Effects of inhaled corticosteroid therapy on expression and DNA-binding activity of nuclear factor kappaB in asthma.
We determined whether inhaled corticosteroid therapy modulates the expression of the transcription factor, nuclear factor kappa B (NF-kappaB), in patients with asthma. Fifteen stable patients with mild asthma underwent bronchoalveolar lavage (BAL) with bronchial biopsies in a double-blind, placebo-controlled and crossover study after placebo or after inhaled fluticasone propionate (500 microg twice daily). Fluticasone reduced the number of eosinophils in BAL fluid (BALF) and in airway biopsies, together with an improvement of bronchial responsiveness to methacholine. However, NF-kappaB DNA-binding in alveolar macrophages and in bronchial biopsies was not affected by fluticasone treatment. NF-kappaB expression was also measured by immunohistochemical staining with an antibody to the p65 component of NF-kappaB. Fluticasone caused an increase in the number of positive nuclear staining cells in the airway epithelium from 34. 1 +/- 5.0 to 64.1 +/- 8.0 per mm(2) (p = 0.002). In vitro studies of A549 epithelial cells stimulated by interleukin-1beta (IL-1beta) showed that dexamethasone increased p65 protein expression analyzed by Western blot. Despite an anti-inflammatory effect of fluticasone, there was no decrease in NF-kappaB-DNA binding and activation, indicating that this may not be a mechanism by which corticosteroids act in asthma. The significance of corticosteroid-induced increase in p65 protein expression is not known.
Hart
L
L
Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine and Royal Brompton Hospital, London, United Kingdom.
Lim
S
S
Adcock
I
I
Barnes
P J
PJ
Chung
K F
KF
D000280:Administration, Inhalation; D000287:Administration, Topical; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002135:Calcium-Binding Proteins; D002452:Cell Count; D002478:Cells, Cultured; D018592:Cross-Over Studies; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004311:Double-Blind Method; D004804:Eosinophils / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D000068298:Fluticasone; D005938:Glucocorticoids; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000166:cytology / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D050863:Synaptotagmin I; D050857:Synaptotagmins
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D002135:Calcium-Binding Proteins; D005938:Glucocorticoids; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D050863:Synaptotagmin I; D050857:Synaptotagmins; D003907:Dexamethasone; D004247:DNA; D000068298:Fluticasone