Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells.
Glucocorticoids (GC) are still the most widely used immunosuppressive agents in clinical medicine. Surprisingly, little is known about the mechanisms of GC action on monocytes, although these cells exert pro- and anti-inflammatory effects. We have shown recently that GC induce a specific monocyte phenotype with anti-inflammatory properties in humans. We now investigated whether this also applies for the murine system and how this subset would relate to recently defined murine subtypes. After treatment with dexamethasone for 48 h, monocytes up-regulated scavenger receptor CD163 and Gr-1, down-regulated CX(3)CR1, and shared with human GC-treated monocytes functional features such as low adhesiveness but high migratory capacity. They specifically up-regulated anti-inflammatory IL-10, but not TGF-beta, and in contrast to their human counterparts, they down-regulated IL-6. Although GC-induced monocytes down-regulated CX(3)CR1, a distinctive marker for classical/proinflammatory human and murine monocytes (CX(3)CR1(lo)CCR2(+)Ly6C(hi)), they differed from this physiologically occurring subset, as they remained Ly6C(med) and unactivated (CD62 ligand(++)). In addition to their immunosuppressive effects, they were CD11b(+)Gr-1(+) and expressed the IL-4Ralpha chain (CD124), a recently described, signature molecule of tumor-induced myeloid-derived suppressor cells (MDSC). We therefore generated murine MDSC in B16 melanoma-bearing mice and indeed found parallel up-regulation of CD11b(+)Gr-1(+) and CD124 on GC-induced monocytes and MDSC. These data allow us to speculate that the GC-induced subtype shares with inflammatory monocytes the ability to migrate quickly into inflamed tissue, where they, however, exert anti-inflammatory effects and that similarities between GC-induced monocytes and MDSC may be involved in progression of some tumors observed in patients chronically treated with GC.
Varga
Georg
G
Institute of Immunology, Muenster, Germany.
Ehrchen
Jan
J
Tsianakas
Athanasios
A
Tenbrock
Klaus
K
Rattenholl
Anke
A
Seeliger
Stephan
S
Mack
Matthias
M
Roth
Johannes
J
Sunderkoetter
Cord
C
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D039481:CD11b Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D053662:Interleukin-4 Receptor alpha Subunit / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000098902:CD163 Antigen
D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D039481:CD11b Antigen; D000098902:CD163 Antigen; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; C471885:Cx3cr1 protein, mouse; C503133:Gr-1 protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D016212:Transforming Growth Factor beta; D003907:Dexamethasone