Genistein Suppression of TNF-α-induced Fractalkine Expression in Endothelial Cells

Abstract

Genistein is a polyphenolic nonsteroidal isoflavonoid with estrogen-like activity has been shown to have anticancer, antioxidant, and anti-inflammatory activities. Fractalkine is a unique chemokine that functions as a chemoattractant and an adhesion molecule on endothelial cells activated by proinflammatory cytokines. In this study, we investigated the effects of genistein (5-25 µM) on fractalkine expression in human umbilical vein endothelial cells (HUVECs) and on its receptor, CX3CR1, in THP-1 cells in response to treatment with tumor necrosis factor (TNF)- α. TNF-α significantly induced fractalkine expression in endothelial cells. Genistein decreased TNF-α-induced fractalkine expression through suppression of Akt and p38 phosphorylation and NF-ĸB activities. Genistein also strongly suppressed TNF-α-induced expression of CX3CR1 in monocytes. Genistein suppressed TNF-α-stimulated adhesion of monocytes to HUVECs. Immunohistochemical analysis revealed that genistein suppressed the in vivo lipopolysaccharide (LPS)-induced arterial endothelial fractalkine expression in the heart, kidney, and small intestine. These results suggest that genistein may provide a new pharmacological approach for suppressing fractalkine/CX3CR1-mediated injury under vascular inflammatory conditions.

CX3CR1(+) B Cells Show Immune Suppressor Properties

“…It seems that CX3CR1 ϩ B cells capture the epithelial cell-derived ␣v␤6 via the interaction of CX3CR1/CX3CL1. The expression of CX3CL1 by epithelial cells is also reported by others (22)(23)(24). There are some other immune regulatory cells, such as regulatory T cells, in the body that play important roles in the maintenance of the homeostasis.…”

Fractalkine Depresses Cardiomyocyte Contractility

“…Furthermore, disruption of the fractalkine receptor reduced the number of macrophages and their products (e.g.TGFα, VEGF) along with collagen deposition in a mouse model of wound repair [10]. Interestingly, TNFα induces fractalkine expression in monocytes and TNFα-stimulated adhesion to endothelial cells was partially blocked by an anti-fractalkine antibody [11]. Administration of cDNA encoding chemokine receptors (CCR2 and CxCR3) prevented dilated cardiomyopathy and death in a model of myocarditis, presumably acting as a decoy receptor [12] and targeted deletion of CCR2 reduced ventricular remodeling after experimental MI [13].…”

Elevated levels of soluble fractalkine and increased expression of CX3CR1 in neuropsychiatric systemic lupus erythematosus

“…Vascular endothelial cells have been shown to be activated by interleukin-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ and lipopolysaccharide (17,18). Moreover, the nuclear factor-κB pathway was activated, expression of FKN increased on the surface of vascular endothelial cells, which is known as membrane-anchored FKN (17,18). If membrane-anchored FKN released from the cytomembrane, it was called soluble FKN (sFKN).…”