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Monique Fangradt

Bio: Monique Fangradt is an academic researcher from Charité. The author has contributed to research in topics: Inflammation & Hypoxia-inducible factors. The author has an hindex of 8, co-authored 10 publications receiving 439 citations.

Papers
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Journal ArticleDOI
27 Sep 2012-PLOS ONE
TL;DR: It is concluded that the effects of hypoxia are crucial for effective bone healing, which may potentially lead to the development of novel therapeutic approaches.
Abstract: Background Bone fracture initiates a series of cellular and molecular events including the expression of hypoxia-inducible factor (HIF)-1. HIF-1 is known to facilitate recruitment and differentiation of multipotent human mesenchymal stromal cells (hMSC). Therefore, we analyzed the impact of hypoxia and HIF-1 on the competitive differentiation potential of hMSCs towards adipogenic and osteogenic lineages.

168 citations

Journal ArticleDOI
TL;DR: The data demonstrate that the human GR gene encodes for both cGR and mGR, and Membrane-bound GR retains functional activity, as indicated by induced phosphorylation of p38 MAPK due to DEX-BSA treatment.
Abstract: Objective Glucocorticoids (GCs) exert their antiinflammatory and immunosuppressive effects in humans primarily via the cytosolic GC receptor (cGR) but also via rapid, nongenomic mechanisms. Most likely, membrane-bound GRs (mGR) are involved in nongenomic GC signaling. The aim of this study was to investigate the origin and functional activity of mGR. Methods We analyzed the origin of mGR using mGR-expressing HEK 293T cells, by transient and stable RNA interference–mediated GR reduction. GR messenger RNA (mRNA) and cGR and mGR protein levels were analyzed by real-time quantitative polymerase chain reaction, immunoblotting, and high-sensitivity immunofluorescence staining. Furthermore, we analyzed the functional activity of mGR, using membrane-impermeable bovine serum albumin (BSA)–bound dexamethasone (DEX-BSA) in human monocytes. Membrane-bound GR–expressing monocytes were treated with DEX, DEX-BSA, or BSA. Cell lysates were analyzed using PepChip arrays in order to identify kinases triggered by DEX-BSA, with validation using Bio-Plex assays and immunoblotting. Results Our data showed that transient reduction of GR mRNA in HEK 293T cells decreased cGR protein levels but not mGR protein levels. However, stably transfected cells showed reduced cGR protein expression and significantly reduced mGR protein expression. Furthermore, 51 kinase substrates were identified for which phosphorylation was either reduced or increased. We observed p38 MAP kinase (MAPK) as one possible upstream kinase. Validation of these data by Bio-Plex phosphoprotein assay and immunoblotting showed increased phosphorylation of p38 MAPK after treatment with DEX-BSA. Conclusion Our data demonstrate that the human GR gene encodes for both cGR and mGR. Membrane-bound GR retains functional activity, as indicated by induced phosphorylation of p38 MAPK due to DEX-BSA treatment. Membrane-bound GR–mediated cellular signaling needs to be investigated further in order to clarify its therapeutic potential.

70 citations

Journal ArticleDOI
TL;DR: In inflamed joint tissue, the microvascular architecture is highly dysregulated; thus, efficiency of oxygen supply to the synovium is poor and invading cells must adapt instantaneously to changes in the oxygen level of the microenvironment.
Abstract: Hypoxia is an important feature of inflamed tissue, such as the RA joint. Activated monocytes/macrophages and endothelial cells play a pivotal role in the pathogenesis of RA, implicated in the mechanism of inflammation and erosion. During development, myeloid progenitor cells sequentially give rise to monoblasts, promonocytes, and monocytes that are released from the bone marrow into the bloodstream. After extravasation, monocytes differentiate into long-lived, tissue-specific macrophages or DCs. The effect of different oxygen concentrations experienced by these cells during maturation represents a novel aspect of this developmental process. In inflamed joint tissue, the microvascular architecture is highly dysregulated; thus, efficiency of oxygen supply to the synovium is poor. Therefore, invading cells must adapt instantaneously to changes in the oxygen level of the microenvironment. Angiogenesis is an early event in the inflammatory joint, which is important in enabling activated monocytes to enter via endothelial cells by active recruitment to expand the synovium into a "pannus", resulting in cartilage degradation and bone destruction. The increased metabolic turnover of the expanding synovial pannus outpaces the dysfunctional vascular supply, resulting in hypoxia. The abnormal bioenergetics of the microenvironment further promotes synovial cell invasiveness. In RA, joint hypoxia represents a potential threat to cell function and survival. Notably, oxygen availability is a crucial parameter in the cellular energy metabolism, itself an important factor in determining the function of immune cells.

