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

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

Journal of immunology (Baltimore, Md. : 1950) (2014-12-17)
Dinara Nurgazieva, Amanda Mickley, Kondaiah Moganti, Wen Ming, Illya Ovsyi, Anna Popova, Sachindra, Kareem Awad, Nan Wang, Karen Bieback, Sergij Goerdt, Julia Kzhyshkowska, Alexei Gratchev
摘要

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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