Abstract
The stilbene derivative DG172 was developed as a highly selective inhibitory PPARβ/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 GM-CSF-induced differentiation of primary BMCs from Ppard null mice into two specific populations, characterized as mature (CD11chiMHCIIhi) and immature (CD11chiMHCIIlo) dendritic cells. IL-4 synergized with DG172 to shift the differentiation from MHCIIlo cells to mature dendritic cells 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 wildtype and Ppard null cells, while macrophage/DC marker genes were upregulated. DG172 also inhibited the expression of transcription factors driving granulocytic differentiation (Cebpe, Gfi1, Klf5), and increased the levels of transcription factors promoting macrophage/DC differentiation (Irf4, Irf8, Spib, Spic). DG172 exerted these effects only at an early stage of BMC differentiation induced by GM-CSF, did not affect M-CSF 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 this data we developed a new compound, DG228, which enhances DC differentiation in the absence of significant PPARβ/δ binding.
- PPARs
- Structure-activity relationships and modeling
- Comparative genome analyses
- Regulation of gene expression
- The American Society for Pharmacology and Experimental Therapeutics