Blockade of cytokine‐induced endothelial cell adhesion molecule expression by licorice compound isoliquiritigenin through NF‐κB signal disruption

Abstract

Licorice root extracts have long been used in the traditional Chinese, Tibetian and Indian medicines for the treatment of pulmonary diseases and inflammatory processes. We attempted to explore whether licorice components, isoliquiritigenin (4,2′,4′-trihydroxychalcone, ISL), 18β-glycyrrhetinic acid, glycyrrhizic acid, formononetin and ononin, inhibit expression of cell adhesion molecules (CAM) induced by tumor necrosis factor-α (TNF-α) in the human umbilical vein endothelial cells (HUVEC). TNF-α induced expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin with increasing their mRNA levels. At non-toxic ≥10 μM ISL blocked the induction of VCAM-1 and E-selectin on activated HUVEC and markedly interfered with the THP-1 monocyte adhesion to TNF-α-activated endothelial cells. ISL abolished TNF-α-induced mRNA accumulation of VCAM-1 and E-selectin. In addition, immunocytochemical staining revealed that ISL attenuated platelet endothelial cell adhesion molecule-1 (PECAM-1) expression induced by TNF-α. In contrast, other components recognized in licorice, 18β-glycyrrhetinic acid, glycyrrhizic acid, formononetin and ononin, did not down-regulate the expression of VCAM-1 and/or PECAM-1 activated by TNF-α, implying that these components is inactive in modulating adhesion of leukocytes to stimulated endothelial cells. ISL inhibited phosphorylation of IκB-α and nuclear translocation NF-κB in TNF-α-activated HUVEC. ISL down-regulate CAM proteins in TNF-α-activated HUVEC at the transcriptional levels by blocking nuclear transactivation of NF-κB. These results demonstrate that the induction blockade of VCAM-1 and E-selectin by ISL was directly mediated by its interference with the CAM mRNA transcription through NF-κB-dependent mechanisms under inflammatory conditions.