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

Jung Hwa Oh, Eun Jung Park, Jong-Wook Park, Jinho Lee, Sang Han Lee, Taeg Kyu Kwon
International Immunopharmacology 2010, 10 (5): 572-9
BAI (a novel cyclin-dependent kinase (CDK) inhibitor, 2-[1,1'-biphenyl]-4-yl-N-[5-(1,1-dioxo-1lambda(6)-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-alpha: (TNF-alpha), resulting in the suppression of leukocyte adhesion to lung epithelial A549 cells. In addition, BAI inhibited TNF-alpha-induced expression of adhesion molecules (ICAM-1 and VCAM-1) protein and mRNA in a dose-dependent manner. BAI inhibited nuclear factor-kappaB (NF-kappaB) activity and nuclear translocation of NF-kappaB. Furthermore, BAI potently inhibits the TNF-alpha-induced increase in ROS generation in A549 cells, suggesting that inhibition of ROS generation is maybe involved in the BAI-mediated inhibition of TNF-alpha-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-kappaB activity.

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