Administration of antisense phosphorothioate oligonucleotide to the p65 subunit of NF-κB inhibits established asthmatic reaction in mice

The transcription factor, nuclear factor (NF)-kappaB, which transactivates various genes for proinflammatory cytokines and many other immunoregulatory genes, plays an important role in the regulation of various inflammatory diseases including asthma. Its increased activation has been demonstrated in the lungs after allergen challenge and in airway epithelial cells and macrophages of asthmatic patients. In the present study, we investigated whether the pretreatment with p65 antisense results in a significant inhibition of asthmatic reactions in a mouse model. Mice sensitized and challenged with ovalbumin (OVA) showed typical asthmatic reactions as follows: (1) an increase in the number of eosinophil in bronchoalveolar lavage fluid; (2) a marked influx of inflammatory cells into the lung around blood vessels and airways, and airway luminal narrowing; (3) the development of airway hyperresponsiveness; (4) the detection of TNF-alpha and Th2 cytokines, such as IL-4 and IL-5 in the bronchoalveolar lavage (BAL) fluid; and (5) detection of allergen-specific IgE and IgG in the serum. Two successive intravenous administration of p65 antisense before the last airway OVA challenge resulted in a significant inhibition of all asthmatic reactions, whereas the p65 nonsense did not produce such effects. In addition, the p65 antisense inhibition of asthmatic reaction appears to be due to the initial Suppression of an allergen-specific IgE response, inducing degranulation of mast cells through the cross-linking of allergen-specific IgE. This study may provide evidence that NF-kappaB plays a critical role in the pathogenesis of asthma in mice. (C) 2004 Elsevier B.V. All rights reserved.