title: Anti-inflammatory effects of selective glucocorticoid receptor modulators are partially dependent on up-regulation of dual specificity phosphatase 1.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors: Kennedy Institute of Rheumatology Division, Imperial College London, Hammersmith, London, UK             Roche Palo Alto LLC, Palo Alto, CA, USA.
authors: Eugénie
authors: E
authors: Joanny
authors: Qize
authors: Q
authors: Ding
authors: Leyi
authors: L
authors: Gong
authors: Philip
authors: P
authors: Kong
authors: Jeremy
authors: J
authors: Saklatvala
authors: Andrew R
authors: AR
authors: Clark
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology; D002460:Cell Line; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005938:Glucocorticoids; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D000439:Pentanols / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists*
chemical_list: D000893:Anti-Inflammatory Agents; D001572:Benzofurans; D048588:Benzoxazines; D016207:Cytokines; D005938:Glucocorticoids; D016328:NF-kappa B; D000439:Pentanols; D011804:Quinolines; C546413:R-1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(((2-methyl-5-quinolyl)amino)methyl)pentan-2-ol; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; C481822:ZK 216348; D003907:Dexamethasone; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse