Selective blockade of NF-kappa B activity in airway immune cells inhibits the effector phase of experimental asthma.
Knockout mice studies have revealed that NF-kappaB plays a critical role in Th2 cell differentiation and is therefore required for induction of allergic airway inflammation. However, the questions of whether NF-kappaB also plays a role in the effector phase of airway allergy and whether inhibiting NF-kappaB could have therapeutic value in the treatment of established asthma remain unanswered. To address these issues, we have assessed in OVA-sensitized wild-type mice the effects of selectively antagonizing NF-kappaB activity in the lungs during OVA challenge. Intratracheal administration of NF-kappaB decoy oligodeoxynucleotides to OVA-sensitized mice led to efficient nuclear transfection of airway immune cells, but not constitutive lung cells and draining lymph node cells, associated with abrogation of NF-kappaB activity in the airways upon OVA provocation. NF-kappaB inhibition was associated with strong attenuation of allergic lung inflammation, airway hyperresponsiveness, and local production of mucus, IL-5, IL-13, and eotaxin. IL-4 and OVA-specific IgE and IgG1 production was not reduced. This study demonstrates for the first time that activation of NF-kappaB in local immune cells is critically involved in the effector phase of allergic airway disease and that specific NF-kappaB inhibition in the lungs has therapeutic potential in the control of pulmonary allergy.
Desmet
Christophe
C
Laboratoires de Physiologie, Université de Liège, Liège, Belgium.
Gosset
Philippe
P
Pajak
Bernard
B
Cataldo
Didier
D
Bentires-Alj
Mohamed
M
Lekeux
Pierre
P
Bureau
Fabrice
F
D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005260:Female; D007136:Immunoglobulins / Q000096:biosynthesis; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007442:Intubation, Intratracheal; D008168:Lung / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009093:Mucus / Q000378:metabolism; D016328:NF-kappa B / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013909:Thorax
D000485:Allergens; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D007136:Immunoglobulins; D018793:Interleukin-13; D015848:Interleukin-5; D016328:NF-kappa B; D020319:Oligodeoxyribonucleotides, Antisense; D015847:Interleukin-4; D010047:Ovalbumin