Anti‐inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up‐regulation of dual specificity phosphatase 1

• Published in: British journal of pharmacology 2012-02, Vol.165 (4b), p.1124-1136
• Main Authors: Joanny, Eugénie, Ding, Qize, Gong, Leyi, Kong, Philip, Saklatvala, Jeremy, Clark, Andrew R
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; anti‐inflammatory drugs; Benzofurans - pharmacology; Benzoxazines - pharmacology; Bone Marrow Cells - cytology; Cell Line; Cell Line, Tumor; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cytokines - metabolism; Dexamethasone; Dual Specificity Phosphatase 1 - deficiency; Dual Specificity Phosphatase 1 - genetics; Dual Specificity Phosphatase 1 - metabolism; Gene expression; gene transcription; Glucocorticoids; HeLa Cells; Humans; immunopharmacology; inflammation; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Knockout; NF-kappa B - metabolism; nuclear receptors; Pentanols - pharmacology; Quinolines - pharmacology; Receptors, Glucocorticoid - agonists; Research Papers; RNA, Messenger - metabolism; steroids/neurosteroids
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01574.x

BACKGROUND AND PURPOSE It is thought that the anti‐inflammatory effects of glucocorticoids (GCs) are largely due to GC receptor (GR)‐mediated transrepression of NF‐κB and other transcription factors, whereas side effects are caused by activation of gene expression (transactivation). Selective GR modulators (SGRMs) that preferentially promote transrepression should retain anti‐inflammatory properties whilst causing fewer side effects. Contradicting this model, we found that anti‐inflammatory effects of the classical GC dexamethasone were partly dependent on transactivation of the dual specificity phosphatase 1 (DUSP1) gene. We wished to determine whether anti‐inflammatory effects of SGRMs are also mediated by DUSP1. EXPERIMENTAL APPROACH Dissociated properties of two SGRMs were confirmed using GR‐ and NF‐κB‐dependent reporters, and capacity to activate GC‐responsive elements of the DUSP1 gene was tested. Effects of SGRMs on the expression of DUSP1 and pro‐inflammatory gene products were assessed in various cell lines and in primary murine Dusp1+/+ and Dusp1−/−macrophages. KEY RESULTS The SGRMs were able to up‐regulate DUSP1 in several cell types, and this response correlated with the ability of the compounds to suppress COX‐2 expression. Several anti‐inflammatory effects of SGRMs were ablated or significantly impaired in Dusp1−/− macrophages. CONCLUSIONS AND IMPLICATIONS Like dexamethasone, SGRMs appear to exert anti‐inflammatory effects partly via the up‐regulation of DUSP1. This finding has implications for how potentially therapeutic novel GR ligands are identified and assessed.