Protective effect of alpha-lipoic acid in lipopolysaccharide-induced endothelial fractalkine expression.
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-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) significantly induced fractalkine mRNA and protein expression in endothelial cells. LA strongly suppressed TNF-alpha- or IL-1beta-induced fractalkine expression in endothelial cells by suppressing the activities of nuclear factor-kappaB and specificity protein-1. LA also decreased TNF-alpha- or IL-1beta-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.
Sung
Mi Jeong
MJ
Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, 560-180, Korea.
Kim
Won
W
Ahn
So Young
SY
Cho
Chung-Hyun
CH
Koh
Gou Young
GY
Moon
Sang-Ok
SO
Kim
Duk Hoon
DH
Lee
Sik
S
Kang
Kyung Pyo
KP
Jang
Kyu Yun
KY
Park
Sung Kwang
SK
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000235:genetics*; D053331:Ectodysplasins; D042783:Endothelial Cells / Q000378:metabolism*; D019446:Endotoxemia / Q000188:drug therapy; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics*; D009000:Monocytes / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016329:Sp1 Transcription Factor / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515540:Cx3cl1 protein, rat; C506018:EDA protein, human; D053331:Ectodysplasins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D008063:Thioctic Acid