PPAR‐α and ‐γ but not ‐δ agonists inhibit airway inflammation in a murine model of asthma: in vitro evidence for an NF‐κB‐independent effect

Abstract

1 Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that have been proposed to regulate inflammation by antagonising the nuclear factor-kB (NF-kB) signalling pathway. We investigated the role of PPARs using synthetic agonists in murine models of airway inflammation, and addressed the possible effect on NF-kB signalling in vitro using a human epithelial cell line, A549. 2 Sensitised BALB/c mice exposed to an aerosol solution of ovalbumin had an increased number of airway eosinophils, neutrophils and lymphocytes. When given intranasally an hour before the aerosol challenge, a PPAR-a (GW 9578) and PPAR-g (GI 262570) selective agonist as well as a dual PPAR-a/g (GW 2331) agonist selectively inhibited allergen-induced bronchoalveolar lavage eosinophil and lymphocyte but not neutrophil influx. In contrast, a PPAR-d agonist (GW 501516) was inactive. 3 When given intranasally an hour before challenge, PPAR-a and PPAR-g selective agonists as well as a dual PPAR-a/g agonist did not inhibit lipopolysaccharide-induced bronchoalveolar lavage neutrophil influx or tumour necrosis factor-a (TNF-a) and KC production. 4 In A549 cells, selective agonists for PPAR-a, -g and -d did not inhibit intracellular adhesion molecule-1 expression following stimulation with proinflammatory cytokines. In addition, IL-8 release and the activation of an NF-kB-responsive reporter gene construct were inhibited only at micromolar concentrations, suggesting that these effects were not PPAR-mediated. 5 Our in vivo data show that agonists of PPAR-a and -g, but not -d, inhibit allergen-induced bronchoalveolar lavage eosinophil and lymphocyte influx. In vitro data suggest that this effect might not be mediated by antagonism of the NF-kB pathway.

Rosiglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, Prevents Microparticle-Induced Vascular Hyporeactivity through the Regulation of Proinflammatory Proteins

“…Other authors suggest the SUMOylation of the PPAR␥ ligand-binding domain, which mediates transrepression of inflammatory response genes by PPAR␥ ligands (Pascual et al, 2005). By contrast, Trifilieff et al (2003) have shown that although PPAR␥ ligands are able to reduce inflammation, this effect might not be mediated by antagonism of the NF-B pathway. In the present study, we demonstrate that MPs from human T cells exert their effects on NF-B cascade at mRNA and protein expressions.…”

Transcription Factor and Drug-Metabolizing Enzyme Gene Expression in Lymphocytes from Healthy Human Subjects

“…These TF are involved in cholesterol (LXR), triglycerides (PPAR), bile acids (VDR, farnesoid X-activated receptor, LXR), steroids (CAR, PXR), and bilirubin (CAR, PXR) (Handschin and Meyer, 2005) metabolism. TF also interact with many other cardiovascular-related pathways, including the cytokines for PPAR (Jones et al, 2002;Trifilieff et al, 2003). To conclude, a biological system approach could be defined for better understanding on the relation of each TF with every P450 or other constituent candidate marker measured in PBMC.…”

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

“…37,86,87 These effects are likely mediated by modulating the function of multiple cell types, including macrophages, T cells, eosinophils, mast cells, epithelial cells, and smooth muscle cells. In vivo, nebulization of PPARa and PPARg ligands decreases allergen-induced eosinophilia and mucus production, as well as cytokine production (IL-2, IL-4, IL-5, IL-6, and IL-13), serum IgE and IgG1, TGF-b, and the expression of GATA-3, a transcription factor that promotes a Th2-type response in T cells.…”