title: Neuroprotectant androst-3β, 5α, 6β-triol suppresses TNF-α-induced endothelial adhesion molecules expression and neutrophil adhesion to endothelial cells by attenuation of CYLD-NF-κB pathway.
abstract: Neuroinflammation is one of key pathologic element in neurological diseases including stroke, traumatic brain injury, Alzheimer' s Disease, Parkinson's Disease, and multiple sclerosis as well. Up-regulation of endothelial adhesion molecules, which facilitate leukocyte adhesion to the endothelium, is the vital process of endothelial cells mediated neuroinflammation. Androst-3β, 5α, 6β-triol (Triol) is a synthetic steroid which has been reported to have neuroprotective effects in hypoxia/re-oxygenation-induced neuronal injury model. In the present study, we firstly investigated whether Triol inhibited the TNF-α-induced inflammatory response in rat brain microvascular endothelial cells (RBMECs). Our data showed that Triol decreased TNF-α-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and the adhesion of neutrophil to RBMECs. We also found that Triol inhibited TNF-α-induced degradation of IκBα and phosphorylation of NF-κBp65 that are required for NF-κB activation. Furthermore, Triol significantly reversed TNF-α-induced down-expression of CYLD, which is a deubiquitinase that negatively regulates activation of NF-κB. These results suggest that Triol displays an anti-inflammatory effect on TNF-α-induced RBMECs via downregulating of CYLD-NF-κB signaling pathways and might have a potential benefit in therapeutic neuroinflammation related diseases.
authors.affiliation: Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, GD 510080, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA.
authors.forename: Tiandong
authors.initials: T
authors.lastname: Leng
authors.affiliation: Department of Pharmacology of Traditional Chinese Medicine, Guangdong Province's Traditional Chinese Medical Hospital, Guangzhou, GD 510120, PR China.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, GD 510080, PR China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, GD 510080, PR China.
authors.forename: Bingzheng
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, GD 510080, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, GD 510080, PR China.
authors.forename: Longxiang
authors.initials: L
authors.lastname: Sheng
authors.affiliation: Guangzhou Cellprotek Pharmaceutical, G Building F/4, 3 Lanyue Road, Science City, Guangzhou, 510663, PR China.
authors.forename: Suizhen
authors.initials: S
authors.lastname: Lin
authors.affiliation: Guangzhou Cellprotek Pharmaceutical, G Building F/4, 3 Lanyue Road, Science City, Guangzhou, 510663, PR China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, GD 510080, PR China.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Yan
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, GD 510080, PR China. Electronic address: yinwei@mail.sysu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
mesh_terms: D000732:Androstanols / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000732:Androstanols; C000609942:ICAM1 protein, rat; D018696:Neuroprotective Agents; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C587859:androst-3,5,6-triol; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; C581019:CYLD protein, rat; D043222:Ubiquitin Thiolesterase
keywords: Adhesion molecules; Androst-3β, 5α, 6β-triol; Brain microvascular endothelial cells; CYLD; Leukocyte adhesion; NF-κB activation