Strain-dependent activation of NF-kappaB in the airway epithelium and its role in allergic airway inflammation.
NF-kappaB activation in the airway epithelium has been established as a critical pathway in ovalbumin (Ova)-induced airway inflammation in BALB/c mice (Poynter ME, Cloots R, van Woerkom T, Butnor KJ, Vacek P, Taatjes DJ, Irvin CG, Janssen-Heininger YM. J Immunol 173: 7003-7009, 2004). BALB/c mice are susceptible to the development of allergic airway disease, whereas other strains of mice, such as C57BL/6, are considered more resistant. The goal of the present study was to determine the proximal signals required for NF-kappaB activation in the airway epithelium in allergic airway disease and to unravel whether these signals are strain-dependent. Our previous studies, conducted in the BALB/c mouse background, demonstrated that transgenic mice expressing a dominant-negative version of IkappaBalpha in the airway epithelium (CC10-IkappaBalpha(SR)) were protected from Ova-induced inflammation. In contrast to these earlier observations, we demonstrate here that CC10-IkappaBalpha(SR) transgenic mice on the C57BL/6 background were not protected from Ova-induced allergic airway inflammation. Consistent with this finding, Ova-induced nuclear localization of the RelA subunit of NF-kappaB was not observed in C57BL/6 mice, in contrast to the marked nuclear presence of RelA in BALB/c mice. Evaluation of cytokine profiles in bronchoalveolar lavage demonstrated elevated expression of TNF-alpha in BALB/c mice compared with C57BL/6 mice after an acute challenge with Ova. Finally, neutralization of TNF-alpha by a blocking antibody prevented nuclear localization of RelA in BALB/c mice after Ova challenge. These data suggest that the mechanism of response of the airway epithelium of immunized C57BL/6 mice to antigen challenge is fundamentally different from that of immunized BALB/c mice and highlight the potential importance of TNF-alpha in regulating epithelial NF-kappaB activation in allergic airway disease.
Alcorn
John F
JF
Department of Pathology, Univ. of Vermont, HSRF Bldg., Rm. 216A, Burlington, VT 05405, USA.
Ckless
Karina
K
Brown
Amy L
AL
Guala
Amy S
AS
Kolls
Jay K
JK
Poynter
Matthew E
ME
Irvin
Charles G
CG
van der Vliet
Albert
A
Janssen-Heininger
Yvonne M W
YM
D000818:Animals; D000941:Antigens / Q000276:immunology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D008679:Metaplasia; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009093:Mucus / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009500:Neutralization Tests; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D013045:Species Specificity; D014132:Trachea / Q000473:pathology; D019076:Transgenes / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014598:Uteroglobin / Q000378:metabolism
D000941:Antigens; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C556390:Scgb1a1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D010047:Ovalbumin; D014598:Uteroglobin; D051550:I-kappa B Kinase