57 citations

Journal ArticleDOI
TL;DR: It is suggested that hypoxia significantly affects the expression of HIF-1α in a MIF-dependent manner leading to a positive-feedback loop in primary human CD4+ T cells, thus influencing the lymphoproliferative response and DEX action via the GC receptor.
Abstract: Hypoxia, a feature of inflammation and tumors, is a potent inducer of the proinflammatory cytokine macrophage migration inhibitory factor (MIF). In transformed cells, MIF was shown to modulate and to be modulated via the oxygen-sensitive transcription factor hypoxia-inducible factor (HIF)-1. Furthermore, anti-inflammatory glucocorticoids (GCs) were described to regulate MIF action. However, in-depth studies of the interaction between MIF and HIF-1 and GC action in nontransformed primary human CD4 + T cells under hypoxia are missing. Therefore, we investigated the functional relationship between MIF and HIF and the impact of the GC dexamethasone (DEX) on these key players of inflammation in human CD4 + T cells. In this article, we show that hypoxia, and specifically HIF-1, is a potent and rapid inducer of MIF expression in primary human CD4 + T cells, as well as in Jurkat T cells. MIF signaling via CD74, in turn, is essential for hypoxia-mediated HIF-1α expression and HIF-1 target gene induction involving ERK/mammalian target of rapamycin activity complemented by PI3K activation upon mitogen stimulation. Furthermore, MIF signaling enhances T cell proliferation under normoxia but not hypoxia. MIF also counterregulates DEX-mediated suppression of MIF and HIF-1α expression. Based on these data, we suggest that hypoxia significantly affects the expression of HIF-1α in a MIF-dependent manner leading to a positive-feedback loop in primary human CD4 + T cells, thus influencing the lymphoproliferative response and DEX action via the GC receptor. Therefore, we suggest that HIF and/or MIF could be useful targets to optimize GC therapy when treating inflammation.

54 citations

Journal ArticleDOI
TL;DR: Severe hypoxia, a feature of joint inflammation, considerably modulates the transcriptome of cells found in the rheumatoid synovium, reflecting a profound influence on immune functions.
Abstract: Objective. Inflamed tissues are usually characterized by low oxygen levels. We investigated whether pathophysiological hypoxia (pO2 Methods. We analyzed the extent to which hypoxia influences the transcriptome in the rheumatoid synovium according to a gene cluster reflecting adaptation to low oxygen levels. Hypoxia-inducible factor-1α (HIF-1α) was detected in the rheumatoid synovium using immunohistochemistry. Isolated human CD4+ T cells were exposed to hypoxia and analyzed using microarray analysis, quantitative polymerase chain reaction, and immunoblot detection. Results. In rheumatoid arthritis (RA) synovial tissue samples, hypoxia modulates the transcription profile. This profile is similar, but not identical, to that found in isolated CD4+ T cells incubated under hypoxic conditions. We show that HIF-1α is expressed in synovial tissue samples and in hypoxic CD4+ cells; and that hypoxia directly affects differential gene expression in human T cells with up to 4.8% modulation of the transcriptome. Functional genome analysis revealed substantial effects of hypoxia on immune response, transcriptional regulation, protein modification, cell growth and proliferation, and cell metabolism. Conclusion. Severe hypoxia, a feature of joint inflammation, considerably modulates the transcriptome of cells found in the rheumatoid synovium. Human CD4+ T cells adapt to hypoxic conditions mainly by HIF-1-driven effects on the transcriptome reflecting a profound influence on immune functions. Thus, hypoxia must be taken into account when therapeutically targeting inflammation.

