Suppression of allergen-induced airway inflammation and immune response by the peroxisome proliferator-activated receptor-alpha agonist fenofibrate.
In the present study, we have assessed the effect of the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist fenofibrate on allergen-induced airway inflammation and immune response. C57BL/6 or PPARalpha knock-out (PPARalpha(-/-)) mice were sensitized with ovalbumin and challenged with ovalbumin alone or with ovalbumin+lipopolysaccharides. Fenofibrate was administered to allergen-exposed animals during challenge only or from the day prior to sensitization to the end of challenge. Inflammation and immune response were assessed by determining cell counts and cytokine levels in bronchoalveolar lavage fluids, expression of the transcription factors Gata-3 and T-bet in lung tissue and ovalbumin-specific IgE and IgG2a in serum. Treatment with fenofibrate (0.15-15 mg/day) during allergen challenge dose-dependently reduced airway inflammatory cell infiltrate induced by ovalbumin in C57BL/6 mice. Reduction reached 74.3% (P<0.001) in animals treated with 15 mg/day of the PPARalpha agonist, whereas this treatment failed to suppress cell infiltrate induced by allergen in PPARalpha(-/-) mice. In addition, when administered from the day prior to sensitization to the end of challenge, fenofibrate (15 mg/day) triggered switching of the immune response to allergen towards a Th1 profile, as evidenced by an increase in IgG2a levels, a reduction in IL(interleukin)-4 and IL-5 together with an increase in interferon-gamma, and a decrease in Gata-3/T-bet expression ratio. Upon challenge with ovalbumin+lipopolysaccharides, sensitized mice developed a severe inflammatory response characterized by infiltration of eosinophils, neutrophils, lymphocytes and macrophages and by increased release of IL-4, IL-5, tumor necrosis factor-alpha, macrophage-inflammatory protein-2 and monocyte chemoattractant protein-1. Administration of fenofibrate during allergen challenge dramatically reduced all responses. In conclusion, our data clearly demonstrate that fenofibrate exhibits an anti-inflammatory activity in allergic asthma, including in severe conditions, and that the PPARalpha agonist is also capable of switching the immune response to allergen towards a Th1 profile when given from the day prior to sensitization.
Delayre-Orthez
Carine
C
EA3771 Inflammation et environnement dans l'asthme, Faculté de Pharmacie, Université Louis Pasteur-Strasbourg I, Illkirch, France.
Becker
Julien
J
Auwerx
Johan
J
Frossard
Nelly
N
Pons
Françoise
F
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D016207:Cytokines / Q000096:biosynthesis; D011345:Fenofibrate / Q000627:therapeutic use*; D007073:Immunoglobulin E / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D047493:PPAR alpha / Q000819:agonists* / Q000502:physiology
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D047493:PPAR alpha; D007073:Immunoglobulin E; D010047:Ovalbumin; D011345:Fenofibrate