title: Hydroxy-Safflower Yellow A inhibits the TNFR1-Mediated Classical NF-κB Pathway by Inducing Shedding of TNFR1.
abstract: Hydroxy-safflower yellow A (HSYA) is the major active component of safflower, a traditional Asia herbal medicine well known for its cardiovascular protective activities. The purpose of this study was to investigate the effect of HSYA on TNF-α-induced inflammatory responses in arterial endothelial cells (AECs) and to explore the mechanisms involved. The results showed that HSYA suppressed the up-regulation of ICAM-1 expression in TNF-α-stimulated AECs in a dose-dependent manner. High concentration (120 μM) HSYA significantly inhibited the TNF-α-induced adhesion of RAW264.7 cells to AECs. HSYA blocked the TNFR1-mediated phosphorylation and degradation of IκBα and also prevented the nuclear translocation of NF-κB p65. Moreover, HSYA reduced the cell surface level of TNFR1 and increased the content of sTNFR1 in the culture media. TNF-α processing inhibitor-0 (TAPI-0) prevented the HSYA inhibition of TNFR1-induced IκBα degradation, implying the occurrence of TNFR1 shedding. Furthermore, HSYA induced phosphorylation of TNF-α converting enzyme (TACE) at threonine 735, which is thought to be required for its activation. Conclusively, HSYA suppressed TNF-α-induced inflammatory responses in AECs, at least in part by inhibiting the TNFR1-mediated classical NF-κB pathway. TACE-mediated TNFR1 shedding can be involved in this effect. Our study provides new evidence for the antiinflammatory and anti-atherosclerotic effects of HSYA. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Shaanxi Provincial Key Laboratory of Infectious and Immunological Diseases, Shaanxi Provincial People's Hospital, Xi'an, 710068, China.
authors.forename: Haifang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Public Health, Medical School of Xi'an JiaoTong University, Xi'an, 710061, China.
authors.forename: Jinlian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Kaifeng Center for Disease Control and Prevention, Kaifeng, 475004, China.
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Public Health, Medical School of Xi'an JiaoTong University, Xi'an, 710061, China.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Shaanxi Provincial Key Laboratory of Infectious and Immunological Diseases, Shaanxi Provincial People's Hospital, Xi'an, 710068, China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Huo
authors.affiliation: Department of Public Health, Medical School of Xi'an JiaoTong University, Xi'an, 710061, China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Ma
authors.affiliation: Shaanxi Provincial Key Laboratory of Infectious and Immunological Diseases, Shaanxi Provincial People's Hospital, Xi'an, 710068, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, 46202, Indiana.
authors.forename: Fredrick M
authors.initials: FM
authors.lastname: Pavalko
authors.affiliation: Department of Public Health, Medical School of Xi'an JiaoTong University, Xi'an, 710061, China.
authors.forename: Qinshe
authors.initials: Q
authors.lastname: Liu
mesh_terms: D002599:Chalcone / Q000031:analogs & derivatives* / Q000737:chemistry; D029001:Herbal Medicine / Q000379:methods*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; C076422:safflower yellow; D002599:Chalcone
keywords: NF-κB pathway; TNF-α; TNF-α converting enzyme; TNFR1; arterial endothelial cell; hydroxy-safflower yellow A