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Tissue glucocorticoid resistance/hypersensitivity syndromes 总被引:12,自引:0,他引:12
Kino T De Martino MU Charmandari E Mirani M Chrousos GP 《The Journal of steroid biochemistry and molecular biology》2003,85(2-5):457-467
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Glucocorticoids (GCs) are routinely used as anti-inflammatory drugs in the treatment of asthma. They act through binding to glucocorticoid receptor α (GRα), which represses numerous genes encoding pro-inflammatory mediators. A hormone binding deficient GR isoform named GRβ has been isolated in humans. When overexpressed by transfection, GRβ may function as a dominant negative modulator of GRα. However, to act as such, GRβ has to be more abundant than GRα, and conflicting data have been obtained concerning the relative levels of the two isoforms in cell lines and freshly isolated cells. Moreover, the dominant negative effect was not confirmed by independent laboratories. In GC-resistant asthmatics, GRβ was expressed by an increased number of peripheral blood mononuclear cells (PBMCs), airway T cells, and cells found in skin biopsies of tuberculin responses. However, the relative amounts of GRα and GRβ in these cells were not determined. In GC-dependent asthmatics, PBMCs expressed GRα predominantly. No cells containing higher levels of GRβ than GRα have yet been reported in asthmatics. Even if the existence of such cells is demonstrated, the role of GRβ in asthma will remain a matter of controversy because functional studies have given discrepant data. 相似文献
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Background
Glucocorticoids are frequently used as a primary chemotherapeutic agent in many types of human lymphoid malignancies because they induce apoptosis through activation of the glucocorticoid receptor, with subsequent alteration of a complex network of cellular mechanisms. Despite clinical usage for over fifty years, the complete mechanism responsible for glucocorticoid-related apoptosis or resistance remains elusive. The mitogen-activated protein kinase pathway is a signal transduction network that influences a variety of cellular responses through phosphorylation of specific target substrates, including the glucocorticoid receptor. In this study we have evaluated the pharmaceutical scenarios which converge on the mitogen-activated protein kinase pathway to alter glucocorticoid sensitivity in clones of human acute lymphoblastic CEM cells sensitive and refractory to apoptosis in response to the synthetic glucocorticoid dexamethasone. 相似文献4.
Bloom JW Chacko J Lohman IC Halonen M Martinez FD Miesfeld RL 《Apoptosis : an international journal on programmed cell death》2004,9(1):97-104
Glucocorticoids are effective drugs for eosinophil-related disorders, such as asthma and allergy. Previous studies have demonstrated that glucocorticoids increase eosinophil apoptosis and block the survival effect of submaximal concentrations of interleukin-5 (IL-5). We investigated the effect of glucocorticoids on eosinophil survival in the presence of a higher concentration of IL-5 (1 ng/ml), comparable to IL-5 levels in bronchoalveolar lavage and sputum specimens from patients with asthma. In contrast to incubation in the presence of submaximal concentrations of IL-5, the addition of dexamethasone (DEX) to media containing 1 ng/ml IL-5 led to a significant increase in eosinophil cell viability from 58 ± 6.9% to 87 ± 2.4% (p < 0.005) after 72 hours in culture. We found that RU486 blocked the DEX effect on cell viability confirming that glucocorticoid receptor functions are required. We investigated the possibility that the glucocorticoid enhancement of eosinophil survival may be due to an effect on IL-5 receptor expression. Our results show that the IL-5 associated decrease in IL-5 receptor -subunit expression was blocked significantly after 24 hrs in culture with media containing IL-5 plus DEX compared to IL-5 alone. It is tempting to speculate that the observed glucocorticoid enhancement of eosinophil survival in the presence of elevated concentrations of IL-5 could be a mechanism that contributes to glucocorticoid resistance in asthma. 相似文献
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Peter J. Schoonheim 《Steroids》2010,75(12):918-1451
