Glucocorticoids promote apoptosis of proinflammatory monocytes by inhibiting ERK activity (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.
Journal of immunology (Baltimore, Md. : 1950), 2014
Glucocorticoids (GCs) are used as first-line therapies for generalized suppression of inflammation (e.g., allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work revealed that GCs induced a stable anti-inflammatory phenotype in monocytes, the GC-stimulated monocytes (GCsMs) that we exploited for targeted GC-mediated therapeutic effects. We demonstrate that GCsMs interact with T cells in suppressing proliferation, as well as cytokine release of CD8(+) and, especially, CD4(+) T cells in vitro, and that they support generation of Foxp3(+) cells. Therefore, we tested their immunosuppressive potential in CD4(+) T cell-induced colitis in vivo. We found that injection of GCsMs into mice with severe colitis abolished the inflammation and resulted in significant clinical improvement within a few days. T cells recovered from GCsM-treated mice exhibited reduced secretion of proinflammatory cytokines IFN-γ and IL-17. Furthermore, clusters ...
Blood, 2010
Active resolution of inflammation is a previously unrecognized process essential for tissue homeostasis. Monocytes play a pivotal role in the generation as well as resolution of inflammation. Glucocorticoids (GCs) are widely used anti-inflammatory agents. We demonstrate that GCs exhibit antiapoptotic effects in monocytes resulting in differentiation to an anti-inflammatory phenotype. The molecular basis of this novel antiapoptotic effect is a prolonged activation of the extracellular signal regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway resulting in inhibition of caspase activities and expression of antiapoptotic genes via activation of c-Myc. We identified up-regulation and activation of A3 adenosine receptor (A3AR) as the initial trigger of this antiapoptotic pathway. In summary, we deciphered a novel molecular pathway promoting survival of anti-inflammatory monocytes. Specific activation of A3AR or its downstream signaling pathways may thus be a novel strate...
The Journal of Clinical Endocrinology & Metabolism, 1999
Resistance to glucocorticoid therapy has been observed in patients with autoimmune/inflammatory diseases and may be related to the inflammatory process itself. The aim of this study was to examine the ability of tumor necrosis factor ␣ (TNF␣, a proinflammatory cytokine) and interleukin (IL)-10 (an anti-inflammatory cytokine) to differentially regulate the sensitivity of human monocytes/macrophages to glucocorticoids. To accomplish this, we first analyzed the pattern of TNF␣ and IL-10 inhibition by dexamethasone in LPS-stimulated whole-blood cell cultures. Second, we studied the modulation of the sensitivity of these cells to dexamethasone by preincubation with TNF␣ or IL-10 and measurement of LPS-stimulated IL-6 secretion. In addition, we evaluated the effect of dexamethasone on phorbolmyristate-acetate-stimulated IL-1 receptor antagonist secretion by the human monocytic cell line U937. Finally, we investigated whether the modulation of corticosensitivity in TNF␣-and IL-10-pretreated U937 cells was related to a change of the glucocorticoid receptor concentration and affinity. Dexamethasone had different effects on LPS-induced TNF␣ and IL-10 secretion; whereas it suppressed TNF␣ in a dose-dependent fashion, its effect on IL-10 secretion was biphasic, producing stimulation at lower, and inhibition at higher doses. The concentration of LPS employed influenced the effect of dexamethasone on IL-10 secretion (P Ͻ 0.001). Pretreatment with TNF␣ diminished, and with IL-10 improved, the ability of dexamethasone to suppress IL-6 secretion in whole-blood cell cultures (P Ͻ 0.01 for both) and to enhance IL-1 receptor antagonist secretion by U937 cells (P Ͻ 0.05 for both). TNF␣ decreased (P Ͻ 0.001), while IL-10 increased (P Ͻ 0.001), the concentration of dexamethasone binding sites in these cells, with no discernible effect on their binding affinity. We conclude that glucocorticoids differentially modulate TNF␣ and IL-10 secretion by human monocytes in a LPS dose-dependent fashion and that the sensitivity of these cells to glucocorticoids is altered by TNF␣ or IL-10 pretreatment; TNF␣ blocks their effects, whereas IL-10 acts synergistically with glucocorticoids. This is accompanied by opposite glucocorticoid receptor changes, respectively opposing and favoring glucocorticoid actions. This study suggests that the pattern of pro-/ antiinflammatory cytokine secretion may alter the response of patients to glucocorticoid therapy. (J Clin Endocrinol Metab 84:
Journal of Immunology, 1995
We examined the direct effects of glucocorticoid treatment on neutrophil survival and function in vitro. Four different glucocorticoids caused a dose-dependent inhibition of apoptosis leading to increased survival of neutrophils. Maximal effects were found with dexamethasone at 1 0-6 M, 16.6 +-6.2 vs 54.6 2 6.9, at 24 h ( p < 0.05). Nonglucocorticoid steroids did not modulate apoptosis in neutrophils. Furthermore, the effect was inhibited in a dose-dependent manner by the glucocorticoid antagonist RU 486. Glucocorticoid-treated neutrophils produced significantly more superoxide in response to FMLP than untreated controls ( p < 0.05). However, both basal and stimulated superoxide production were less than that found with freshly isolated cells. Such lack of priming or activation by glucocorticoids is in contrast to previous experience when increased survival was accompanied by cell activation. When compared with other stimuli, the effect of glucocorticoids at 24 h was similar to that of LPS but less than that of granulocyte-macrophage colony-stimulating factor (GM-CSF), 52 ? 4, 57 1-6, and 70 t 4, respectively ( p < 0.05). When added in combination, dexamethasone did not increase survival with LPS, but did augment the effect of GM-CSF, suggesting diversity in the mechanisms by which these stimuli regulate apoptosis. These data indicate that glucocorticoids can augment the effector potential of neutrophils by prolonging their survival and functional responsiveness, and such treatment might be detrimental in vivo because of delay in neutrophil apoptosis and in ultimate clearance of them from tissues.
Glucocorticoids as Regulators of Macrophage-Mediated Tissue Homeostasis
Frontiers in Immunology, 2021
Our immune system has evolved as a complex network of cells and tissues tasked with maintaining host homeostasis. This is evident during the inflammatory responses elicited during a microbial infection or traumatic tissue damage. These responses seek to eliminate foreign material or restore tissue integrity. Even during periods without explicit disturbances, the immune system plays prominent roles in tissue homeostasis. Perhaps one of the most studied cells in this regard is the macrophage. Tissue-resident macrophages are a heterogenous group of sensory cells that respond to a variety of environmental cues and are essential for organ function. Endogenously produced glucocorticoid hormones connect external environmental stress signals with the function of many cell types, producing profound changes in immune cells, including macrophages. Here, we review the current literature which demonstrates specific effects of glucocorticoids in several organ systems. We propose that tissue-resid...