Kang Jong Soon, Yoon Yeo Dae, Han Mi Hwa, Han Sang-Bae, Lee Kiho, Lee Ki Hoon, Park Song-Kyu, Kim Hwan Mook
Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Taejon, 305-333, Korea.
Mol Pharmacol. 2006 Mar;69(3):941-9. doi: 10.1124/mol.105.017442. Epub 2005 Dec 14.
(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.
（R）-4-（3,4-二氢-8,8-二甲基）-2H，8H-苯并[1,2-b：3,4-b']二吡喃-3-基）-1,3-苯二酚（光甘草定）已知具有抗炎、抗菌和心血管保护活性。在本研究中，我们报道了光甘草定对肿瘤坏死因子-α（TNF-α）刺激的人脐静脉内皮细胞（HUVECs）中细胞间黏附分子-1（ICAM-1）表达的抑制作用。光甘草定抑制THP-1细胞与TNF-α刺激的HUVECs的黏附以及TNF-α刺激的HUVECs中ICAM-1的细胞表面表达。包括ICAM-1、血管细胞黏附分子-1和E-选择素在内的黏附分子的mRNA表达也受到光甘草定的抑制。进一步研究表明，光甘草定对TNF-α刺激的HUVECs中的核因子（NF）-κB/Rel DNA结合、抑制因子-κBα（IkappaBα）和IkappaBβ降解、IkappaB激酶激活以及p65核转位具有抑制作用。用光甘草定处理多种细胞系表明，光甘草定对NF-κB/Rel激活的抑制作用不是细胞类型特异性的，并且诱导型和组成型NF-κB/Rel激活均被光甘草定处理所抑制。此外，在HUVECs中，光甘草定处理可阻断TNF-α诱导的Akt和细胞外信号调节激酶（ERK）的磷酸化。光甘草定还抑制鞘氨醇-1-磷酸（S1P）诱导的ICAM-1的细胞表面表达和mRNA表达。进一步研究表明，光甘草定抑制TNF-α诱导的鞘氨醇激酶活性，并且添加外源性S1P可逆转光甘草定对TNF-α诱导的ICAM-1表达的抑制作用。总之，我们的结果表明，光甘草定对ICAM-1表达的抑制作用可能至少部分是通过抑制鞘氨醇激酶途径以及随后抑制包括Akt、ERK和NF-κB/Rel信号通路在内的信号通路来介导的。
