Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids
Clinical treatment with glucocorticoids (GC) can be complicated by cytokine-induced glucocorticoid low-responsiveness (GC-resistance, GCR), a condition associated with a homogeneous reduction in the expression of GC-receptor- (GR-) driven anti-inflammatory genes. However, GR level and phosphorylatio...
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2015/347965 |
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| author | Pedro Escoll Ismael Ranz Norman Muñoz-Antón Ana van-den-Rym Melchor Alvarez-Mon Carlos Martínez-Alonso Eva Sanz Antonio de-la-Hera |
| author_facet | Pedro Escoll Ismael Ranz Norman Muñoz-Antón Ana van-den-Rym Melchor Alvarez-Mon Carlos Martínez-Alonso Eva Sanz Antonio de-la-Hera |
| author_sort | Pedro Escoll |
| collection | DOAJ |
| description | Clinical treatment with glucocorticoids (GC) can be complicated by cytokine-induced glucocorticoid low-responsiveness (GC-resistance, GCR), a condition associated with a homogeneous reduction in the expression of GC-receptor- (GR-) driven anti-inflammatory genes. However, GR level and phosphorylation changes modify the expression of individual GR-responsive genes differently. As sustained IL-1β exposure is key in the pathogenesis of several major diseases with prevalent GCR, we examined GR signaling and the mRNA expression of six GR-driven genes in cells cultured in IL-1β and afterwards challenged with GC. After a GC challenge, sustained IL-1β exposure reduced the cytoplasmic GR level, GRSer203 and GRSer211 phosphorylation, and GR nuclear translocation and led to selective GCR in the expression of the studied genes. Compared to GC alone, in a broad range of GC doses plus sustained IL-1β, FKBP51 mRNA expression was reduced by 1/3, TTP by 2/3, and IRF8 was completely knocked down. In contrast, high GC doses did not change the expression of GILZ and DUSP1, while IGFBP1 was increased by 5-fold. These effects were cytokine-selective, IL-1β dose- and IL-1R1-dependent. The integrated gain and loss of gene functions in the “split GCR” model may provide target cells with a survival advantage by conferring resistance to apoptosis, chemotherapy, and GC. |
| format | Article |
| id | doaj-art-6a9f204788ba4601865361b5c29efc5f |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-6a9f204788ba4601865361b5c29efc5f2025-02-03T05:51:38ZengWileyMediators of Inflammation0962-93511466-18612015-01-01201510.1155/2015/347965347965Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by GlucocorticoidsPedro Escoll0Ismael Ranz1Norman Muñoz-Antón2Ana van-den-Rym3Melchor Alvarez-Mon4Carlos Martínez-Alonso5Eva Sanz6Antonio de-la-Hera7Department of Medicine, School of Medicine, Alcala University (UAH), Alcalá de Henares, 28805 Madrid, SpainImmunology and Individualized Medicine, IMMPA CSIC/UAH Joint Unit, Alcalá de Henares, 28805 Madrid, SpainImmunology and Individualized Medicine, IMMPA CSIC/UAH Joint Unit, Alcalá de Henares, 28805 Madrid, SpainImmunology and Individualized Medicine, IMMPA CSIC/UAH Joint Unit, Alcalá de Henares, 28805 Madrid, SpainDepartment of Medicine, School of Medicine, Alcala University (UAH), Alcalá de Henares, 28805 Madrid, SpainDepartment of Immunology and Oncology, National Biotechnology Center, Spanish National Research Council (CNB-CSIC), 28049 Madrid, SpainDepartment of Medicine, School of Medicine, Alcala University (UAH), Alcalá de Henares, 28805 Madrid, SpainImmunology and Individualized Medicine, IMMPA CSIC/UAH Joint Unit, Alcalá de Henares, 28805 Madrid, SpainClinical treatment with glucocorticoids (GC) can be complicated by cytokine-induced glucocorticoid low-responsiveness (GC-resistance, GCR), a condition associated with a homogeneous reduction in the expression of GC-receptor- (GR-) driven anti-inflammatory genes. However, GR level and phosphorylation changes modify the expression of individual GR-responsive genes differently. As sustained IL-1β exposure is key in the pathogenesis of several major diseases with prevalent GCR, we examined GR signaling and the mRNA expression of six GR-driven genes in cells cultured in IL-1β and afterwards challenged with GC. After a GC challenge, sustained IL-1β exposure reduced the cytoplasmic GR level, GRSer203 and GRSer211 phosphorylation, and GR nuclear translocation and led to selective GCR in the expression of the studied genes. Compared to GC alone, in a broad range of GC doses plus sustained IL-1β, FKBP51 mRNA expression was reduced by 1/3, TTP by 2/3, and IRF8 was completely knocked down. In contrast, high GC doses did not change the expression of GILZ and DUSP1, while IGFBP1 was increased by 5-fold. These effects were cytokine-selective, IL-1β dose- and IL-1R1-dependent. The integrated gain and loss of gene functions in the “split GCR” model may provide target cells with a survival advantage by conferring resistance to apoptosis, chemotherapy, and GC.http://dx.doi.org/10.1155/2015/347965 |
| spellingShingle | Pedro Escoll Ismael Ranz Norman Muñoz-Antón Ana van-den-Rym Melchor Alvarez-Mon Carlos Martínez-Alonso Eva Sanz Antonio de-la-Hera Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids Mediators of Inflammation |
| title | Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids |
| title_full | Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids |
| title_fullStr | Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids |
| title_full_unstemmed | Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids |
| title_short | Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids |
| title_sort | sustained interleukin 1β exposure modulates multiple steps in glucocorticoid receptor signaling promoting split resistance to the transactivation of prominent anti inflammatory genes by glucocorticoids |
| url | http://dx.doi.org/10.1155/2015/347965 |
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