PPARs and molecular mechanisms of transrepression

Abstract

In the last few years, PPARs have emerged as key regulators of inflammatory and immune responses. However, the mechanistic basis of the anti-inflammatory effects of peroxisome proliferator-activated receptors (PPARs) remains poorly understood. Accumulating evidence suggests that these effects result from inhibition of signal-dependent transcription factors that mediate inflammatory programs of gene activation. Several mechanisms underlying negative regulation of gene expression by PPARs have been described. Recent studies, using siRNA, microarray analysis and macrophage-specific knockout mice, have highlighted PPARs molecular transrepression mechanism in macrophages. Identification of their mechanism of action should help promote the understanding of the physiologic roles that PPARs play in immunity and contribute to the development of new therapeutic agents.

Fig. 1

PPARs functions as sensors of lipids that are derived either from the diet and intracellular fatty acid metabolism. PPARγ expression is upregulated in macrophages and T cells during the inflammatory response, and can be induced by IL-4 and GM-CSF. In contrast, IFN-γ and LPS repress the expression of PPARγ. IL-4, Interleukin-4; GM-CSF, granulocyte-macrophage-colony stimulation factor; IFN-γ, interferon-γ; LPS, lipopolysaccharide.

Fig. 2

Trancriptional activities of the Peroxisome Proliferator Activated receptors. PPARs can both activate and inhibit gene expression. (a) Ligand-dependent transactivation. PPARs activate transcription in a ligand-dependent manner by binding directly to specific PPAR-response elements (PPRE) in target genes as heterodimers with RXR. Binding of agonists ligand leads to the recruitment of coactivator complexes that modify chromatin structure and facilitate assembly of the general transcriptional machinery to the promoter. (b) Ligand-dependent transrepression. PPARs repress transcription in a ligand-dependent manner by antagonizing the actions of other transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). (c) Ligand-independent repression. PPARs bind to response elements in the absence of ligand and recruit corepressor complexes that mediate active repression. This complex antagonizes the actions of coactivators and maintains genes in a repressed state in the absence of ligand.

Fig. 3

Mechanisms of PPAR-mediated transrepression. (a) Direct interaction between PPAR and p65 subunit. (b) Induction of IκBα expression. (c) Activation of PPAR inhibits c-Jun N-terminal kinase (JNK) MAPK activity. (d) Competition for a limiting pool of coactivators, such as CREB-binding protein. (e) Corepressor-dependent model of transrepression. PPARγ can inhibit inflammatory responses by blocking the signal-dependent clearance of NCoR corepressor complexes. LPS stimulation promotes the ubiquitin-dependent proteosomal degradation of NCoR corepressor complexes. In the presence of ligand, PPARγ is sumoylated and targeted to the NCoR corepressor complexes on gene promoters, preventing the clearance of these complexes. AP-1, activator protein-1; NCoR, nuclear-receptor co-repressor complexes; HDAC3, histone deacetylase 3; TBL1, transducin-β-like 1, TBL1; TBL1-related protein, TBLR1; PIAS1, protein inhibitor of activated STAT1; Tab2, TAK1-binding proteins; K, SUMO target lysine within PPARγ DNA-binding domain; Su, SUMO conjugate on target cystine.