The Glucocorticoid Receptor: A Revisited Target for Toxins
Abstract
:1. Introduction
2. The Hypothalamic-Pituitary-Adrenal (HPA) Axis and Glucocorticoid Responses
2.1. Disruption of the HPA Axis/Glucocorticoid Responses Increases Mortality
2.2. Glucocorticoid Receptor (GR)
3. Effect of Bacterial Toxins on GR
Toxin | Effect on GR | Reference |
---|---|---|
Aflatoxin B1 | Decreases glucocorticoid induction of liver ribonucleic acid synthesis | [61] |
Decreases nuclear GR ligand binding | [62,63] | |
Decreases glucocorticoid induction of liver enzymes | [64,65] | |
Anthrax lethal toxin | Represses GR-mediated gene activation | [66,67] |
Clostridial toxins | Represses GR-induced gene activation | [68] |
Prevents glucocorticoid repression of cytokine production | [68] | |
Endotoxin/LPS | Impairs glucocorticoid regulation of liver enzymes | [69,70,71,72] |
Decreases GR ligand binding | [11,70,71,72,73,74,75] | |
Decreases GR numbers and affinity in lungs | [76] | |
Increases GR numbers but decreases affinity in bronchial epithelial cell line | [77] | |
Reduces glucocorticoid induction of GR responsive promoter in cell culture | [78,79,80] | |
Increases GR numbers in murine macrophages | [81] | |
No effect on hepatic GR numbers or affinity | [82] | |
Shiga toxin | Increases GR numbers in neutrophils | [17] |
Superantigen | Induces glucocorticoid resistance | [83,84,85] |
Impairs GR nuclear translocation | [84] | |
Induces GRβ | [83,86,87] |
3.1. Anthrax Lethal Toxin
3.2. Endotoxin/LPS
3.3. Shiga Toxin
3.4. Bacterial Superantigens
3.5. Clostridia Toxins
4. Effect of Mycotoxins and Plant Toxins on GR
5. Effect of Environmental and Chemical Toxins on GR
Toxin | Effect on GR | Reference |
---|---|---|
Arsenic | Low dose represses GR-mediated gene activation | [116,117,118,119,120] |
Inhibits GR ligand binding | [121,122,123,124,125] | |
Extreme low dose enhances GR-mediated gene activation | [117,118,119] | |
Reduces CARM1 binding to GR-regulated promoter | [116] | |
Beryllium | Inhibits glucocorticoid induction of liver enzymes | [126,127] |
Cadmium | Low dose reduces GR-mediated gene activation | [121,128] |
High dose enhances GR-mediated activation | [121] | |
Inhibits GR ligand binding in liver | [121,124] | |
Inhibits GR DNA binding in liver | [121] | |
Chromium | Extreme low dose enhances GC-induced liver enzymes | [119,129] |
Decreases glucocorticoid-induced liver genes | [119,129] | |
Lead | Inhibits glucocorticoid induction of liver genes | [130] |
Mercury | Reduces glucocorticoid induction of liver genes | [131] |
Decreases GR ligand binding | [132] | |
Enhances interaction between GR and Hsp proteins | [133] | |
Enhances GR-responsive MMTV promoter | [134] | |
Selenite | Inhibits GR ligand binding | [123,135] |
Decreases glucocorticoid induction of GR-regulated genes | [85] | |
Zinc | Reduces GR ligand binding in liver | [136] |
Enhances GR-responsive MMTV promoter | [134] |
Effect on GR | Reference |
---|---|
Reduces GR ligand binding affinity in bronchial epithelial cells | [137] |
No difference in GR mRNA levels in bronchial epithelial cells | [138] |
Reduces GRα protein levels in mouse lungs exposed to cigarette smoke | [139] |
No difference in GRα/β mRNA levels in bronchial epithelial cells | [138] |
Reduces GR α/β protein levels in PBMCs | [140] |
Reduces CYP3A5 expression in alveolar macrophages | [141] |
Inhibits glucocorticoid-induction of ENaC mRNA | [142] |
Inhibits glucocorticoid repression of cytokine production in BAL macrophages | [143] |
Inhibits HDAC2 expression and activity | [143] |
5.1. Heavy Metals
5.2. Cigarette Smoke
6. Effect of Toxins on Other Nuclear Hormone Receptors
7. Clinical Relevance
8. Conclusions
Acknowledgements
References
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Webster Marketon, J.I.; Sternberg, E.M. The Glucocorticoid Receptor: A Revisited Target for Toxins. Toxins 2010, 2, 1357-1380. https://doi.org/10.3390/toxins2061357
Webster Marketon JI, Sternberg EM. The Glucocorticoid Receptor: A Revisited Target for Toxins. Toxins. 2010; 2(6):1357-1380. https://doi.org/10.3390/toxins2061357
Chicago/Turabian StyleWebster Marketon, Jeanette I., and Esther M. Sternberg. 2010. "The Glucocorticoid Receptor: A Revisited Target for Toxins" Toxins 2, no. 6: 1357-1380. https://doi.org/10.3390/toxins2061357