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

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 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.

Chitosan oligosaccharides downregulate the expression of E-selectin and ICAM-1 induced by LPS in endothelial cells by inhibiting MAP kinase signaling

“…Consistent with previous reports demonstrating that the tyrosine phosphorylation of p38 MAPK and ERK is involved in signal transduction occurring in LPS-stimulated endothelial cells (23,38), and further mediates cellular Figure 8. Lipopolysaccharide (LPS)-induced nuclear factor-κB (NF-κB) translocation is suppressed by chitosan oligosaccharides (COS) in a dose-dependent manner in porcine iliac artery endothelial cells (PIECs).…”

Nobiletin Inhibits Expression of Inflammatory Mediators and Regulates JNK/ERK/p38 MAPK and PI3K/Akt Pathways in Human Osteoarthritic Chondrocytes

“…Binion et al [28] reported that the activation of Akt further caused activation of MAPK pathways. Stimulating chondrocytes by IL-1β has been shown to induce phosphorylation and activation of ERK1/2, JNK, and p38 MAPKs [17].…”

Renal tumor-derived exosomes inhibit hepaCAM expression of renal carcinoma cells in a p-AKT-dependent manner

“…Thus far, studies have been conducted to investigate the correlation between the AKT activity and its expression of cell adhesion molecules. Some of these studies have focused on the regulation of PI3-kinase/Akt/MAPK/NF-kappaB in the expression of vascular cell adhesion molecule-1 (VCAM-1) in human intestinal microvascular endothelial cells [21]; these studies have also observed withaferin A inhibition on VCAM-1 expression by blocking Akt and downregulating NF-kappaB activity [22]. In contrast to conventional cell adhesion molecules, hepaCAM largely functions as a tumor suppressor gene, but the correlation between AKT activity and hepaCAM expression of the primary tumor has not been evaluated.…”