@article {Spiecker856, author = {Martin Spiecker and Ioana Lorenz and Nikolaus Marx and Harald Darius}, title = {Tranilast Inhibits Cytokine-Induced Nuclear Factor κB Activation in Vascular Endothelial Cells}, volume = {62}, number = {4}, pages = {856--863}, year = {2002}, doi = {10.1124/mol.62.4.856}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Tranilast [N-(3,4-dimethoxycinnamoyl)anthranilic acid] inhibits vascular inflammation. However, the relevant anti-inflammatory mechanisms are not completely understood. We studied the effects of tranilast on nuclear factor-κB (NF-κB)-dependent endothelial cell adhesion molecule expression and transcriptional regulation. Cultured human umbilical vein endothelial cells were preincubated with 12.5 to 100 μg/ml tranilast. Tumor necrosis factor-α (TNF-α)-induced endothelial VCAM-1, ICAM-1, and E-selectin surface expression was inhibited dose dependently. Maximal inhibition achieved with 100 μg/ml tranilast was 38 {\textpm} 6.9, 31.8 {\textpm} 1.5, and 31.9 {\textpm} 1.9\%, respectively (mean {\textpm} S.E.M.,p \< 0.001, n = 5). Secretion of interleukin 6, which is also NF-κB{\textendash}sensitive, was significantly inhibited by tranilast. Endothelial MHC-I expression, which is independent of NF-κB, was not inhibited. Although cytokine-induced degradation of NF-κB inhibitor proteins (IκB-α, -β, and -ε), nuclear translocation of NF-κB, and binding of NF-κB to κBcis-acting elements in the adhesion molecule promoters were not affected by tranilast, ICAM-1-κB and E-selectin-κB reporter gene activity was inhibited by 53\% (n = 5, p \< 0.01) and 51\% (n = 5,p \< 0.001), respectively. In contrast, using SP-1 and C/EBP constructs, reporter gene activity was not altered. Expression of the transcriptional coactivator cAMP response element binding protein binding protein (CBP) was inhibited by tranilast, resulting in a loss of interaction between NF-κB and CBP. Therefore, in therapeutically relevant concentrations (50 μg/ml), tranilast inhibits NF-κB-dependent transcriptional activation by interfering with the NF-κB/CBP association. We propose that inhibition of NF-κB dependent gene transcription contributes to the anti-inflammatory effects of tranilast.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/62/4/856}, eprint = {https://molpharm.aspetjournals.org/content/62/4/856.full.pdf}, journal = {Molecular Pharmacology} }