Glycyrrhetinic acid inhibits ICAM-1 expression via blocking JNK and NF-kappaB pathways in TNF-alpha-activated endothelial cells.
OBJECTIVE
To investigate the effects of glycyrrhetinic acid (GA), an active component extracted from the root of Glycyrrhizae glabra, on the expression of intercellular adhesion molecule-1 (ICAM-1) in tumor necrosis factor-alpha (TNF-alpha)-activated human umbilical vein endothelial cells (HUVEC).


METHODS
ICAM-1 mRNA and protein levels were detected using RT-PCR and cell enzyme-linked immunosorbent assays. The adherence of human monocytic THP-1 cells labeled with [(3)H]thymidine to HUVEC was determined by counting radioactivity with a scintillation counter. The activation of mitogen-activated protein kinases as well as the degradation of I kappaB and nuclear factor-kappaB (NF-kappaB) or phospho-c-Jun in the nucleus were detected by western blots. NF-kappaB binding activity was detected using electrophoretic mobility shift assay.


RESULTS
GA (50 and 100 micromol/L) significantly inhibits TNF-alpha-induced ICAM-1 mRNA and protein expressions, as well as THP-1 cell adhesiveness in HUVEC. GA selectively inhibited TNF-alpha-activated signal pathway of c-Jun N-terminal kinase (JNK), without affecting extracellular signal-regulated kinase 1/2 and p38. Furthermore, GA apparently inhibited I kappaB/NF-kappaB signaling system by preventing I kappaB degradation, NF-kappaB translocation, and NF-kappaB/DNA binding activity. Finally, pretreatment with GA or the inhibitors of NF-kappaB, JNK, and p38 reduced the ICAM-1 protein expression induced by TNF-alpha.


CONCLUSIONS
GA inhibits TNF-alpha-stimulated ICAM-1 expression, leading to a decrease in adherent monocytes to HUVEC. This inhibition is attributed to GA interruption of both JNK/c-Jun and I kappaB/NF-kappaB signaling pathways, which decrease activator protein-1 (AP-1) and NF-kappaB mediated ICAM-1 expressions. The results suggest that GA may provide a beneficial effect in treating vascular diseases associated with inflammation, such as atherosclerosis.
Chang
Ying-ling
YL
School of Traditional Chinese Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan, China. c1220@mail.cgu.edu.tw
Chen
Chien-lin
CL
Kuo
Chao-Lin
CL
Chen
Bor-chyuan
BC
You
Jyh-sheng
JS
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D006035:Glycyrrhiza / Q000737:chemistry; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology*; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000276:immunology; D018517:Plant Roots / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D014471:Umbilical Veins / Q000166:cytology
D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D006034:Glycyrrhetinic Acid