Glucocorticoids regulate a wide range of systems in vertebrate organisms, and their effects are mediated by the glucocorticoid receptor (GR). The responsiveness to glucocorticoids differs largely between individuals. Resistance to glucocorticoids is an important medical problem, since it limits the efficacy of glucocorticoids when they are used to treat immune-related diseases like asthma and rheumatoid arthritis. Glucocorticoid resistance also contributes to the pathogenesis of other diseases, like major depression because of the decreased negative feedback on the hypothalamic pituitary adrenal axis. In this review, we present the zebrafish as an excellent in vivo model system to study glucocorticoid resistance. First, the zebrafish is the only non-primate animal model in which a β-isoform of GR occurs, which is a splice variant with dominant-negative activity. Zebrafish are easily genetically modified, so the expression of GRβ can be varied, creating an in vivo model for GRβ-induced glucocorticoid resistance. Second, by performing a forward-genetic screen using the glucocorticoid-induced decrease in POMC expression in the pituitary gland as a readout, several zebrafish mutants have been obtained which appear to be resistant to glucocorticoid treatment. We present here two types of in vivo models for studying glucocorticoid resistance, that will be used to study the molecular mechanism of glucocorticoid signaling and resistance. Finally these models will be used to screen for small molecules that can alleviate glucocorticoid resistance. 相似文献
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《Journal of receptor and signal transduction research》2013,33(5):297-305
AbstractTo determine the mechanism of glucocorticoid mediated enhancement of insulin receptor (IR) gene expression, we cotransfected a glucocorticoid receptor expression vector and a plasmid containing a reporter gene driven by an MMTV or IR promoter into COS 7 cells. Dexamethasone (Dex) increased MMTV promoter activity by 100% but had no effect on IR promoter activity. In the glucocorticoid responsive breast cancer cell line, MCF-7, Dex increased IR mRNA by 60%, and increased the IR mRNA half-life from approximately 6hrs to >24hrs. No glucocorticoid responsive element could be located in the insulin receptor 3′ untranslated region. Glucocorticoids stabilize IR mRNA. 相似文献
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Osman W Laine S Zilliacus J 《Biochemical and biophysical research communications》2006,348(4):1239-1244
Glucocorticoids are widely used to treat inflammatory diseases but have a number of side effects that partly are connected to inhibition of cell proliferation. Glucocorticoids mediated their action by binding to the glucocorticoid receptor. In the present study, we have identified by two-hybrid screens the germinal center-associated protein (GANP) and MCM3-associated protein (MCM3AP), a splicing variant of GANP, as glucocorticoid receptor interacting proteins. GANP and MCM3AP can bind to the MCM3 protein involved in initiation of DNA replication. Glutathione-S-transferase-pull-down and co-immunoprecipitation assays showed that the C-terminal domain of GANP, encompassing MCM3AP, interacts with the ligand-binding domain of the glucocorticoid receptor. Characterization of the intracellular localization of GANP revealed that GANP is shuttling between the nucleus and the cytoplasm. Furthermore, we show that glucocorticoids are unable to inhibit DNA replication in HeLa cells overexpressing MCM3AP suggesting a role for both glucocorticoid receptor and GANP/MCM3AP in regulating cell proliferation. 相似文献
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Toru Yasuda Hideki Mochizuki 《Apoptosis : an international journal on programmed cell death》2010,15(11):1312-1321
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder beyond Alzheimer’s disease, affecting
approximately 1% of people over the age of 65. The major pathological hallmarks of PD are significant loss of nigrostriatal
dopaminergic (DA) neurons and the presence of intraneuronal protein inclusions termed Lewy bodies. Sporadic cases represent
more than 90% of total patients with PD, while there exist several inherited forms caused by mutations in single genes. Identification
and characterization of these causative genes and their products can help us understand the molecular mechanisms of DA neuronal
cell death and design new approaches to treat both the inherited and sporadic forms of PD. Based on the finding that a point
mutation in the gene encoding α-synuclein (αSyn) protein causes a rare familial form of PD, PARK1, it is now confirmed that
αSyn is a major component of Lewy bodies in patients with sporadic PD. Abnormal accumulation of αSyn protein is considered
a neurotoxic event in the development of PD. PARK4, another dominantly inherited form of familial PD, is caused by duplication
or triplication of the αSyn gene locus. This genetic mutation results in the production of large amounts of wild-type αSyn protein, supporting the αSyn-induced
neurodegeneration hypothesis. On the other hand, the recessively inherited early-onset Parkinsonism is caused in about half
of the cases with loss-of-function mutations in PARK2, which encodes E3 ubiquitin ligase parkin in the ubiquitin–proteasome
system. These findings have shed light on DA neurodegeneration caused by accumulation of toxic protein species that can be
degraded and/or detoxicated through parkin activity. In this review, we will focus on the regulatory roles of αSyn and parkin
