PPARγ and PPARδ negatively regulate specific subsets of lipopolysaccharide and IFN-γ target genes in macrophages

Abstract

Natural and synthetic agonists of the peroxisome proliferatoractivated receptor ␥ (PPAR␥) regulate adipocyte differentiation, glucose homeostasis, and inflammatory responses. Although effects on adipogenesis and glucose metabolism are genetically linked to PPAR␥, the PPAR␥ dependence of antiinflammatory responses of these substances is less clear. Here, we have used a combination of mRNA expression profiling and conditional disruption of the PPAR␥ gene in mice to characterize programs of transcriptional activation and repression by PPAR␥ agonists in elicited peritoneal macrophages. Natural and synthetic PPAR␥ agonists, including the thiazolidinedione rosiglitazone (Ro), modestly induced the expression of a surprisingly small number of genes, several of which were also induced by a specific PPAR␦ agonist. The majority of these genes encode proteins involved in lipid homeostasis. In contrast, Ro inhibited induction of broad subsets of lipopolysaccharide and IFN-␥ target genes in a genespecific and PPAR␥-dependent manner. At high concentrations, Ro inhibited induction of lipopolysaccharide target genes in PPAR␥-deficient macrophages, at least in part by activating PPAR␦. These studies establish overlapping transactivation and transrepression functions of PPAR␥ and PPAR␦ in macrophages and suggest that a major transcriptional role of PPAR␥ is negative regulation of specific subsets of genes that are activated by T helper 1 cytokines and pathogenic molecules that signal through pattern recognition receptors. These findings support a physiological role of PPAR␥ in regulating both native and acquired immune responses. P PAR␥ is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that regulates adipocyte differentiation and glucose homeostasis (1-3). Although the endogenous ligands that regulate peroxisome proliferatoractivated receptor (PPAR) ␥ activity in vivo remain poorly characterized, several naturally occurring polyunsaturated fatty acids and their metabolites have been identified that activate PPAR␥, including products that are generated through the actions of specific lipoxygenases (e.g., 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid) and prostaglandin synthases (e.g., 15 deoxy-⌬ 12,14 prostaglandin J 2 ) (4-7). In addition, numerous synthetic PPAR␥ agonists have been identified, including the thiazolidinedione class of drugs used clinically in the treatment of type 2 diabetes mellitus (1, 3).Natural and synthetic PPAR␥ ligands have been also been shown to exert antiinflammatory effects in models of atherosclerosis (8-10), inflammatory bowel disease (11, 12), and allergic encephalomyelitis (13-15). The investigation of potential antiinflammatory effects of PPAR␥ agonists in these settings was initially based on studies demonstrating that they could inhibit transcriptional activation of inflammatory response genes by activators such as lipopolysaccharide (LPS), IL-1␤, and IFN-␥ in macrophages and other cell types (16-18). PPAR␥ expression is dramatically up...

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

“…Based on previous studies on the human IL-1Ra promoter, one can suggest that rosiglitazone could have affected alternate IL-1-sensitive transacting factors such as CCAAT/enhancer binding proteins or activator protein 1 (60,61). Second, we searched for the possible contribution of PPAR␤/␦, since high-dose rosiglitazone was shown to activate the PPAR-responsive promoter in cells expressing PPAR␤/␦ but not PPAR␥ (19), whereas it inhibited inflammatory genes through activation of the PPAR␤/␦ isotype in macrophages (62). This hypothesis was further supported by the inability of other PPAR␥ (troglitazone) and PPAR␣ (Wy-14,643) agonists to affect IL-1␤-induced IL-1Ra production.…”

Peroxisome Proliferator‐Activated Receptors: Potential Therapeutic Targets in Lung Disease?

“…12 In contrast to other tissues, however, PPARg is downregulated in adipose tissue by proinflammatory cytokines (TNF-a, IL-1b, and IL-6), 7 indicating that, like PPARa, regulation of PPARg expression can be cell typespecific. PPARg is also downregulated by IFN-g and LPS in macrophages, 45 and by steroids in the lung. 66 Far fewer studies have examined the regulation of PPARb/d gene expression.…”

“…For example, in mouse macrophages, rosiglitazone (RG), a PPARg ligand, inhibits some but not all proteins that are upregulated by lipopolysaccharide (LPS, endotoxin) or interferon-gamma (IFN-g). 45 Those proteins whose expression is inhibited in these cells require activation of AP-1, SP-1, and/or STAT-1. Conversely, RG does not inhibit macrophage expression of proteins that are upregulated in these cells by activation of the Nonsteroidal anti-inflammatory drugs.…”

“…45 Similarly, in human monocytic THP-1 cells, PPARa and PPARg ligands inhibit the LPS-dependent expression of matrix metalloprotease-9 (MMP-9), but not of interleukin-8 (IL-8). 41 This differential effect is seen despite the fact that both proteins are upregulated by the activation of AP-1 and NF-kB.…”

“…50 In these cases, the observed inhibitory effects may be due, at least in part, to PPARb/d, which is activated at higher TZD concentrations. 45 Additionally, 15-D 12,14 -PGJ 2 , but not other PPARg ligands, increases heme oxygenase-1 (HO-1) expression in human hepatoma (HEPG2) cells and inhibits the cytokine-dependent expression of epithelial neutrophil attractant-78 (ENA-78) and inducible NO synthase (iNOS) in endothelial and microglial cells, respectively. 31,[51][52][53] In each case, the effects were shown to be PPARg-independent.…”