Activation of a TGF-β-Specific Multistep Gene Expression Program in Mature Macrophages Requires Glucocorticoid-Mediated Surface Expression of TGF-β Receptor II

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-β, 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-β1. In this study, we show that mature human macrophages differentiated in the presence of IL-4, and dexamethasone (M2IL-4/GC) but not M2IL-4 responds to TGF-β1 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-β cooperation revealed that surface expression of TGF-βRII was high in M2GC and M2IL-4/GC, but absent from M2IL-4, whereas the expression of TGF-βRI/II mRNA, TGF-βRII total protein, and surface expression of TGF-βRIII were unchanged. GC dexamethasone was essential for increased surface expression of functional TGF-βRII because its effect was observed also in combination with IL-13, M-CSF, and GM-CSF. Prolonged Smad2-mediated signaling observed in TGF-β1-treated M2IL-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-βRII complex on the cell surface. In summary, mature human M2 macrophages made permissive to TGF-β by GC-induced surface expression of TGF-βRII activate in response to TGF-β1, a multistep gene expression program featuring traits of macrophages found within an atherosclerotic lesion.

Computational Approach To Characterize Causative Factors and Molecular Indicators of Chronic Wound Inflammation

“…For example, macrophages differentiated in the presence of the glucocorticoid dexamethasone exhibit increased sensitivity to TGF-b resulting from an increase in TGF-b receptor expression and induced lipid uptake (76). However, the relative contributions of these numerous factors to macrophage polarization, as well as the complex and synergistic interactions between the factors, are unknown.…”

TGF-β1, but Not Bone Morphogenetic Proteins, Activates Smad1/5 Pathway in Primary Human Macrophages and Induces Expression of Proatherogenic Genes

“…Strong arguments in favor of therapeutic targeting of macrophages is provided by recent findings made by us and others demonstrating high levels of macrophage functional plasticity (5,8,9). It was demonstrated that every combination of cytokines, hormone growth factors, or even nutritional conditions leads to the development of a specific macrophage phenotype (10)(11)(12). Highly specific effects on macrophages are demonstrated for cytokines like IFN-g, various ILs, CC-chemokines, glucocorticoids, retinoids, and increased glucose concentration in culture medium (13)(14)(15)(16)(17).…”

“…For example, TGF-b inhibits LPS-induced and proinflammatory cytokineinduced expression of a number of macrophage activation markers (e.g., matrix metalloproteinase-12 -12, inducible NO synthase, TNF) in a Smad-dependent manner (27)(28)(29)(30). The knowledge of the signaling that is induced by TGF-b in macrophages is, however, limited to the activation of the canonical Smad2/3-mediated pathway (12,31).…”

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