TGF-β1, but not bone morphogenetic proteins, activates Smad1/5 pathway in primary human macrophages and induces expression of proatherogenic genes
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 activate...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
January 15, 2015
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| In: |
The journal of immunology
Year: 2015, Volume: 194, Issue: 2, Pages: 709-718 |
| ISSN: | 1550-6606 |
| DOI: | 10.4049/jimmunol.1300272 |
| Online Access: | Verlag, teilw. kostenfrei, Volltext: http://dx.doi.org/10.4049/jimmunol.1300272 Verlag, teilw. kostenfrei, Volltext: http://www.jimmunol.org.ezproxy.medma.uni-heidelberg.de/content/194/2/709 
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| Author Notes: | 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 |
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| 520 | |a 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. | ||
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