Blockade of cytokine-induced endothelial cell adhesion molecule expression by licorice isoliquiritigenin through NF-kappaB signal disruption.

Numerous polyphenolic compounds have been found to inhibit adhesion and migration of leukocytes to sites of inflammation that are partly regulated by the expression of cell adhesion molecules (CAM) such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and platelet endothelial cell adhesion molecule-1 (PECAM-1). Licorice root extracts have been used in traditional Chinese, Tibetan, and Indian medicine for the treatment of pulmonary diseases and inflammatory processes. Expression of CAM proteins was examined in human umbilical vein endothelial cells (HUVEC) treated with a licorice component (isoliquiritigenin, 18beta-glycyrrhetinic acid, glycyrrhizin, formononetin, or ononin) and exposed to TNF-alpha. The involvement of NF-kappaB in the transcriptional control of CAM proteins was assessed by degradation of IkappaBalpha and nuclear translocation of NF-kappaB using Western blotting techniques and immunocytochemical staining. At nontoxic > or =10 microM, isoliquiritigenin blocked the induction of VCAM-1 and E-selectin on activated HUVEC and markedly interfered with THP-1 monocyte adhesion to TNF-alpha-activated endothelial cells. Isoliquiritigenin abolished TNF-alpha-induced mRNA accumulation of VCAM-1 and E-selectin. Additionally, immunocytochemical staining revealed that isoliquiritigenin attenuated PECAM-1 expression induced by TNF-alpha. In contrast, other components recognized in licorice, 18beta-glycyrrhetinic acid, glycyrrhizin, formononetin, and ononin did not down-regulate the expression of VCAM-1 and/or PECAM-1 activated by TNF-alpha, implying that these components are inactive in modulating adhesion of leukocytes to stimulated endothelial cells. Isoliquiritigenin downregulated CAM proteins in TNF-alpha-activated HUVEC at the transcriptional levels by blocking degradation of IkappaBalpha and nuclear translocation of NF-kappaB. These results demonstrate that the induction blockade of VCAM-1 and E-selectin by isoliquiritigenin was directly mediated by its interference with the CAM mRNA transcription through NF-kappaB-dependent mechanisms under inflammatory conditions.