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.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|