Vascular cell adhesion molecule-1 expression in human intestinal microvascular endothelial cells is regulated by PI 3-kinase/Akt/MAPK/NF-kappaB: inhibitory role of curcumin. Am J Physiol Gastrointest Liver Physiol 2009 Aug;297(2):G259-68
Date
06/13/2009Pubmed ID
19520742Pubmed Central ID
PMC2724083DOI
10.1152/ajpgi.00087.2009Scopus ID
2-s2.0-68049083799 (requires institutional sign-in at Scopus site) 69 CitationsAbstract
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 alpha4-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 alpha4-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-kappaB (NF-kappaB) 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-kappaB (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-kappaB activity and prevented nuclear translocation of the p65 NF-kappaB 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-kappaB. Curcumin may represent a novel therapeutic agent targeting endothelial activation in IBD.
Author List
Binion DG, Heidemann J, Li MS, Nelson VM, Otterson MF, Rafiee PAuthors
Mona S. Li MD Assistant Professor in the Surgery department at Medical College of WisconsinMary F. Otterson MS, MD Emeritus Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Active Transport, Cell NucleusCell Adhesion
Cell Adhesion Molecules
Cells, Cultured
Curcumin
Endothelial Cells
Gastrointestinal Agents
Humans
Immunoglobulins
Intestines
Leukocytes
Lipopolysaccharides
Microvessels
Mucoproteins
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
RNA Interference
Signal Transduction
Time Factors
Transcription Factor RelA
Tumor Necrosis Factor-alpha
Vascular Cell Adhesion Molecule-1
p38 Mitogen-Activated Protein Kinases