44 citations


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Journal ArticleDOI
TL;DR: CD8+ memory T cells have an Akt-dependent 'imprinted' glycolytic potential that is required for efficient immediate-early IFN-γ recall responses.
Abstract: Antigen-experienced memory T cells acquire effector function with innate-like kinetics; however, the metabolic requirements of these cells are unknown. Here we show that rapid interferon-γ (IFN-γ) production of effector memory (EM) CD8(+) T cells, activated through stimulation mediated by the T cell antigen receptor (TCR) and the costimulatory receptor CD28 or through cognate interactions, was linked to increased glycolytic flux. EM CD8(+) T cells exhibited more glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity at early time points, before proliferation commenced, than did naive cells activated under similar conditions. CD28 signaling via the serine-threonine kinase Akt and the metabolic-checkpoint kinase mTORC2 was needed to sustain TCR-mediated immediate-early glycolysis. Unlike glycolysis in proliferating cells, immediate-early glycolysis in memory CD8(+) T cells was rapamycin insensitive. Thus, CD8(+) memory T cells have an Akt-dependent 'imprinted' glycolytic potential that is required for efficient immediate-early IFN-γ recall responses.

406 citations

Journal ArticleDOI
TL;DR: This review will focus on biological and physicomechanical considerations currently being explored in bone tissue engineering.

377 citations

Journal ArticleDOI
TL;DR: Although patience is a virtue when it comes to deciphering the many mechanisms GR uses to influence various signaling pathways, the current review is testimony of the fact that groundbreaking mechanistic work has been accumulating over the past years and steadily continues to grow.

353 citations

Journal ArticleDOI
TL;DR: The roles of GCs on the innate immune system with a particular focus on the CNS compartment are examined and the numerous molecular mechanisms through which GCs exert their effects are dissected, including the paradoxical immunomodulatory functions ofGCs in the brain.
Abstract: In response to physiological and psychogenic stressors, the hypothalamic-pituitary adrenal (HPA) axis orchestrates the systemic release of glucocorticoids (GCs). By virtue of nearly ubiquitous expression of the GC receptor (GR) and the multifaceted metabolic, cardiovascular, cognitive and immunologic functions of GCs, this system plays an essential role in the response to stress and restoration of an homeostatic state. GCs act on almost all types of immune cells and were long recognized to perform salient immunosuppressive and anti-inflammatory functions through various genomic and non-genomic mechanisms. These renowned effects of the steroid hormone have been exploited in the clinic for the past 70 years and synthetic GC derivatives are commonly used for the therapy of various allergic, autoimmune, inflammatory and haematological disorders. The role of the HPA axis and GCs in restraining immune responses across the organism is however still debated in light of accumulating evidence suggesting that GCs can also have both permissive and stimulatory effects on the immune system under specific conditions. Such paradoxical actions of GCs are particularly evident in the brain, where substantial data support either a beneficial or detrimental role of the steroid hormone. In this review, we examine the roles of GCs on the innate immune system with a particular focus on the CNS compartment. We also dissect the numerous molecular mechanisms through which GCs exert their effects and discuss the various parameters influencing the paradoxical immunomodulatory functions of GCs in the brain.

295 citations

Journal ArticleDOI
TL;DR: Understanding the complex interplay between hypoxia-induced signaling pathways, oxidative stress and mitochondrial function will provide better insight into the underlying mechanisms of disease pathogenesis.

278 citations