Treatment of experimental asthma by decoy-mediated local inhibition of activator protein-1.
BACKGROUND
Asthma is associated with increased expression of a typical array of genes involved in immune and inflammatory responses, including those encoding the prototypic Th2 cytokines interleukin (IL) 4, IL-5, and IL-13. Most of these genes contain binding sites for activator protein-1 (AP-1) within their promoter and are therefore believed to depend on AP-1 for their expression, suggesting that this transcription factor could be of particular importance in asthma pathophysiology.


OBJECTIVE
To clarify the role of AP-1 in the effector phase of pulmonary allergy.


METHODS
Ovalbumin (OVA)-sensitized mice were intratracheally given decoy oligodeoxyribonucleotides (ODNs) specifically directed to AP-1 or scrambled control ODNs before challenge with aerosolized OVA. Twenty-four hours after the last OVA challenge, airway hyperresponsiveness was measured and allergic airway inflammation was evaluated quantitatively. AP-1 decoys were localized using flow cytometry and immunohistochemistry. AP-1 activity in the lung was assessed using electrophoretic mobility shift assay.


RESULTS
Intratracheally delivered AP-1 decoys efficiently targeted airway immune cells, thus precluding AP-1 activation on OVA challenge. Decoy-mediated local inhibition of AP-1 resulted in significant attenuation of all the pathophysiologic features of experimental asthma-namely, eosinophilic airway inflammation, airway hyperresponsiveness, mucous cell hyperplasia, production of allergen-specific immunoglobulins, and synthesis of IL-4, IL-5, and IL-13. Scrambled control ODNs had no detectable effects.


CONCLUSIONS
Our results reveal a key role for AP-1 in the effector phase of pulmonary allergy and indicate that specific AP-1 inhibition in the airways may have therapeutic value in the control of established asthma.
Desmet
Christophe
C
Laboratoire de Physiologie, Faculté de Médecine Vétérinaire, Centre de Thérapie Cellulaire et Moléculaire, Université de Liège, Belgium.
Gosset
Philippe
P
Henry
Emmanuelle
E
Garzé
Virginie
V
Faisca
Pedro
P
Vos
Nanda
N
Jaspar
Fabrice
F
Mélotte
Dorothée
D
Lambrecht
Bart
B
Desmecht
Daniel
D
Pajak
Bernard
B
Moser
Muriel
M
Lekeux
Pierre
P
Bureau
Fabrice
F
D000818:Animals; D001249:Asthma / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects; D005260:Female; D006967:Hypersensitivity / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D007107:Immune System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology; D014132:Trachea / Q000276:immunology / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
D009838:Oligodeoxyribonucleotides; D018808:Transcription Factor AP-1; D010047:Ovalbumin