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

ABSTRACT: Peroxisome proliferator-activated receptor ?/? (PPAR?/?) 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?/?-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?B and STAT1 target genes that are repressed by agonists. Accordingly, PPAR?/? 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?/? 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? 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?/? transcriptome with coexpression modules characteristic of both anti-inflammatory and pro-inflammatory cytokines. Our findings indicate that PPAR?/? 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?/? in immune regulation.

SUBMITTER: Adhikary T 

PROVIDER: S-EPMC4446423 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature