2. Academic Validation
  3. 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

  • Mol Pharmacol. 2015 Feb;87(2):162-73. doi: 10.1124/mol.114.094672.
Sonja Lieber 1,  Frithjof Scheer 1,  Florian Finkernagel 1,  Wolfgang Meissner 1,  Gavin Giehl 1,  Cornelia Brendel 1,  Wibke E Diederich 1,  Sabine Müller-Brüsselbach 1,  Rolf Müller 2
Affiliations

Affiliations

  • 1 Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany (S.L., F.F., W.M., S.M.-B., R.M.); Institute of Pharmaceutical Chemistry, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany (F.S., W.E.D.); and Clinic for Hematology, Oncology and Immunology (G.G., C.B.); Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany.
  • 2 Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany (S.L., F.F., W.M., S.M.-B., R.M.); Institute of Pharmaceutical Chemistry, Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany (F.S., W.E.D.); and Clinic for Hematology, Oncology and Immunology (G.G., C.B.); Center for Tumor Biology and Immunology (ZTI), Philipps University, Marburg, Germany [email protected].
PMID: 25398837 DOI: 10.1124/mol.114.094672
Abstract

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)β/δ ligand. Here, we describe a novel PPARβ/δ-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 MHCII(lo) 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 PPARβ/δ-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 PPARβ/δ 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 PPARβ/δ binding.

Figures
Products