granulocytic Gr1(+)Ly6B(+) cells. In agreement with these findings, transcriptome analyses showed a strong DG172-mediated repression of genes encoding neutrophilic markers in both differentiating wild-type and Ppard null cells, while macrophage/DC marker genes were up-regulated. DG172 also inhibited the expression of transcription factors driving granulocytic differentiation (Cebpe, Gfi1, and Klf5), and increased the levels of transcription factors promoting macrophage/DC differentiation (Irf4, Irf8, Spib, and Spic). DG172 exerted these effects only at an early stage of BMC differentiation induced by GM-CSF, did not affect macrophage-colony-stimulating factor-triggered differentiation to macrophages and had no detectable PPAR beta/delta-independent effect on other cell types tested. Structure-function analyses demonstrated that the 4-methylpiperazine moiety in DG172 is required for its effect on DC differentiation, but is dispensable for PPAR beta/delta binding. Based on these data we developed a new compound, (Z)-2-(4-chlorophenyl)-3-[4( 4-methylpiperazine-1-yl) phenyl] acrylonitrile (DG228), which enhances DC differentiation in the absence of significant PPAR beta/delta binding.