IKKβ-I-κBε-c-Rel/p50: a new axis of NF-κB activation in lung epithelial cells

Cigarette smoke (CS), a major risk factor for developing lung cancer, is known to activate transcriptional activator nuclear factor kappa B (NF-kappa B). However, the underlying mechanism of this activation remains unclear because of conflicting reports. As NF-kappa has a pivotal role in the generation and maintenance of malignancies, efforts were targeted towards understanding its activation mechanism using both ex vivo and in vivo studies. The results show that CS-induced NF-kappa B activation mechanism is different from that of other pro-inflammatory signals such as lipopolysaccharide (LPS). The NF-kappa B dimer that translocates to the nucleus upon stimulation with CS is predominantly composed of c-Rel/p50 and this translocation involves degradation of I-kappa B epsilon and not I-kappa B epsilon. This degradation of I-kappa B epsilon depends on IKK beta activity, which preferentially targets I-kappa B epsilon. Consistently, CS-activated form of IKK beta was found to be different from that involved in LPS activation as neither Ser177 nor Ser181 of IKK beta is crucial for CS-induced NF-kappa B activation. Thus, unlike other pro-inflammatory stimulations where p65 and I-kappa B alpha have a central role, the predominantly active signaling cascade in CS-induced NF-kappa B activation in the lung epithelial cells comprises of IKK beta-I-kappa B epsilon-c-Rel/p50. Thus, this study uncovers a new axis of NF-kappa B activation wherein I-kappa B epsilon and c-Rel have the central role.