Anti-inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up-regulation of dual specificity phosphatase 1.
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 m...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
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2012
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| _version_ | 1826301993700818944 |
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| author | Joanny, E Ding, Q Gong, L Kong, P Saklatvala, J Clark, A |
| author_facet | Joanny, E Ding, Q Gong, L Kong, P Saklatvala, J Clark, A |
| author_sort | Joanny, E |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T05:40:47Z |
| format | Journal article |
| id | oxford-uuid:e57e9d43-e679-4f3b-aa8c-8be73fad1c48 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:40:47Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:e57e9d43-e679-4f3b-aa8c-8be73fad1c482022-03-27T10:24:22ZAnti-inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up-regulation of dual specificity phosphatase 1.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e57e9d43-e679-4f3b-aa8c-8be73fad1c48EnglishSymplectic Elements at Oxford2012Joanny, EDing, QGong, LKong, PSaklatvala, JClark, A 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. |
| spellingShingle | Joanny, E Ding, Q Gong, L Kong, P Saklatvala, J Clark, A Anti-inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up-regulation of dual specificity phosphatase 1. |
| title | Anti-inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up-regulation of dual specificity phosphatase 1. |
| title_full | Anti-inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up-regulation of dual specificity phosphatase 1. |
| title_fullStr | Anti-inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up-regulation of dual specificity phosphatase 1. |
| title_full_unstemmed | Anti-inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up-regulation of dual specificity phosphatase 1. |
| title_short | Anti-inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up-regulation of dual specificity phosphatase 1. |
| title_sort | anti inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up regulation of dual specificity phosphatase 1 |
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