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

被引：69

作者：

Adhikary, Till ^{[1
]}

Wortmann, Annika ^{[1
]}

Schumann, Tim ^{[1
]}

Finkernagel, Florian ^{[1
]}

Lieber, Sonja ^{[1
]}

Roth, Katrin ^{[2
]}

Toth, Philipp M. ^{[3
,4
]}

Diederich, Wibke E. ^{[3
,4
]}

Nist, Andrea ^{[5
]}

Stiewe, Thorsten ^{[5
]}

Kleinesudeik, Lara ^{[6
]}

Reinartz, Silke ^{[6
]}

Mueller-Bruesselbach, Sabine ^{[1
]}

Mueller, Rolf ^{[1
]}

机构：

[1] Univ Marburg, Ctr Tumor Biol & Immunol ZTI, Inst Mol Biol & Tumor Res IMT, D-35043 Marburg, Germany

[2] Univ Marburg, Ctr Tumor Biol & Immunol ZTI, Cellular Imaging Core Facil, D-35043 Marburg, Germany

[3] Univ Marburg, Ctr Tumor Biol & Immunol ZTI, Med Chem Core Facil, D-35043 Marburg, Germany

[4] Univ Marburg, Ctr Tumor Biol & Immunol ZTI, Inst Pharmaceut Chem, D-35043 Marburg, Germany

[5] Univ Marburg, Ctr Tumor Biol & Immunol ZTI, Gen Core Facil, D-35043 Marburg, Germany

[6] Univ Marburg, Ctr Tumor Biol & Immunol ZTI, Clin Gynecol Gynecol Oncol & Gynecol Endocrinol, D-35043 Marburg, Germany

来源：

NUCLEIC ACIDS RESEARCH | 2015年 / 43卷 / 10期

关键词：

NF-KAPPA-B; GENE-EXPRESSION; DELTA; ADHERENCE; INFLAMMATION; RECEPTORS; MONOCYTE; BINDING; CELLS; POLARIZATION;

D O I：

10.1093/nar/gkv331

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5033 / 5051

页数：19

共 70 条

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