title: TGF-β1, but not bone morphogenetic proteins, activates Smad1/5 pathway in primary human macrophages and induces expression of proatherogenic genes.
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.
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany; N.N. Blokhin Cancer Research Center, 115478 Moscow, Russia;
authors.forename: Dinara
authors.initials: D
authors.lastname: Nurgazieva
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany; Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany;
authors.forename: Amanda
authors.initials: A
authors.lastname: Mickley
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany; Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany;
authors.forename: Kondaiah
authors.initials: K
authors.lastname: Moganti
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany;
authors.forename: Wen
authors.initials: W
authors.lastname: Ming
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany;
authors.forename: Illya
authors.initials: I
authors.lastname: Ovsyi
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany;
authors.forename: Anna
authors.initials: A
authors.lastname: Popova
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany;
authors.lastname: Sachindra
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany; Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany;
authors.forename: Kareem
authors.initials: K
authors.lastname: Awad
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany;
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany;
authors.forename: Karen
authors.initials: K
authors.lastname: Bieback
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany;
authors.forename: Sergij
authors.initials: S
authors.lastname: Goerdt
authors.affiliation: Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany; Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia; and Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, 634050 Tomsk, Russia.
authors.forename: Julia
authors.initials: J
authors.lastname: Kzhyshkowska
authors.affiliation: Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany; N.N. Blokhin Cancer Research Center, 115478 Moscow, Russia; alexei.gratchev@gmail.com.
authors.forename: Alexei
authors.initials: A
authors.lastname: Gratchev
mesh_terms: D030301:Activin Receptors, Type II / Q000276:immunology; D019485:Bone Morphogenetic Proteins / Q000276:immunology; D002478:Cells, Cultured; D064451:Hepcidins / Q000276:immunology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000276:immunology; D058226:Plaque, Atherosclerotic / Q000276:immunology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology; D055293:Receptors, Urokinase Plasminogen Activator / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D051898:Smad1 Protein / Q000276:immunology*; D051899:Smad2 Protein / Q000276:immunology; D051900:Smad3 Protein / Q000276:immunology; D051902:Smad5 Protein / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000276:immunology*
chemical_list: D019485:Bone Morphogenetic Proteins; C578702:HAMP protein, human; D064451:Hepcidins; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; C524898:PLAUR protein, human; D018125:Receptors, Transforming Growth Factor beta; D055293:Receptors, Urokinase Plasminogen Activator; C497399:SMAD1 protein, human; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497797:SMAD5 protein, human; D051898:Smad1 Protein; D051899:Smad2 Protein; D051900:Smad3 Protein; D051902:Smad5 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C075640:ID3 protein, human; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human