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INFLAMMATION/IMMUNITY/MEDIATORS

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

¹Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; ²Department of Medicine B, University of Muenster, Muenster, Germany; and Departments of ³Surgery and ⁴Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 9 March 2009 ; accepted in final form 2 June 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 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 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-B (NF-B) activation and nuclear translocation of its p65 subunit were determined. Tumor necrosis factor (TNF)-/lipopolysaccharide (LPS)-induced VCAM-1 expression in HIMEC was suppressed by Akt small-interfering RNA, curcumin, and inhibitors of NF-B (SN-50), p38 MAPK (SB-203580) and PI 3-kinase/Akt (LY-294002). 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-B activity and prevented nuclear translocation of the p65 NF-B subunit following TNF-/LPS. At physiological shear stress, curcumin attenuated leukocyte adhesion to TNF-/LPS-activated HIMEC monolayers. In conclusion, curcumin inhibited the expression of VCAM-1 in HIMECs through blockade of Akt, p38 MAPK, and NF-B. Curcumin may represent a novel therapeutic agent targeting endothelial activation in IBD.

phosphatidylinositol 3-kinase; protein kinase B; mitogen-activated protein kinase; nuclear factor-B