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

来源：

JOURNAL OF IMMUNOLOGY | 2015年 / 194卷 / 02期

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

页码：709 / 718

页数：10