Glycyrrhetinic acid inhibits ICAM-1 expression via blocking JNK and NF-κB pathways in TNF-α-activated endothelial cells

Aim: 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 [3H] 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 kappa B and nuclear factor-kappa B (NF-kappa B) or phospho-cJun in the nucleus were detected by western blots. NF-kappa B binding activity was detected using electrophoretic mobility shift assay. Results: GA (50 and 100 mmol/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 kappa B/NF-kappa B signaling system by preventing I kappa B degradation, NF-kappa B translocation, and NF-kappa B/DNA binding activity. Finally, pretreatment with GA or the inhibitors of NF-kappa B, JNK, and p38 reduced the ICAM-1 protein expression induced by TNF-alpha. Conclusion: 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 kappa B/NF-kappa B signaling pathways, which decrease activator protein-1 (AP-1) and NF-kappa B mediated ICAM-1 expressions. The results suggest that GA may provide a beneficial effect in treating vascular diseases associated with inflammation, such as atherosclerosis.