Nuclear factor kappaB-mediated down-regulation of adhesion molecules: possible mechanism for inhibitory activity of bigelovin against inflammatory monocytes adhesion to endothelial cells.
The flowers of Inula britannica L. var. chinensis (Rupr.) Reg. (Compositae) are used in traditional medicine to treat asthma, chronic bronchitis, and acute pleurisy in China and Korea. However, the pharmacological actions of Inula britannica L. var. chinensis on endothelial cells and inflammatory monocytes are not clear. In this study, we investigated whether bigelovin, a sesquiterpene lactone isolated from the flowers of Inula britannica L. var. chinensis, inhibits monocyte adhesion and adhesion molecule expression in brain endothelial cells. We measured tumor necrosis factor-alpha (TNF-alpha)-enhanced Raw264.7 monocyte binding to brain endothelial cells and the levels of cell adhesion molecules, including vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and endothelial-selectin (E-selectin) on the surface of brain endothelial cells. Bigelovin significantly inhibited these in a dose-dependent manner without affecting cell viability. Furthermore, bigelovin suppressed the nuclear factor kappaB (NF-kappaB) promoter-driven luciferase activity, NF-kappaB activation, and degradation of NF-kappaB inhibitor protein alpha (IkappaBalpha). These results indicate that bigelovin inhibits inflammatory monocyte adhesion to endothelial cells and the expression of VCAM-1, ICAM-1, and E-selectin by blocking IkappaBalpha degradation and NF-kappaB activation.
Nam
Kung-Woo
KW
Department of Manufacturing Pharmacy & Natural Products Research Institute, College of Pharmacy, Seoul National University, Gwanak-gu, Seoul 151-742, Republic of Korea.
Oh
Goo Taeg
GT
Seo
Eun-Kyoung
EK
Kim
Kyeong Ho
KH
Koo
Uk
U
Lee
Sung-Jin
SJ
Mar
Woongchon
W
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D019040:E-Selectin / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D035264:Flowers; D005786:Gene Expression Regulation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D038143:Inula / Q000737:chemistry*; D007783:Lactones / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D008518:Medicine, East Asian Traditional; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism
D019040:E-Selectin; D020672:I-kappa B Proteins; D007783:Lactones; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; C099796:bigelovin