title: Honokiol suppresses TNF-α-induced neutrophil adhesion on cerebral endothelial cells by disrupting polyubiquitination and degradation of IκBα.
abstract: Adhesion molecules expressed on cerebral endothelial cells (ECs) mediate leukocyte recruitment and play a significant role in cerebral inflammation. Increased levels of adhesion molecules on the EC surface induce leukocyte infiltration into inflammatory areas and are thus hallmarkers of inflammation. Honokiol, isolated from the Chinese medicinal herb Magnolia officinalis, has various pharmacological activities, including anti-inflammatory effects, yet the nature of honokiol targeting molecules remains to be revealed. Here, we investigated the inhibitory effect of honokiol on neutrophil adhesion and vascular cell adhesion molecule-1 (VCAM-1) expression, which underlie its molecular target, and mechanisms for inactivating nuclear factor κ enhancer binding protein (NF-κB) in mouse cerebral ECs. Honokiol inhibited tumour necrosis factor-α (TNF-α)-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs. The inflammatory transcription factor NF-κB was downregulated by honokiol. Honokiol significantly blocked TNF-α-induced NF-κB p65 nuclear translocation and degradation of the proteasome-dependent inhibitor of NF-κB α (IκBα). From docking model prediction, honokiol directly targeted the ubiquitin-ubiquitin interface of Lys48-linked polychains. Moreover, honokiol prevented the TNF-α-induced Lys48-linked polyubiquitination, including IκBα-polyubiquitin interaction. Honokiol has protective anti-inflammatory effects on TNF-α-induced neutrophil adhesion and VCAM-1 gene expression in cerebral ECs, at least in part by directly inhibiting ubiquitination-mediated IκBα degradation and then preventing NF-κB nuclear translocation.
authors.affiliation: Graduate Institute of Natural Products, School of Traditional Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.|Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Po-Jen
authors.initials: PJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Natural Products, School of Traditional Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.|Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.|Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
authors.forename: Liang-Mou
authors.initials: LM
authors.lastname: Kuo
authors.affiliation: Research Center for Industry of Human Ecology and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan.
authors.forename: Chwan-Fwu
authors.initials: CF
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.|Department of Anaesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.|Department of Anaesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
authors.forename: Yung-Fong
authors.initials: YF
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Natural Products, School of Traditional Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.|Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Jiann-Jong
authors.initials: JJ
authors.lastname: Shen
authors.affiliation: Graduate Institute of Natural Products, School of Traditional Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.|Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan.|Research Center for Industry of Human Ecology and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan.|Department of Anaesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
authors.forename: Tsong-Long
authors.initials: TL
authors.lastname: Hwang
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001921:Brain / Q000166:cytology*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha / Q000737:chemistry / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D001713:Biphenyl Compounds; D017705:Lignans; D000072000:NF-KappaB Inhibitor alpha; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C000606205:Nfkbia protein, mouse; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols