Immune suppression via glucocorticoid-stimulated monocytes: a novel mechanism to cope with inflammation (original) (raw)
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Journal of Leukocyte Biology, 2008
Monocytes and macrophages may either promote or down-regulate inflammatory reactions depending on their state of activation. The effects of glucocorticoids (GCs), the most widely used immunosuppressive drugs, on monocytes are currently not well defined. By 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 antiinflammatory molecules such as adenosine A3 receptor, CD1d, and IL-1 receptor II. The results were independently con-firmed by real-time polymerase chain reaction (PCR) and flow cytometry. Functional clustering of GC-regulated genes indicated induction of monocytic properties such as phagocytosis and motility as well as repression of adhesion, apoptosis, and oxidative burst. These predictions were confirmed by independent functional assays. GCs up-regulate fMLP receptors and specifically promote chemotaxis to this chemoattractant. Furthermore, GCs promote survival of an antiinflammatory monocytic phenotype in inflammatory reactions, probably by inhi-bition of apoptosis because of oxidative stress. GCs limit tissue damage because of induction of antioxidative properties and high capacity for phagocytosis of proinflammatory agents. Thus, GC treatment did not cause a global suppression of monocytic effector functions but results in differentiation of a specific antiinflammatory phenotype which seems to be actively involved in resolution of inflammatory reactions. (Blood. 2007;109: 1265-1274)
Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells
The FASEB Journal, 2002
Glucocorticoids continue to be the major immunomodulatory agents used in clinical medicine today. However, their actions as anti-inflammatory and immunosuppressive drugs are both beneficial and deleterious. We analyzed the effect of glucocorticoids on the gene expression profile of peripheral blood mononuclear cells from healthy donors. DNA microarray analysis combined with quantitative TaqMan PCR and flow cytometry revealed that glucocorticoids induced the expression of chemokine, cytokine, and complement family members as well as of newly discovered innate immune-related genes, including scavenger and Toll-like receptors. In contrast, glucocorticoids repressed the expression of adaptive immune-related genes. Simultaneous inhibitory and stimulatory effects of glucocorticoids were found on inflammatory T helper subsets and apoptosis-related gene clusters. In cells activated by T cell receptor cross-linking, glucocorticoids down-regulated the expression of specific genes that were previously up-regulated in resting cells, suggesting a potential new mechanism by which they exert positive and negative effects. Considering the broad and continuously renewed interest in glucocorticoid therapy, the profiles we describe here will be useful in designing more specific and efficient treatment strategies. G., Boettner, A., Ehrhart-Bornstein, M., O'Shea, J. J., Chrousos, G. P., Bornstein, S. R. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J. 16, 61-71 (2002) 61 0892-6638/02/0016-0061 © FASEB a S: sense primer; AS: antisense primer; TM: TaqMan probe; Primer size: Base pairs; TLR4: Toll-like receptor 4; MARCO: macrophage receptor with collagenouse structure; THBS1: thrombospondin 1; STAT1: signal transducer and activator of transcription 1; IRF4: interferon regulatory factor 4; PAI2: plasminogen activator inhibitor type2; CD127: interleukin 7 receptor; IL10: interleukin 10; CCR2: chemokine receptor 2.
European Journal of Immunology, 2006
IL-2 is crucial for the production of CD4 + CD25 + T regulatory (Treg) cells while important for the generation of effective T cell-mediated immunity. How to exploit the capacity of IL-2 to expand Treg cells, while restraining activation of T effector (Teff) cells, is an important and unanswered therapeutic question. Dexamethasone (Dex), a synthetic glucocorticoid steroid, has been reported to suppress IL-2-mediated activation of Teff cells and increase the proportion of Treg cells. Thus, we hypothesized that glucocorticoids may be useful as costimulants to amplify IL-2-mediated selective expansion of Treg cells. We show in this study that short-term simultaneous administration of Dex and IL-2 markedly expanded functional suppressive Foxp3 + CD4 + CD25 + T cells in murine peripheral lymphoid tissues. In a myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) mouse model, we observed that splenic CD4 + CD25 + T cells failed to suppress the proliferation of CD4 + CD25-T cells. Pretreatment with Dex/IL-2 remarkably increased the proportion of CD4 + FoxP3 + cells and partially restored the function of splenic CD4 + CD25 + T cells, and inhibited the development of EAE. Therefore, the combination of glucocorticoid and IL-2, two currently used therapeutics, may provide a novel approach for the treatment of autoimmune diseases, transplant rejection and graft-vs.host disease.
Trends in Endocrinology & Metabolism, 2013
Glucocorticoids are essential for maintaining homeostasis and regulate a wide variety of physiological processes. Therapeutically, synthetic glucocorticoids are widely prescribed for the treatment of inflammation, autoimmune disorders, and malignancies of lymphoid origin. In this review we examine emerging evidence highlighting both proinflammatory and anti-inflammatory actions of glucocorticoids on both the innate and adaptive immune systems. We incorporate these findings into the more traditional anti-inflammatory role attributed to glucocorticoids, and propose how the two seemingly disparate processes seamlessly work together to resolve cellular responses to inflammatory stimuli. These ideas provide a framework by which glucocorticoids ready and reinforce the innate immune system, and repress the adaptive immune system, to help to resolve inflammation and restore homeostasis.
