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Glabridin Suppresses Intercellular Adhesion Molecule-1 Expression in Tumor Necrosis Factor--Stimulated Human Umbilical Vein Endothelial Cells by Blocking Sphingosine Kinase Pathway: Implications of Akt, Extracellular Signal-Regulated Kinase, and Nuclear Factor-B/Rel Signaling Pathways

Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Taejon, Korea

(R)-4-(3,4-Dihydro-8,8-dimethyl)-2H,8H-benzo[1,2-b:3,4-b'] dipyran-3yl)-1,3-benzenediol (glabridin) is known to have anti-inflammatory, antimicrobial, and cardiovascular protective activities. In the present study, we report the inhibitory effect of glabridin on intercellular adhesion molecule-1 (ICAM-1) expression in tumor necrosis factor- (TNF-)-stimulated human umbilical vein endothelial cells (HUVECs). Glabridin inhibited THP-1 cell adhesion to HUVECs stimulated by TNF- and cell surface expression of ICAM-1 in TNF--stimulated HUVECs. The mRNA expression of adhesion molecules, including ICAM-1, vascular cell adhesion molecule-1, and E-selectin, was also suppressed by glabridin. Further study demonstrated the inhibitory effect of glabridin on nuclear factor (NF)-B/Rel DNA binding, inhibitory factor-B (IB), and IB degradation, IB kinase activation, and p65 nuclear translocation in TNF--stimulated HUVECs. Treatment of a variety of cell lines with glabridin revealed that inhibitory effect of glabridin on NF-B/Rel activation is not cell type-specific, and both inducible and constitutive NF-B/Rel activation was suppressed by glabridin treatment. Moreover, TNF--induced phosphorylation of Akt and extracellular signal-regulated kinase (ERK) was blocked by glabridin treatment in HUVECs. Glabridin also suppressed sphingosine-1-phosphate (S1P)-induced cell surface expression and mRNA expression of ICAM-1. Further study demonstrated that TNF--induced sphingosine kinase activity was inhibited by glabridin, and the inhibitory effect of glabridin on TNF--induced ICAM-1 expression was reversed by addition of exogenous S1P. Together, our results indicate that the inhibitory effect of glabridin on ICAM-1 expression might be mediated, at least in part, by inhibiting sphingosine kinase pathway and subsequent inhibition of signaling pathways, including Akt, ERK, and NF-B/Rel signaling pathway.

Address correspondence to: Dr. Hwan Mook Kim, LMO Evaluation Laboratory, Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Taejon, 305-333, Korea. E-mail: hwanmook{at}kribb.re.kr

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