A novel cyclin-dependent kinase inhibitor down-regulates tumor necrosis factor-α (TNF-α)-induced expression of cell adhesion molecules by inhibition of NF-κB activation in human pulmonary epithelial cells

BAI (a novel cyclin-dependent kinase (CDK) inhibitor, 2-[1,1′-biphenyl]-4-yl-N-[5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1H-indazol-3-yl] acetamide) is known to have anti-proliferative activity, but the mechanism responsible for it remains unclear. We here investigated the functional effect of BAI on airway inflammation and its action mechanism. BAI down-regulated the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human lung epithelial A549 cells stimulated with tumor necrosis factor-α: (TNF-α), resulting in the suppression of leukocyte adhesion to lung epithelial A549 cells. In addition, BAI inhibited TNF-α-induced expression of adhesion molecules (ICAM-1 and VCAM-1) protein and mRNA in a dose-dependent manner. BAI inhibited nuclear factor-κB (NF-κB) activity and nuclear translocation of NF-κB. Furthermore, BAI potently inhibits the TNF-α-induced increase in ROS generation in A549 cells, suggesting that inhibition of ROS generation is maybe involved in the BAI-mediated inhibition of TNF-α-induced ICAM-1 down-regulation to A549 cells. Taken together, these results suggest that BAI inhibits cell adhesion through inhibition of ICAM-1 and VCAM-1 expressions, at least in part, by inhibition of ROS generation and down-regulation of NF-κB activity.