Pro- and anti-inflammatory control of M-CSF-mediated macrophage differentiation.
Macrophages play a key role in inflammation, tissue regeneration and tolerance. Their differentiation is regulated by tissue cells derived CSF-1 (M-CSF). The ability of macrophages to use autocrine M-CSF to control their differentiation and function remained controversial. In this study we investigated the regulation of M-CSF production by Th1 and Th2 cytokines (IFN-γ and IL-4) and tolerogenic stimuli - glucocorticoid dexamethasone in primary human monocyte derived macrophages. We show that IFN-γ and IL-4 efficiently induce production of M-CSF while glucocorticoid inhibited it in a dose dependent manner. Since glucocorticoid inhibits production of inflammatory cytokines we tested whether this effect is a result of inhibited M-CSF production. We showed that exogenous M-CSF rescues the ability of glucocorticoid-treated macrophages to produce TNF and IL-6 in response to LPS. These data indicate that glucocorticoid-treated macrophages retain the ability to respond to M-CSF. Analyzing the mechanism of this responsiveness, we showed that dexamethasone up-regulates surface expression of M-CSF receptor - CSF-1R. We conclude that the ability of macrophages to produce M-CSF secures macrophage differentiation under Th1 and Th2 conditions if tissue cells are unable to supply enough M-CSF. Increased surface expression of CSF-1R in tolerogenic conditions guarantees response to minute amounts of exogenous M-CSF.
Popova
Anna
A
Department of Dermatology, University Medical Center and Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, and Center of Excellence in Dermatology, The State of Baden-Württemberg, Mannheim, Germany.
Kzhyshkowska
Julia
J
Nurgazieva
Dinara
D
Goerdt
Sergij
S
Gratchev
Alexei
A
D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D058408:Th1-Th2 Balance
D016207:Cytokines; D003907:Dexamethasone; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor