ORIGINAL ARTICLE

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