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Receptor II b of TGF-Glucocorticoid-Mediated Surface Expression Macrophages Requires Gene Expression Program in Mature -Specific Multistep b Activation of a TGF-Muller-Molinet,

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- (cid:1) , 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- (cid:1) 1. 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- (cid:1) 1 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- (cid:1) cooperation revealed that surface expression of TGF- (cid:1) RII was high in M2 GC and M2 IL-4/GC , but absent from M2 IL-4 , whereas the expression of TGF- (cid:1) RI/II mRNA, TGF- (cid:1) RII total protein, and surface expression of TGF- (cid:1) RIII were unchanged. GC dexamethasone was essential for increased surface expression of functional TGF- (cid:1) RII because its effect was observed also in combination with IL-13, M-CSF, and GM-CSF. Prolonged Smad2-mediated signaling observed in TGF- (cid:1) 1-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- (cid:1) RII complex on the cell surface. In summary, mature human M2 macrophages made permissive to TGF- (cid:1) by GC-induced surface expression of TGF- (cid:1) RII activate in response to TGF- (cid:1) 1, a multistep gene expression program featuring traits of macrophages found within an atherosclerotic lesion. The Journal of Immunology, 2008, 180: 6553–6565.