Protective Effect of α-Lipoic Acid in Lipopolysaccharide-Induced Endothelial Fractalkine Expression

Abstract

Abstract-Fractalkine is a unique chemokine that functions as a chemoattractant as well as an adhesion molecule on endothelial cells activated by proinflammatory cytokines. Alpha-lipoic acid (LA), a naturally occurring dithiol compound, is an essential cofactor for mitochondrial bioenergetic enzymes. LA improves glycemic control, reduces diabetic polyneuropathies, and mitigates toxicity associated with heavy metal poisoning. The effects of LA on processes associated with sepsis, however, are unknown. We evaluated the antiinflammatory effect of LA on fractalkine expression in a lipopolysaccharide-induced endotoxemia model. Tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤) significantly induced fractalkine mRNA and protein expression in endothelial cells. LA strongly suppressed TNF-␣-or IL-1␤-induced fractalkine expression in endothelial cells by suppressing the activities of nuclear factor-B and specificity protein-1. LA also decreased TNF-␣-or IL-1␤-stimulated monocyte adhesion to human umbilical vein endothelial cells. As shown by immunohistochemistry, fractalkine protein expression was markedly increased by treatment with lipopolysaccharide in arterial endothelial cells, endocardium, and endothelium of intestinal villi. LA suppressed lipopolysaccharide-induced fractalkine protein expression and infiltration of endothelin 1-positive cells into the heart and intestine in vivo. LA protected against lipopolysaccharide-induced myocardial dysfunction and improved survival in lipopolysaccharide-induced endotoxemia. These results suggest that LA could be an effective agent to reduce fractalkine-mediated inflammatory processes in endotoxemia. Key Words: ␣-lipoic acid Ⅲ fractalkine Ⅲ endothelial cells Ⅲ inflammation S epsis is a clinical syndrome that represents the systemic response to an infection and is characterized by systemic inflammation and widespread tissue injury. At the site of injury, the endothelium expresses various adhesion molecules that attract leukocytes. 1 At the same time, inflammatory cells are activated and express a variety of adhesion molecules that cause the aggregation and margination of these cells to the vascular endothelium. 2 When the inflammatory response is initiated, a wide variety of chemical mediators are released into circulation. These chemical mediators, including tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤), are associated with the continuation of the inflammatory response. 3 Sepsis is caused mainly by an exaggerated systemic response to endotoxemia induced by gram-negative bacteria and their characteristic cell wall component, lipopolysaccharide (LPS). 4 In mice, challenge with high doses of LPS results in a syndrome resembling septic shock in humans. 5 Fractalkine (CX3CL1) is a structurally novel protein in which a soluble chemokine-like domain is fused to a mucin stalk that extends into the cytoplasm across the cell membrane. 6 Fractalkine is expressed in activated endothelial cells, and its expression is upregulated by TNF-␣, IL-1␤, and LPS. 7,8 As a full-...

Lipoic acid inhibits leptin secretion and Sp1 activity in adipocytes

“…Taking together our present results in cultured adipocytes and previous data of other groups in Hep G2 [46,23] and HUVEC [45] cells suggest a role of Sp1 in mediating some of the actions observed for LA in in vitro models. However, it still remains to be addressed the potential physiological involvement of Sp1 in the effects of LA after dietary supplementation in animal models.…”

“…Our results demonstrated that LA treatment (250 μM for 24 h) inhibited Sp1-DNA binding activity in mature 3T3-L1 adipocytes. In support of these data, a previous study demonstrated that LA decreased the TNF-α and or IL-1β-induced Sp1 binding activity in human umbilical vein endothelial cells [45]. Moreover, a recent trial has also observed that LA inhibited in a dose-dependent manner the activation of Sp1 binding induced by TGF-β in HepG2 cells [46].…”

Fractalkine-Induced MFG-E8 Leads to Enhanced Apoptotic Cell Clearance by Macrophages

“…Although increased concentrations of these aforementioned proinflammatory mediators play an important role in sepsis, data on fractalkine levels in sepsis were unavailable. Sung et al described how TNF-α and IL-1β stimulate fractalkine release peaking at 4-6 h after stimulation with a steady decline in fractalkine concentrations thereafter (37). Five hours after CLP, plasma levels were slightly elevated compared with sham operated animals.…”

Janex-1, a JAK3 inhibitor, ameliorates tumor necrosis factor‑α‑induced expression of cell adhesion molecules and improves myocardial vascular permeability in endotoxemic mice

“…In this study, we used 10 ng/ml of TNF-α in accordance with our previous work (17). To investigate the effect of JAK3 inhibition on the TNF-α-induced expression of ICAM-1, VCAM-1, and fractalkine, HUVECs were pretreated with JANEX-1 for 30 min and then incubated with TNF-α for 6 h. Western blot analyses revealed that TNF-α significantly increased the levels of ICAM-1, VCAM-1, and fractalkine proteins relative to the levels observed in the control samples.…”