title: Selective Activator of the Glucocorticoid Receptor Compound A Dissociates Therapeutic and Atrophogenic Effects of Glucocorticoid Receptor Signaling in Skin.
abstract: BACKGROUND
  Glucocorticoids are effective anti-inflammatory drugs widely used in dermatology and for the treatment of blood cancer patients. Unfortunately, chronic treatment with glucocorticoids results in serious metabolic and atrophogenic adverse effects including skin atrophy. Glucocorticoids act via the glucocorticoid receptor (GR), a transcription factor that causes either gene transactivation (TA) or transrepression (TR). