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

摘要

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