Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Allergens / administration & dosage
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Allergens / immunology
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Animals
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Apoptosis / drug effects
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Apoptosis / immunology
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Asthma / immunology*
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Asthma / metabolism*
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Asthma / pathology
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Bronchial Hyperreactivity / immunology
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Bronchial Hyperreactivity / metabolism
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Bronchial Hyperreactivity / pathology
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Chemokine CCL11
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Chemokines, CC / antagonists & inhibitors
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Chemokines, CC / biosynthesis
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Female
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Immunoglobulins / biosynthesis
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Interleukin-13 / antagonists & inhibitors
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Interleukin-13 / biosynthesis
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Interleukin-4 / biosynthesis
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Interleukin-5 / antagonists & inhibitors
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Interleukin-5 / biosynthesis
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Intubation, Intratracheal
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Lung / immunology*
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Lung / metabolism*
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Lung / pathology
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Lymph Nodes / pathology
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Mice
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Mice, Inbred BALB C
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Mucus / metabolism
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NF-kappa B / administration & dosage
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / metabolism*
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Oligodeoxyribonucleotides, Antisense / administration & dosage
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Oligodeoxyribonucleotides, Antisense / metabolism
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Ovalbumin / administration & dosage
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Ovalbumin / immunology
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Respiratory Mucosa / immunology*
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Respiratory Mucosa / metabolism*
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Respiratory Mucosa / pathology
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Th2 Cells / immunology
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Th2 Cells / metabolism
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Thorax
Substances
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Allergens
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Ccl11 protein, mouse
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Chemokine CCL11
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Chemokines, CC
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Immunoglobulins
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Interleukin-13
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Interleukin-5
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NF-kappa B
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Oligodeoxyribonucleotides, Antisense
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Interleukin-4
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Ovalbumin