Journal
JOURNAL OF IMMUNOLOGY
Volume 194, Issue 2, Pages 709-718Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1300272
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Funding
- Deutsche Forschungsgemeinschaft [GRK880/3, GRK1874]
- Bundesministerium fur Bildung und Forschung, project BIO-IN
- Deutscher Akademischer Austauschdienst
- European Commission Seventh Framework Programme IMMODGEL project
- Russian Science Foundation [14-15-00396, 14-15-00350]
- Tomsk State University Competitiveness Improvement Program
- Russian Science Foundation [14-15-00396, 14-15-00350] Funding Source: Russian Science Foundation
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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.
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