The transcriptional PPARβ/δ network in human macrophages defines a unique agonist-induced activation state.

Peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) is a lipid ligand-inducible transcription factor with established metabolic functions, whereas its anti-inflammatory function is poorly understood. To address this issue, we determined the global PPAR beta/delta-regulated signaling network in human monocyte-derived macrophages. Besides cell type-independent, canonical target genes with metabolic and immune regulatory functions we identified a large number of inflammation-associated NF kappa B and STAT1 target genes that are repressed by agonists. Accordingly, PPAR beta/delta agonists inhibited the expression of multiple pro-inflammatory mediators and induced an anti-inflammatory, IL-4-like morphological phenotype. Surprisingly, bioinformatic analyses also identified immune stimulatory effects. Consistent with this prediction, PPAR beta/delta agonists enhanced macrophage survival under hypoxic stress and stimulated CD8(+) T cell activation, concomitantly with the repression of immune suppressive target genes and their encoded products CD274 (PD-1 ligand), CD32B (inhibitory Fc gamma receptor IIB) and indoleamine 2,3-dioxygenase 1 (IDO-1), as well as a diminished release of the immune suppressive IDO-1 metabolite kynurenine. Comparison with published data revealed a significant overlap of the PPAR beta/delta transcriptome with coexpression modules characteristic of both anti-inflammatory and proinflammatory cytokines. Our findings indicate that PPAR beta/delta agonists induce a unique macrophage activation state with strong anti-inflammatory but also specific immune stimulatory components, pointing to a context-dependent function of PPAR beta/delta in immune regulation.