Glabridin suppresses intercellular adhesion molecule-1 expression in tumor necrosis factor-alpha-stimulated human umbilical vein endothelial cells by blocking sphingosine kinase pathway: implications of Akt, extracellular signal-regulated kinase, and nuclear factor-kappaB/Rel signaling pathways.
(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-alpha (TNF-alpha)-stimulated human umbilical vein endothelial cells (HUVECs). Glabridin inhibited THP-1 cell adhesion to HUVECs stimulated by TNF-alpha and cell surface expression of ICAM-1 in TNF-alpha-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)-kappaB/Rel DNA binding, inhibitory factor-kappaB alpha (IkappaB alpha), and IkappaB beta degradation, IkappaB kinase activation, and p65 nuclear translocation in TNF-alpha-stimulated HUVECs. Treatment of a variety of cell lines with glabridin revealed that inhibitory effect of glabridin on NF-kappaB/Rel activation is not cell type-specific, and both inducible and constitutive NF-kappaB/Rel activation was suppressed by glabridin treatment. Moreover, TNF-alpha-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-alpha-induced sphingosine kinase activity was inhibited by glabridin, and the inhibitory effect of glabridin on TNF-alpha-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-kappaB/Rel signaling pathway.
Kang
Jong Soon
JS
Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Taejon, 305-333, Korea.
Yoon
Yeo Dae
YD
Han
Mi Hwa
MH
Han
Sang-Bae
SB
Lee
Kiho
K
Lee
Ki Hoon
KH
Park
Song-Kyu
SK
Kim
Hwan Mook
HM
D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000187:drug effects*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007529:Isoflavones; D008246:Lysophospholipids / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D000099157:Sphingosine Kinase
D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D018799:Intercellular Adhesion Molecule-1; D007529:Isoflavones; D008246:Lysophospholipids; D010636:Phenols; D017853:Phosphotransferases (Alcohol Group Acceptor); D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C107601:glabridin