NF-κB Activation in Airways Modulates Allergic Inflammation but Not Hyperresponsiveness

Abstract

Airways display robust NF-κB activation and represent targets for anti-inflammatory asthma therapies, but the functional importance of NF-κB activation in airway epithelium remains enigmatic. Therefore, transgenic mice were created in which NF-κB activation is repressed specifically in airways (CC10-IκBαSR mice). In response to inhaled Ag, transgenic mice demonstrated significantly ameliorated inflammation, reduced levels of chemokines, T cell cytokines, mucus cell metaplasia, and circulating IgE compared with littermate controls. Despite these findings, Ag-driven airways hyperresponsiveness was not attenuated in CC10-IκBαSR mice. This study clearly demonstrates that airway epithelial NF-κB activation orchestrates Ag-induced inflammation and subsequent adaptive immune responses, but does not contribute to airways hyperresponsiveness, the cardinal feature that underlies asthma.

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

“…Poynter et al reported that NF-kB repression selectively in airway epithelium significantly reduced the lymphocytes and eosinophils as well as eotaxin and IL-5 in BAL but did not alter AHR in a mouse model of asthma [29]. The dissociation between the number of inflammatory cells in BAL and AHR is consistent with our data and Poynter et al proposed the possibility of alternative signaling pathways, residual NF-kB activity and residual inflammatory cells in the lungs to account for the apparent lack of effect of absent epithelial NF-kB activity on AHR [29]. Although NF-kB appeared to be activated in our study it did not seem to be altered by EGFR inhibition in lung tissue as assessed by Western analysis.…”

“…The production of eotaxin has also been reported to be mediated through NF-kB activation in a mouse model of allergic inflammation [28] and thus, in our study the blockade of the EGFR pathway could potentially have resulted from suppression of NF-kB activation followed by the reductions of IL-6, CINC-1 and eotaxin in BAL. Poynter et al reported that NF-kB repression selectively in airway epithelium significantly reduced the lymphocytes and eosinophils as well as eotaxin and IL-5 in BAL but did not alter AHR in a mouse model of asthma [29]. The dissociation between the number of inflammatory cells in BAL and AHR is consistent with our data and Poynter et al proposed the possibility of alternative signaling pathways, residual NF-kB activity and residual inflammatory cells in the lungs to account for the apparent lack of effect of absent epithelial NF-kB activity on AHR [29].…”

Airway Epithelial NF-κB Activation Modulates Asbestos-Induced Inflammation and Mucin Production In Vivo

“…For example, IL-6 (11) and IL-8 (12)/MIP-2 (13), two putative mediators of inflammation and fibrogenesis in lung, have NF-B binding sequences in their promoter regions that are critical to their transcriptional activation. NF-B is also linked to increased cell survival and may govern proliferative responses after stress (14).…”

“…To test this hypothesis, we created a transgenic (Tg) mouse expressing an I B␣ mutant (also referred to as an I B␣ superrepressor) resistant to phosphorylation-induced degradation and under transcriptional control of the CC10 promoter to inhibit NF-B selectively in airway epithelial cells. The CC10-I B␣sr mice, as previously characterized (14,16), were then bred into the C57BL/6 background and evaluated in a murine inhalation model of chrysotile asbestos-induced fibrogenesis at time points of peak epithelial cell proliferation, inflammation and fibrogenesis, i.e., 3, 9, and 40 days, respectively (4,5). Based on results with CC10-I B␣sr mice after intranasal instillation of LPS (16) and in the OVA sensitization and challenge model (14), we hypothesized that acute inflammation in response to asbestos would be curtailed.…”

“…The CC10-I B␣sr mice, as previously characterized (14,16), were then bred into the C57BL/6 background and evaluated in a murine inhalation model of chrysotile asbestos-induced fibrogenesis at time points of peak epithelial cell proliferation, inflammation and fibrogenesis, i.e., 3, 9, and 40 days, respectively (4,5). Based on results with CC10-I B␣sr mice after intranasal instillation of LPS (16) and in the OVA sensitization and challenge model (14), we hypothesized that acute inflammation in response to asbestos would be curtailed. However, our results show that inhalation of chrysotile asbestos causes lung recruitment of eosinophils that are proportionally greater in Tg ϩ mice at 9 days and minimal recruitment of neutrophils.…”