Activation of a TGF-beta-specific multistep gene expression program in mature macrophages requires glucocorticoid-mediated surface expression of TGF-beta receptor II.
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.
Gratchev
Alexei
A
Department of Dermatology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany. alexei.gratchev@gmail.com
Kzhyshkowska
Julia
J
Kannookadan
Sheila
S
Ochsenreiter
Miriam
M
Popova
Anna
A
Yu
Xiaolei
X
Mamidi
Srinivas
S
Stonehouse-Usselmann
Eugenia
E
Muller-Molinet
Isabelle
I
Gooi
Liming
L
Goerdt
Sergij
S
D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism; D008262:Macrophage Activation / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053722:Receptors, Interleukin-17; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D005938:Glucocorticoids; C408922:IL17RB protein, human; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D015847:Interleukin-4