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Updated: Jul 5, 2026

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Activation of a TGF-beta-specific multistep gene expression program in mature macrophages requires
Alexei Gratchev1, Julia Kzhyshkowska, Sheila Kannookadan
1Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany. alexei.gratchev@gmail.com
Abstract:
Alternatively activated (M2) macrophages regulate steady state-, cancer-, and inflammation-related tissue remodeling. They are induced by Th2-cytokines and glucocorticoids (GC). The responsiveness of mature macrophages to TGF-beta, a cytokine involved in inflammation, cancer, and atherosclerosis, is currently controversial. Recently, we demonstrated that IL-17 receptor B is up-regulated in human monocyte-derived macrophages differentiated in the presence of Th2 cytokines IL-4 and TGF-beta1. In this study, we show that mature human macrophages differentiated in the presence of IL-4, and dexamethasone (M2(IL-4/GC)) but not M2(IL-4) responds to TGF-beta1 which induced a gene expression program comprising 111 genes including transcriptional/signaling regulators (ID3 and RGS1), immune modulators (ALOX5AP and IL-17 receptor B) and atherosclerosis-related genes (ALOX5AP, ORL1, APOC1, APOC2, and APOE). Analysis of molecular mechanism underlying GC/TGF-beta cooperation revealed that surface expression of TGF-betaRII was high in M2(GC) and M2(IL-4/GC), but absent from M2(IL-4), whereas the expression of TGF-betaRI/II mRNA, TGF-betaRII total protein, and surface expression of TGF-betaRIII were unchanged. GC dexamethasone was essential for increased surface expression of functional TGF-betaRII because its effect was observed also in combination with IL-13, M-CSF, and GM-CSF. Prolonged Smad2-mediated signaling observed in TGF-beta1-treated M2(IL-4/GC) was due to insufficient activity of negative feedback mechanism what can be explained by up-regulation of SIRT1, a negative regulator of Smad7, and the retention of TGF-betaRII complex on the cell surface. In summary, mature human M2 macrophages made permissive to TGF-beta by GC-induced surface expression of TGF-betaRII activate in response to TGF-beta1, a multistep gene expression program featuring traits of macrophages found within an atherosclerotic lesion.
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