Matthew E. Poynter, Ph.D.
Background: Asthma is a complex disease characterized by airway inflammation, production of mucus, and airway hyperresponsiveness to inhaled bronchoconstricting agents. The transcription factor NFκB is a major regulator of immune function and inflammation and has been widely implicated in asthma. NFκB normally resides in the cytoplasm bound by an inhibitory protein known as IκB. Phosphorylation of IκB by IκB kinase-β (IKK-β) releases NFκB, which then moves into the cell's nucleus where it acts in the induction of numerous regulatory genes of the immune system. Transgenic mice lacking subunits of NFκB develop less airway inflammation after antigen challenges; however, the exact mechanism by which NFκB modulates allergic airway disease is unclear.
Advance: To address the significance of airway epithelial cell activation of NFκB in allergic airway disease, investigators at the University of Vermont generated a transgenic mouse with suppressed IκB activity thus inhibiting NFκB activation selectively in airway epithelial cells. When the transgenic mice were then challenged with antigen, airway inflammation and the production of inflammatory mediators were significantly reduced. However, the airway hyperresponsiveness typically seen after antigen challenge was not affected suggesting that NFκB is not responsible for hyperresponsiveness, a hallmark of asthma.
Implications: This study demonstrates that NFκB activation in airway cells drives the majority of antigen-induced inflammation and is a significant contributor to adaptive immune responses. The findings also show that NFκB does not exert control over hyperresponsiveness. The authors speculate that these processes may be controlled deeper in the lungs in the alveoli. Alveolar injury or surfactant dysfunction may be responsible for inducing the airway responses. Thus, to minimize airway hyperresponsiveness in allergic airway diseases, treatments that target deeper lung tissues are necessary.
Citation: Poynter ME, Cloots R, van Woerkom T, Butnor KJ, Vacek P, Taatjes DJ, Irvin CG, Janssen-Heininger YM. NF-κB activation in airways modulates allergic inflammation but not hyperresponsiveness. J Immunol. 2004 Dec 1;173(11):7003-9.