[en] Rationale: 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. Measurements and Main 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.
Disciplines :
Veterinary medicine & animal health Biochemistry, biophysics & molecular biology
Author, co-author :
Desmet, Christophe ; Université de Liège - ULiège > Département de sciences fonctionnelles > GIGA-R : Biochimie et biologie moléculaire
Gosset, P.
Henry, E.
Garze, V.
Faisca, P.
Vos, N.
Jaspar, Fabrice ; Université de Liège - ULiège > Clinique des grands animaux
Burin Kefer, D.
Lambrecht, B.
Desmecht, Daniel ; Université de Liège - ULiège > Département de morphologie et pathologie > Pathologie spéciale et autopsies
Pajak, B.
Moser, M.
Lekeux, Pierre ; Université de Liège - ULiège > Département de sciences fonctionnelles > Physiologie
Bureau, Fabrice ; Université de Liège - ULiège > Département de sciences fonctionnelles > Biochimie et biologie moléculaire
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