Nuclear factor kappa B induction in airway epithelium increases lung inflammation in allergen-challenged mice.
Nuclear factor kappa B (NF-kappa B) is a critical transcription factor for the production of many inflammatory cytokines. It is activated in the airway epithelium of human asthmatics and in mice after allergic stimulation. To examine the role of NF-kappa B activation in allergic inflammation, the authors generated transgenic mouse lines that allowed for the inducible stimulation of NF-kappa B in airway epithelial cells. After allergic sensitization with ovalbumin and alum, mice were challenged daily with ovalbumin aerosols and NF-kappa B was activated in airway epithelium by administration of doxycycline. Enhancement of airway epithelial NF-kappa B expression alone did not lead to increased airway responsiveness to methacholine. However, induction of epithelial NF-kappa B during allergic inflammation caused airway hyperresponsiveness, increased airway neutrophilic and lymphocytic inflammation and goblet cell hyperplasia. Accompanying the exaggerated inflammation was an increase in the cytokines granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-15, and KC. Interestingly, the counter regulatory interleukin, IL-10, was suppressed by NF-kappa B activation. The epithelial NF-kappa B dependent modulation of these cytokines provides a plausible explanation for the increased inflammation seen with overexpression of NF-kappa B. Modulation of airway epithelial NF-kappa B activation enhances the airway hyperresponsiveness and mucus secretion found in the mouse lung during allergic inflammation. NF-kappa B represents a potential target for pharmacologic intervention in human asthma.
Sheller
James R
JR
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. james.sheller@vanderbilt.edu
Polosukhin
Vasiliy V
VV
Mitchell
Daphne
D
Cheng
D-S
DS
Peebles
R Stokes
RS
Blackwell
Timothy S
TS
D000485:Allergens / Q000008:administration & dosage*; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004848:Epithelium / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000096:biosynthesis*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D012137:Respiratory System / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
D000485:Allergens; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D010047:Ovalbumin