期刊
MOLECULAR PHARMACOLOGY
卷 62, 期 4, 页码 856-863出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.62.4.856
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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-kappaB (NF-kappaB)-dependent endothelial cell adhesion molecule expression and transcriptional regulation. Cultured human umbilical vein endothelial cells were preincubated with 12.5 to 100 mug/ml tranilast. Tumor necrosis factor-alpha (TNF-alpha)-induced endothelial VCAM-1, ICAM-1, and E-selectin surface expression was inhibited dose dependently. Maximal inhibition achieved with 100 mug/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-kappa B-sensitive, was significantly inhibited by tranilast. Endothelial MHC-I expression, which is independent of NF-kappa B, was not inhibited. Although cytokine-induced degradation of NF-kappa B inhibitor proteins (I kappa B-alpha,-beta, and -epsilon), nuclear translocation of NF-kappa B, and binding of NF-kappa B to kappa B cis-acting elements in the adhesion molecule promoters were not affected by tranilast, ICAM-1-kappa B and E-selectin-kappa B 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-kappa B and CBP. Therefore, in therapeutically relevant concentrations (50 mu g/ml), tranilast inhibits NF-kappa B-dependent transcriptional activation by interfering with the NF-kappa B/CBP association. We propose that inhibition of NF-kappa B dependent gene transcription contributes to the antiinflammatory effects of tranilast.
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