proteins in DA neuronal cell apoptosis and provide evidence for the possible therapeutic action of parkin in sporadic patients
with PD. 相似文献
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Karen A. Lewis Arynn Yaeger George N. DeMartino Philip J. Thomas 《Journal of bioenergetics and biomembranes》2010,42(1):85-95
A hallmark of Parkinson disease (PD) is the formation of intracellular protein inclusions called Lewy bodies that also contain
mitochondria. α-Synuclein (αSyn) is a major protein component of Lewy bodies, where it is in an amyloid conformation and a
significant fraction is truncated by poorly understood proteolytic events. Previously, we demonstrated that the 20S proteasome
cleaves αSyn in vitro to produce fragments like those observed in Lewy bodies and that the fragments accelerate the formation
of amyloid fibrils from full-length αSyn. Three point mutations in αSyn are associated with early-onset familial PD: A30P,
E46K, and A53T. However, these mutations have very different effects on the amyloidogenicity and vesicle-binding activity
of αSyn, suggesting neither of these processes directly correlate with neurodegeneration. Here, we evaluate the effect of
the disease-associated mutations on the fragmentation, conformation, and association reactions of αSyn in the presence of
the 20S proteasome and liposomes. The 20S proteasome produced the C-terminal fragments from both the mutant and wildtype αSyn.
These truncations accelerated fibrillization of all α-synucleins, but again there was no clear correlation between the PD-associated
mutations and amyloid formation in the presence of liposomes. Recent data suggests that cellular toxicity is caused by a soluble
oligomeric species, which is a precursor to the amyloid form and is immunologically distinguishable from both soluble monomeric
and amyloid forms of αSyn. Notably, the rate of formation of the soluble, presumptively cytotoxic oligomers correlated with
the disease-associated mutations when both 20S proteasome and liposomes were present. Under these conditions, the wildtype
protein was also cleaved and formed the oligomeric structures, albeit at a slower rate, suggesting that 20S-mediated truncation
of αSyn may play a role in sporadic PD as well. Evaluation of the biochemical reactions of the PD-associated α-synuclein mutants
in our in vitro system provides insight into the possible pathogenetic mechanism of both familial and sporadic PD. 相似文献
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Julie E. Goodwin Junhui Zhang David S. Geller 《Biochemical and biophysical research communications》2010,394(2):266-271
Glucocorticoids are used as a treatment for a variety of conditions and hypertension is a well-recognized side effect of their use. The mechanism of glucocorticoid-induced hypertension is incompletely understood and has traditionally been attributed to promiscuous activation of the mineralocorticoid receptor by cortisol. Multiple lines of evidence, however, point to the glucocorticoid receptor as an important mediator as well. We have developed a mouse model of glucocorticoid-induced hypertension, which is dependent on the glucocorticoid receptor. To determine the site(s) of glucocorticoid receptor action relevant to the development of hypertension, we studied glucocorticoid-induced hypertension in a mouse with a tissue-specific knockout of the glucocorticoid receptor in the distal nephron. Although knockout mice had similar body weight, nephron number and renal histology compared to littermate controls, their baseline blood pressure was mildly elevated. Nevertheless, distal nephron glucocorticoid receptor knockout mice and controls had a similar hypertensive response to dexamethasone. Urinary excretion of electrolytes, both before and after administration of glucocorticoid was also indistinguishable between the two groups. We conclude that the glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension in our model. 相似文献
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Tom Van Bogaert Karolien De Bosscher Claude Libert 《Cytokine & growth factor reviews》2010,21(4):275-286
TNF is a Janus-faced protein. It possesses impressive anti-tumor activities, but it is also one of the strongest known pro-inflammatory cytokines, which hampers its use as a systemic anti-cancer agent. TNF has been shown to play a detrimental role in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Glucocorticoids are strongly anti-inflammatory and exert their therapeutic effects through binding to their receptor, the glucocorticoid receptor. Therefore, glucocorticoids have been used for over half a century for the treatment of inflammatory diseases. However, many patients are or become resistant to the therapeutic effects of glucocorticoids. Inflammatory cytokines have been suggested to play an important role in this steroid insensitivity or glucocorticoid resistance. This review aims to highlight the mechanisms of mutual inhibition between TNF and GR signaling pathways. 相似文献