文摘
Nuclear factor-κB (NF-κB) plays a central role in the development of bleomycin (BLM) lung toxicity, but the regulatory mechanisms are still unknown. In the present study, we investigated the cytotoxic effect of BLM on cultured human bronchial epithelial cells (BECs) and first confirmed that BLM induced the transcriptional activation of NF-κB signaling in BECs. We also found that BLM activated Akt (protein kinase B, PKB) and increased the phosphorylation level of glycogen synthase kinase 3β (GSK3β). GSK3β is known to be a key downstream target of Akt, and LY294002, the PI3K (phosphatidylinositol 3-kinase)/Akt inhibitor, which promoted the dephosphorylation of GSK3β, significantly attenuated BLM-induced NF-κB activation. Next, we further observed that constitutively active GSK3β stabilized the inhibitor of NF-κB (IκBα), inhibited p65 nuclear translocation and partially blocked BLM-induced NF-κB activation. Importantly, a co-immunoprecipitation assay revealed that GSK3β formed a complex with IκBα, while GSK3β phosphorylation caused by BLM led to their dissociation. These results suggest that BLM can induce the activation of NF-κB signaling in BECs and this process is tightly associated with the phosphorylation status of GSK3β, implying a possible regulatory mechanism of NF-κB signaling in BECs during the toxic lung injury induced by BLM.
