Vascular cell adhesion molecule-1 expression in human intestinal microvascular endothelial cells is regulated by PI 3-kinase/Akt/MAPK/NF-κB: inhibitory role of curcumin

Binion DG, Heidemann J, Li MS, Nelson VM, Otterson MF, Rafiee P. Vascular cell adhesion molecule-1 expression in human intestinal microvascular endothelial cells is regulated by PI 3-kinase/Akt/MAPK/NF-kappa B: inhibitory role of curcumin. Am J Physiol Gastrointest Liver Physiol 297: G259-G268, 2009. First published June 11, 2009; doi: 10.1152/ajpgi.00087.2009.-Endothelial activation and surface expression of cell adhesion molecules (CAMs) is critical for binding and recruitment of circulating leukocytes in tissues during the inflammatory response. Endothelial CAM expression plays a critical role in the intestinal microvasculature in inflammatory bowel disease (IBD), as blockade of leukocyte alpha(4)-integrin binding by gut endothelial CAM ligands has therapeutic benefit in IBD. Mechanisms underlying expression of vascular cell adhesion molecule (VCAM)-1, a ligand for alpha(4)-integrin in primary cultures of human intestinal microvascular endothelial cells (HIMEC) has not been defined. We investigated the effect of curcumin, phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt), and mitogen-activated protein kinase (MAPK) inhibitors on VCAM-1 expression and function in HIMEC. CAM expression was assessed and HIMEC-leukocyte adhesion was visualized under static and flow conditions. Western blotting and in vitro kinase assays were used to assess Akt and MAPK activation. Nuclear factor-kappa B (NF-kappa B) activation and nuclear translocation of its p65 subunit were determined. Tumor necrosis factor (TNF)-alpha/lipopolysaccharide (LPS)-induced VCAM-1 expression in HIMEC was suppressed by Akt small-interfering RNA, curcumin, and inhibitors of NF-kappa B (SN-50), p38 MAPK (SB-203580) and PI 3-kinase/Akt (LY294002). VCAM-1 induction was partially suppressed by p44/42 MAPK (PD-098059) but unaffected by c-Jun NH2-terminal kinase (SP-600125) inhibition. Curcumin inhibited Akt/MAPK/NF-kappa B activity and prevented nuclear translocation of the p65 NF-kappa B subunit following TNF-alpha/LPS. At physiological shear stress, curcumin attenuated leukocyte adhesion to TNF-alpha/LPS-activated HIMEC monolayers. In conclusion, curcumin inhibited the expression of VCAM-1 in HIMECs through blockade of Akt, p38 MAPK, and NF-kappa B. Curcumin may represent a novel therapeutic agent targeting endothelial activation in IBD.