Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits marked anti-inflammatory capacities. The first-generation PPARα agonists, the fibrates, have however been hampered by drug-drug interaction issues, statin drop-in, and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the molecular mechanisms by which PPARα works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component. Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications.

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Glucocorticoid receptor ␣ (GR␣) and peroxisome proliferatoractivated receptor ␣ (PPAR␣) are transcription factors with clinically important immune-modulating properties. Either receptor can inhibit cytokine gene expression, mainly through interference with nuclear factor B (NF-B)-driven gene expression. The present work aimed to investigate a functional cross-talk between PPAR␣-and GR␣-mediated signaling pathways. Simultaneous activation of PPAR␣ and GR␣ dose-dependently enhances transrepression of NF-B-driven gene expression and additively represses cytokine production. In sharp contrast and quite unexpectedly, PPAR␣ agonists inhibit the expression of classical glucocorticoid response element (GRE)-driven genes in a PPAR␣-dependent manner, as demonstrated by experiments using PPAR␣ wild-type and knockout mice. The underlying mechanism for this transcriptional antagonism relies on a PPAR␣-mediated interference with the recruitment of GR␣, and concomitantly of RNA polymerase II, to GRE-driven gene promoters. Finally, the biological relevance of this phenomenon is underscored by the observation that treatment with the PPAR␣ agonist fenofibrate prevents glucocorticoid-induced hyperinsulinemia of mice fed a high-fat diet. Taken together, PPAR␣ negatively interferes with GREmediated GR␣ activity while potentiating its antiinflammatory effects, thus providing a rationale for combination therapy in chronic inflammatory disorders.cross-talk ͉ gluconeogenesis ͉ inflammation ͉ hyperinsulinema ͉ side effects G lucocorticoids (GCs) are presently the most potent drugs for the treatment of acute and chronic inflammatory diseases. Nevertheless, side effects such as osteoporosis, muscle wasting, hypertension, behavioral alterations, and disorders of glucose (Glc) and lipid metabolism, burden their therapeutical use. GCs mediate their effect via the glucocorticoid receptor ␣ (GR␣), a member of the nuclear receptor superfamily. After binding of GCs, a conformational change in the receptor is induced, releasing cytosolic chaperoning proteins followed by GR␣ translocation into the nucleus. Activated GR␣ can directly regulate the expression of its target genes through GR␣ binding onto promoter-imbedded GREs. Target genes of GR␣ homodimers include proteins involved in Glc, fat, and protein metabolism. Alternatively, GR␣ can also influence gene expression by interfering with the activity of nuclear factor B (NF-B), a key regulatory proinflammatory transcription factor (1). Peroxisome proliferator-activated receptor ␣ (PPAR␣), a ligand-activated transcription factor, also belonging to the nuclear receptor superfamily, is highly expressed in liver, skeletal and cardiac muscle, kidney, and in cells involved in inflammatory processes. Besides its involvement in lipid and Glc metabolism, PPAR␣ exhibits potent antiinflammatory properties. Recently, a protective role for PPAR␣ has also been demonstrated in obesityinduced hepatic inflammation (2). Fatty acid derivates and hypolipidemic fibrates are natural and synthetic PPAR␣ ligands, respect...

Glucocorticoids (GCs) block inflammation via interference of the liganded glucocorticoid receptor (GR) with the activity of pro-inflammatory transcription factors NF-κB and AP-1, a mechanism known as transrepression. This mechanism is believed to involve the activity of GR monomers. Here, we explored how the GR monomer-favoring Compound A (CpdA) affects AP-1 activation and activity. Our results demonstrate that non-steroidal CpdA, unlike classic steroidal GCs, blocks NF-κB- but not AP-1-driven gene expression. CpdA rather sustains AP-1-driven gene expression, a result which could mechanistically be explained by the failure of CpdA to block upstream JNK kinase activation and concomitantly also phosphorylation of c-Jun. In concordance and in contrast to DEX, CpdA maintained the expression of the activated AP-1 target gene c-jun, as well as the production of the c-Jun protein. As for the underlying mechanism, GR is a necessary intermediate in the CpdA-mediated gene expression of AP-1-regulated genes, but seems to be superfluous to CpdA-mediated JNK phosphorylation prolongation. The latter phenomenon concurs with the inability of CpdA to stimulate DUSP1 gene expression. ChIP analysis demonstrates that DEX-activated GR, but not CpdA-activated GR, is recruited to AP-1-driven promoters. Furthermore, in mice we observed that CpdA instigates a strong enhancement of TNF-induced AP-1-driven gene expression. Finally, we demonstrate that this phenomenon coincides with an increased sensitivity towards TNF lethality, and implicate again a role for JNK2. In conclusion, our data support the hypothesis that a ligand-induced differential conformation of GR yields a different transcription factor cross-talk profile.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-013-1367-4) contains supplementary material, which is available to authorized users.

Glucocorticoids are widely used anti-inflammatory and immunomodulatory agents, of which the action mechanism is mainly based on interference of hormone-activated glucocorticoid receptor (GR) with the activity of transcription factors, such as nuclear factor-jB (NF-jB). In addition to the well described interaction-based mutual repression mechanism between the GR and NF-jB, additional mechanisms are at play, which help to explain the efficacy of glucocorticoid-mediated gene repression. In this respect, we found that glucocorticoids counteract the recruitment of activated Mitogen-and Stress-activated protein Kinase-1 (MSK1) at inflammatory gene promoters resulting in the inhibition of NF-jB p65 transactivation and of concurrent histone H3 phosphorylation. Additionally, we observed that activated GR can trigger redistribution of nuclear MSK1 to the cytoplasm through a CRM1-dependent export mechanism, as a result of an interaction between liganded GR and activated MSK1. These findings unveil a novel aspect within the GR-mediated NF-jB-targeting anti-inflammatory mechanism.