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Mediators of Inflammation
Volume 2015 (2015), Article ID 347965, 16 pages
http://dx.doi.org/10.1155/2015/347965
Research Article

Sustained Interleukin-1β Exposure Modulates Multiple Steps in Glucocorticoid Receptor Signaling, Promoting Split-Resistance to the Transactivation of Prominent Anti-Inflammatory Genes by Glucocorticoids

1Department of Medicine, School of Medicine, Alcala University (UAH), Alcalá de Henares, 28805 Madrid, Spain
2Biologie des Bactéries Intracellulaires, Departement Genomes et Génétique, Institut Pasteur, 75015 Paris, France
3Immunology and Individualized Medicine, IMMPA CSIC/UAH Joint Unit, Alcalá de Henares, 28805 Madrid, Spain
4MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, King’s College London, Division of Asthma, Allergy & Lung Biology, 5th Floor Tower Wing, Guy’s Hospital, London SE1 9RT, UK
5Department of Immunology and Oncology, National Biotechnology Center, Spanish National Research Council (CNB-CSIC), 28049 Madrid, Spain

Received 10 December 2014; Revised 22 February 2015; Accepted 26 February 2015

Academic Editor: Tânia Silvia Fröde

Copyright © 2015 Pedro Escoll et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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, and 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.