Cell-Specific Immune Regulation by Glucocorticoids in Murine Models of Infection and Inflammation
Cells
Glucocorticoids (GC) are highly potent negative regulators of immune and inflammatory responses. Effects of GC are primarily mediated by the glucocorticoid receptor (GR) which is expressed by all cell types of the immune system. It is, therefore, difficult to elucidate how endogenous GC mediate their effects on immune responses that involve multiple cellular interactions between various immune cell subsets. This review focuses on endogenous GC targeting specific cells of the immune system in various animal models of infection and inflammation. Without the timed release of these hormones, animals infected with various microbes or challenged in inflammatory disease models succumb as a consequence of overshooting immune and inflammatory responses. A clearer picture is emerging that endogenous GC thereby act in a cell-specific and disease model-dependent manner, justifying the need to develop techniques that target GC to individual immune cell types for improved clinical application.
Glucocorticoids and Inflammation Revisited: The State of the Art
Neuroimmunomodulation, 2002
Glucocorticoids have been used in the treatment of inflammatory and autoimmune diseases and to prevent graft rejection for over 50 years. These hormones exert their effects through cytoplasmic, heat shock proteinbound glucocorticoid receptors that translocate into the nucleus, where they regulate the transcriptional activity of responsive genes by binding to specific promoter DNA sequences (transactivation) or by interacting with transcription factors (transrepression). By interacting with different signaling pathways, newly characterized nuclear receptor coregulators enhance or diminish the actions of glucocorticoids, thus explaining the gene-, cell-, tissue-and context-dependent actions of glucocorticoids. Glucocorticoids modulate genes involved in the priming of the innate immune response, while their actions on the adaptive immune response are to suppress cellular [T helper (Th)1-directed] immunity and promote humoral (Th2-directed) immunity and tolerance. The past decade has produced new insights into the mechanisms of glucocorticoid sensitivity and resistance of inflammatory, autoimmune and allergic diseases. Both the quality and severity of the inflammatory stimulus, as well as the genetics and constitution of the patient, play key roles in the glucocorticoid sensitivity, dependency and resistance of these diseases. Although glucocorticoids increase susceptibility to opportunistic infections, they are also highly beneficial in the presence of serious systemic inflammation, such as that observed in septic shock and acute respiratory distress syndrome, when administered in a sustained fashion throughout the course of the disease. Glucocorticoids produce their cardiovascular, metabolic and antigrowth side effects through molecular mechanisms distinct from those involved in immunomodulation. Fortunately, the first generation of tissue-and immune-versus cardiovascular/ metabolic effect-selective glucocorticoids is available for study and further improvement. 'Designer' glucocorticoids promise to be a great new advance in the therapy of inflammatory diseases.
Defining the role of glucocorticoids in inflammation
Clinical Science, 2018
An established body of knowledge and clinical practice has argued in favor of the use of glucocorticoids in various chronic inflammatory and autoimmune diseases. However, the very well-known adverse effects associated with their treatment hampers continuation of therapy with glucocorticoids. Analyses of the molecular mechanisms underlying the actions of glucocorticoids have led to the discovery of several mediators that add complexity and diversity to the puzzling world of these hormones and anti-inflammatory drugs. Such mediators hold great promise as alternative pharmacologic tools to be used as anti-inflammatory drugs with the same properties as glucocorticoids, but avoiding their metabolic side effects. This review summarizes findings about the molecular targets and mediators of glucocorticoid function.
Selective depletion of CD14+ CD16+ monocytes by glucocorticoid therapy
Clinical and Experimental Immunology, 1998
Glucocorticoids (GC) are potent anti-inflammatory and immunosuppressive agents that act on many cells of the body, including monocytes. Here we show that a 5-day course of high dose GC therapy differentially affected the CD14 þþ and the CD14 þ CD16 þ monocyte subpopulations in 10 patients treated for multiple sclerosis. While the classical (CD14 þþ ) monocytes exhibited a substantial increase from 495 Ϯ 132 to 755 Ϯ 337 cells/ml, the CD14 þ CD16 þ monocytes responded with a pronounced decrease from 36 Ϯ 15 to 2 Ϯ 3 cells/ml (P < 0·001). In 4/10 patients the CD14 þ CD16 þ monocytes fell below detection limits (< 0·2 cells/ml). This observation was confirmed when the CD14 þ CD16 þ monocytes were identified by virtue of their low CD33 expression as these cells decreased as well. After discontinuation of GC therapy the CD14 þ CD16 þ monocytes reappeared and reached normal levels after 1 week. The profound depletion of CD14 þ CD16 þ monocytes by GC as described here is a novel effect of GC action in vivo and may contribute to GC-mediated immunosuppression. Determination of the number of this monocyte subset may also serve to monitor the effectiveness of GC therapy in patients requiring immunosuppressive treatment.