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

摘要

Cigarette smoke (CS), a major risk factor for developing lung cancer, is known to activate transcriptional activator nuclear factor kappa B (NF-κB). However, the underlying mechanism of this activation remains unclear because of conflicting reports. As NF-κB 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-κB activation mechanism is different from that of other pro-inflammatory signals such as lipopolysaccharide (LPS). The NF-κB dimer that translocates to the nucleus upon stimulation with CS is predominantly composed of c-Rel/p50 and this translocation involves degradation of I-κB? and not I-κBα. This degradation of I-κB? depends on IKKβ activity, which preferentially targets I-κB?. Consistently, CS-activated form of IKKβ was found to be different from that involved in LPS activation as neither Ser177 nor Ser181 of IKKβ is crucial for CS-induced NF-κB activation. Thus, unlike other pro-inflammatory stimulations where p65 and I-κBα have a central role, the predominantly active signaling cascade in CS-induced NF-κB activation in the lung epithelial cells comprises of IKKβ–I-κB?–c-Rel/p50. Thus, this study uncovers a new axis of NF-κB activation wherein I-κB? and c-Rel have the central role.. ? 2012 Macmillan Publishers Limited