title: Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway.
abstract: Vascular inflammation plays a significant role in the pathogenesis of atherosclerosis. Luteolin, a naturally occurring flavonoid present in many medicinal plants and some commonly consumed fruits and vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of luteolin at physiological concentrations remain unclear. Here, we report that luteolin as low as 0.5 μM significantly inhibited tumor necrosis factor (TNF)-α-induced adhesion of monocytes to human EA.hy 926 endothelial cells, a key event in triggering vascular inflammation. Luteolin potently suppressed TNF-α-induced expression of the chemokine monocyte chemotactic protein-1 (MCP-1) and adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), key mediators involved in enhancing endothelial cell-monocyte interaction. Furthermore, luteolin inhibited TNF-α-induced nuclear factor (NF)-κB transcriptional activity, IκBα degradation, expression of IκB kinase β and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that luteolin can inhibit inflammation by suppressing NF-κB signaling. In an animal study, C57BL/6 mice were fed a diet containing 0% or 0.6% luteolin for 3 weeks, and luteolin supplementation greatly suppressed TNF-α-induced increase in circulating levels of MCP-1/JE, CXCL1/KC and sICAM-1 in C57BL/6 mice. Consistently, dietary intake of luteolin significantly reduced TNF-α-stimulated adhesion of monocytes to aortic endothelial cells ex vivo. Histology shows that luteolin treatment prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers' delicate organization as shown by Verhoeff-Van Gieson staining. Immunohistochemistry studies further show that luteolin treatment also reduced VCAM-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, luteolin protects against TNF-α-induced vascular inflammation in both in vitro and in vivo models. This anti-inflammatory effect of luteolin may be mediated via inhibition of the NF-κB-mediated pathway.
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412. Electronic address: z_jia@uncg.edu.
authors.forename: Zhenquan
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412.
authors.forename: Palanisamy
authors.initials: P
authors.lastname: Nallasamy
authors.affiliation: Departments of Human Nutrition, Foods and Exercise, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24062, USA. Electronic address: doliu@vt.edu.
authors.forename: Dongmin
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412.
authors.forename: Halley
authors.initials: H
authors.lastname: Shah
authors.affiliation: College and Graduate School of Arts & Sciences, University of Virginia, Charlottesville, VA 22904.
authors.forename: Jason Z
authors.initials: JZ
authors.lastname: Li
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412.
authors.forename: Rojin
authors.initials: R
authors.lastname: Chitrakar
authors.affiliation: Department of Family Consumer Sciences, College of Agriculture, Human and Natural Sciences, Tennessee State University, Nashville, TN 37209, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Si
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412.
authors.forename: John
authors.initials: J
authors.lastname: McCormick
authors.affiliation: Department of Pharmacology, Campbell University, School of Osteopathic Medicine, Buies Creek, NC 27506, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Departments of Human Nutrition, Foods and Exercise, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA 24062, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhen
authors.affiliation: Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC 27412; Department of Pharmacology, Campbell University, School of Osteopathic Medicine, Buies Creek, NC 27506, USA. Electronic address: yli@campbell.edu.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000627:therapeutic use; D001011:Aorta / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000378:metabolism; D019587:Dietary Supplements; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D047311:Luteolin / Q000378:metabolism / Q000627:therapeutic use*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D019010:Vascular Cell Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism; D014657:Vasculitis / Q000178:diet therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D020672:I-kappa B Proteins; C573420:ICAM1 protein, human; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D047311:Luteolin
keywords: Luteolin; Mice; NF-κB; TNF-α; Vascular inflammation