Abstract 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 α 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 α 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-κB (NF-κB) activation and nuclear translocation of its p65 subunit were determined. Tumor necrosis factor (TNF)-α/lipopolysaccharide (LPS)-induced VCAM-1 expression in HIMEC was suppressed by Akt small-interfering RNA, curcumin, and inhibitors of NF-κB (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 NH 2 -terminal kinase (SP-600125) inhibition. Curcumin inhibited Akt/MAPK/NF-κB activity and prevented nuclear translocation of the p65 NF-κB subunit following TNF-α/LPS. At physiological shear stress, curcumin attenuated leukocyte adhesion to TNF-α/LPS-activated HIMEC monolayers. In conclusion, curcumin inhibited the expression of VCAM-1 in HIMECs through blockade of Akt, p38 MAPK, and NF-κB. Curcumin may represent a novel therapeutic agent targeting endothelial activation in IBD.
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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, David G.; Heidemann, Jan; Li, Mona S.; Nelson, Victoria M.; Otterson, Mary F.; Rafiee, Parvaneh
Follow AJP - Gastrointestinal and Liver Physiology
, Volume 297 (2): G259
The American Physiological Society – Aug 1, 2009
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