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.
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.
Oh
Jung Hwa
JH
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, 704-701, South Korea.
Park
Eun Jung
EJ
Park
Jong-Wook
JW
Lee
Jinho
J
Lee
Sang Han
SH
Kwon
Taeg Kyu
TK
D021581:Active Transport, Cell Nucleus; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D015536:Down-Regulation; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053778:Thiazolidines / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
C545562:2-(1,1'-biphenyl)-4-yl-N-(5-(1,1-dioxo-1lambda(6)-isothiazolidin-2-yl)-1H-indazol-3-yl)acetamide; D007191:Indazoles; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D053778:Thiazolidines; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D018844:Cyclin-Dependent Kinases