Tranilast Inhibits Cytokine-Induced Nuclear Factor κB Activation in Vascular Endothelial Cells

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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 ± 6.9, 31.8 ± 1.5, and 31.9 ± 1.9%, respectively (mean ± S.E.M.,p < 0.001, n = 5). Secretion of interleukin 6, which is also NF-κB–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.