Glucocorticoids induce differentiation of a specifically activated, anti- inflammatory subtype of human monocytes Short title: Glucocorticoid action on monocytes

(project Ro2/012/06) of the University of Muenster and by a grant of the Deutsche Forschungsgemeinschaft (DFG SU 195/3-1). Abstract Monocytes and macrophages may either promote or down-regulate inflammatory reactions depending on their state of activation. The effects of glucocorticoids (GC), the most widely used immunosuppressive drugs, on monocytes are currently not well defined. Analyzing the GC-induced expression pattern in human monocytes by microarray technology we identified for the first time GC-dependent regulation of 133 genes, including anti-inflammatory molecules like adenosine A3 receptor, CD1d, and IL1 receptor II. The results were independently confirmed by real-time PCR and flow cytometry. Functional clustering of GC-regulated genes indicated induction of monocytic properties like " phagocytosis " and " motility " as well as repression of " adhesion " , " apoptosis " and " oxidative burst ". These predictions were confirmed by independent functional assays. GC up-regulate fMLP receptors and specifically promote chemotaxis to this chemoattractant. Furthermore, GC promote survival of an anti-inflammatory monocytic phenotype in inflammatory reactions probably by inhibition of apoptosis due to oxidative stress. GC limit tissue damage due to induction of anti-oxidative properties and high capacity for phagocytosis of pro-inflammatory agents. Thus, GC-treatment did not cause a global suppression of monocytic effector functions but results in differentiation of a specific anti-inflammatory phenotype which seems to be actively involved in resolution of inflammatory reactions.