Nuclear Factor - kappa B (NF-B) activation in the airway epithelium has been established as a critical pathway in ovalbumin (Ova)-induced airway inflammation in BALB/c mice (35). BALB/c mice are susceptible to the development of allergic airway disease while other strains of mice, such as C57BL/6, are considered more resistant. The goal of this study was to determine the proximal signals required for NF-B 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 (35) demonstrated that transgenic mice expressing a dominant negative version of the IB in the airway epithelium (CC10-IB_SR) were protected from Ova-induced inflammation. In contrast to those observations, we demonstrate here that CC10-IB_SR transgenic mice on the C57BL/6 background were not protected from Ova-induced allergic airway inflammation. In agreement with this, Ova-induced nuclear localization of the RelA subunit of NF-B 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 that BALB/c mice expressed elevated TNF- levels compared to C57BL/6 mice following an acute challenge with Ova. Lastly, neutralization of TNF- using a blocking antibody prevented nuclear localization of RelA in BALB/c mice following Ova challenge. These data suggest that immunized C57BL/6 and BALB/c mice respond to antigen challenge by fundamentally different mechanisms regarding the airway epithelium, and highlight the potential importance of TNF- in regulating epithelial NF-B activation in allergic airway disease.