TGF-β1, but Not Bone Morphogenetic Proteins, Activates Smad1/5 Pathway in Primary Human Macrophages and Induces Expression of Proatherogenic Genes

被引:36
作者
Nurgazieva, Dinara [1 ,2 ]
Mickley, Amanda [1 ,3 ]
Moganti, Kondaiah [1 ,3 ]
Ming, Wen [1 ]
Ovsyi, Illya [1 ]
Popova, Anna [1 ]
Sachindra [1 ]
Awad, Kareem [1 ,3 ]
Wang, Nan [1 ]
Bieback, Karen [3 ]
Goerdt, Sergij [1 ]
Kzhyshkowska, Julia [3 ,4 ,5 ]
Gratchev, Alexei [1 ,2 ]
机构
[1] Heidelberg Univ, Ctr Excellence Dermatol, Dept Dermatol Venereol & Allergol, D-68167 Mannheim, Germany
[2] NN Blokhin Canc Res Ctr, Moscow 115478, Russia
[3] Heidelberg Univ, Med Fac Mannheim, Inst Transfus Med & Immunol, D-68167 Mannheim, Germany
[4] Inst Gen Pathol & Pathophysiol, Moscow 125315, Russia
[5] Tomsk State Univ, Lab Translat Cellular & Mol Biomed, Tomsk 634050, Russia
基金
俄罗斯科学基金会;
关键词
GROWTH-FACTOR-BETA; TUMOR-ASSOCIATED MACROPHAGES; ANTIGEN-PRESENTING CELLS; TGF-BETA; INSULIN-RESISTANCE; RECEPTOR; ATHEROSCLEROSIS; INHIBITION; CANCER; DEACETYLATION;
D O I
10.4049/jimmunol.1300272
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Macrophages are responsible for the control of inflammation and healing, and their malfunction results in cardiometabolic disorders. TGF-beta is a pleiotropic growth factor with dual ( protective and detrimental) roles in atherogenesis. We have previously shown that in human macrophages, TGF-beta 1 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-beta 1-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-beta 1, 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-beta 1 in mature human macrophages. Activation of Smad1/5 by TGF-beta 1 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-beta on atherosclerosis where Smad1/5 is responsible for proatherogenic effects, whereas Smad2/3 regulate atheroprotective effects of TGF-beta.
引用
收藏
页码:709 / 718
页数:10
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