PPAR-alpha and -gamma but not -delta agonists inhibit airway inflammation in a murine model of asthma: in vitro evidence for an NF-kappaB-independent effect.
1. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that have been proposed to regulate inflammation by antagonising the nuclear factor-kappaB (NF-kappaB) signalling pathway. We investigated the role of PPARs using synthetic agonists in murine models of airway inflammation, and addressed the possible effect on NF-kappaB 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-alpha (GW 9578) and PPAR-gamma (GI 262570) selective agonist as well as a dual PPAR-alpha/gamma (GW 2331) agonist selectively inhibited allergen-induced bronchoalveolar lavage eosinophil and lymphocyte but not neutrophil influx. In contrast, a PPAR-delta agonist (GW 501516) was inactive. 3. When given intranasally an hour before challenge, PPAR-alpha and PPAR-gamma selective agonists as well as a dual PPAR-alpha/gamma agonist did not inhibit lipopolysaccharide-induced bronchoalveolar lavage neutrophil influx or tumour necrosis factor-alpha (TNF-alpha) and KC production. 4. In A549 cells, selective agonists for PPAR-alpha, -gamma and -delta did not inhibit intracellular adhesion molecule-1 expression following stimulation with proinflammatory cytokines. In addition, IL-8 release and the activation of an NF-kappaB-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-alpha and -gamma, but not -delta, 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-kappaB pathway.
Novartis Respiratory Research Centre, Wimblehurst Road, Horsham RH12 5AB, UK. alexandre.trifilieff@pharma.novartis.com
Alexandre
A
Trifilieff
Anne
A
Bench
Marcus
M
Hanley
Debbie
D
Bayley
Emma
E
Campbell
Paul
P
Whittaker
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid; D002460:Cell Line; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010047:Ovalbumin; D011014:Pneumonia / Q000188:drug therapy / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012485:Salmonella typhi; D014157:Transcription Factors / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D010047:Ovalbumin