IκBNS induces Muc5ac expression in epithelial cells and causes airway hyper-responsiveness in murine asthma models.

Background: In allergic asthma, environmental allergens including house dust mite (HDM) trigger pattern recognition receptors and activate downstream signaling pathways including NF-kappa B pathways not only in immune cells but also in airway epithelial cells. Recent studies have shown that NF-kappa B activation is regulated positively or negatively depending on the cellular context by I kappa BNS (encoded by the gene Nfkbid), one of atypical I kappa B proteins, in the nucleus. Therefore, we hypothesized that I kappa BNS expressed in immune cells or epithelial cells is involved in the regulation of asthmatic responses. Aim: To determine the roles of I kappa BNS in HDM-induced asthmatic responses. Methods: Roles of I kappa BNS in HDM-induced airway inflammation and airway hyper-responsiveness (AHR) were examined by using I kappa BNS-deficient (Nfkbid(-/-)) mice. Roles of I kappa BNS expressed in hematopoietic cells and nonhematopoietic cells were separately evaluated by bone marrow chimeric mice. Roles of I kappa BNS expressed in murine tracheal epithelial cells (mTECs) were examined by air-liquid interface culture. Results: House dust mite-induced airway inflammation and AHR were exacerbated in mice lacking I kappa BNS in hematopoietic cells. In contrast, HDM-induced airway inflammation was exacerbated, but AHR was attenuated in mice lacking I kappa BNS in nonhematopoietic cells. The induction of Muc5ac, a representative mucin in asthmatic airways, was reduced in Nfkbid(-/-) mTEC, whereas the induction of Spdef, a master regulator of goblet cell metaplasia, was not impaired in Nfkbid(-/-) mTEC. Moreover, I kappa BNS bound to and activated the MUC5AC distal promoter in epithelial cells. Conclusion: I kappa BNS is involved in inducing Muc5ac expression in lung epithelial cells and causing AHR in HDM-induced asthma models.