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.
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, GR(Ser203) and GR(Ser211) 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.
authors.affiliation: Department of Medicine, School of Medicine, Alcala University (UAH), Alcalá de Henares, 28805 Madrid, Spain ; Biologie des Bactéries Intracellulaires, Departement Genomes et Génétique, Institut Pasteur, 75015 Paris, France.
authors.forename: Pedro
authors.identifier: 0000-0002-5933-094X
authors.initials: P
authors.lastname: Escoll
authors.affiliation: Immunology and Individualized Medicine, IMMPA CSIC/UAH Joint Unit, Alcalá de Henares, 28805 Madrid, Spain ; MRC & 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.
authors.forename: Ismael
authors.identifier: 0000-0003-4871-6721
authors.initials: I
authors.lastname: Ranz
authors.affiliation: Immunology and Individualized Medicine, IMMPA CSIC/UAH Joint Unit, Alcalá de Henares, 28805 Madrid, Spain.
authors.forename: Norman
authors.identifier: 0000-0003-0805-7629
authors.initials: N
authors.lastname: Muñoz-Antón
authors.affiliation: Immunology and Individualized Medicine, IMMPA CSIC/UAH Joint Unit, Alcalá de Henares, 28805 Madrid, Spain.
authors.forename: Ana
authors.identifier: 0000-0001-5016-5901
authors.initials: A
authors.lastname: van-den-Rym
authors.affiliation: Department of Medicine, School of Medicine, Alcala University (UAH), Alcalá de Henares, 28805 Madrid, Spain.
authors.forename: Melchor
authors.identifier: 0000-0003-1309-7510
authors.initials: M
authors.lastname: Alvarez-Mon
authors.affiliation: Department of Immunology and Oncology, National Biotechnology Center, Spanish National Research Council (CNB-CSIC), 28049 Madrid, Spain.
authors.forename: Carlos
authors.identifier: 0000-0002-2121-189X
authors.initials: C
authors.lastname: Martínez-Alonso
authors.affiliation: Department of Medicine, School of Medicine, Alcala University (UAH), Alcalá de Henares, 28805 Madrid, Spain.
authors.forename: Eva
authors.identifier: 0000-0003-0974-1238
authors.initials: E
authors.lastname: Sanz
authors.affiliation: Immunology and Individualized Medicine, IMMPA CSIC/UAH Joint Unit, Alcalá de Henares, 28805 Madrid, Spain.
authors.forename: Antonio
authors.identifier: 0000-0003-2220-1439
authors.initials: A
authors.lastname: de-la-Hera
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics; D053583:Interleukin-1beta / Q000494:pharmacology*; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D051816:Tristetraprolin / Q000235:genetics; D000099185:Interferon Regulatory Factor-8; D000099159:Tacrolimus Binding Protein 5
chemical_list: D005938:Glucocorticoids; D018970:Insulin-Like Growth Factor Binding Protein 1; D050835:Interferon Regulatory Factors; D053583:Interleukin-1beta; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D051816:Tristetraprolin; D000099185:Interferon Regulatory Factor-8; D000099159:Tacrolimus Binding Protein 5; C032231:IGFBP1 protein, human; C497552:ZFP36 protein, human