TGF-β1, but not bone morphogenetic proteins, activates Smad1/5 pathway in primary human macrophages and induces expression of proatherogenic genes

• Verfasst von: Nurgazieva, Dinara [VerfasserIn]
• Verfasst von: Bieback, Karen [VerfasserIn]
• Verfasst von: Goerdt, Sergij [VerfasserIn]
• Verfasst von: Kzhyshkowska, Julia [VerfasserIn]
• Titel: TGF-β1, but not bone morphogenetic proteins, activates Smad1/5 pathway in primary human macrophages and induces expression of proatherogenic genes
• Verf.angabe: Dinara Nurgazieva, Amanda Mickley, Kondaiah Moganti, Wen Ming, Illya Ovsyi, Anna Popova, Sachindra, Kareem Awad, Nan Wang, Karen Bieback, Sergij Goerdt, Julia Kzhyshkowska, and Alexei Gratchev
• E-Jahr: 2015
• Jahr: January 15, 2015
• Umfang: 10 S.
• Fussnoten: Gesehen am 23.10.2017
• Titel Quelle: Enthalten in: The journal of immunology
• Ort Quelle: Rockville, Md. : American Association of Immunologists, 1916
• Jahr Quelle: 2015
• Band/Heft Quelle: 194(2015), 2, Seite 709-718
• ISSN Quelle: 1550-6606
• DOI: doi:10.4049/jimmunol.1300272
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1564682951

Abstract

Macrophages are responsible for the control of inflammation and healing, and their malfunction results in cardiometabolic disorders. TGF-β is a pleiotropic growth factor with dual (protective and detrimental) roles in atherogenesis. We have previously shown that in human macrophages, TGF-β1 activates Smad2/3 signaling and induces a complex gene expression program. However, activated genes were not limited to known Smad2/3-dependent ones, which prompted us to study TGF-β1-induced signaling in macrophages in detail. Analysis of Id3 regulatory sequences revealed a novel enhancer, located between +4517 and 4662 bp, but the luciferase reporter assay demonstrated that this enhancer is not Smad2/3 dependent. Because Id3 expression is regulated by Smad1/5 in endothelial cells, we analyzed activation of Smad1/5 in macrophages. We demonstrate here for the first time, to our knowledge, that TGF-β1, but not BMPs, activates Smad1/5 in macrophages. We show that an ALK5/ALK1 heterodimer is responsible for the induction of Smad1/5 signaling by TGF-β1 in mature human macrophages. Activation of Smad1/5 by TGF-β1 induces not only Id3, but also HAMP and PLAUR, which contribute to atherosclerotic plaque vulnerability. We suggest that the balance between Smad1/5- and Smad2/3-dependent signaling defines the outcome of the effect of TGF-β on atherosclerosis where Smad1/5 is responsible for proatherogenic effects, whereas Smad2/3 regulate atheroprotective effects of TGF-β.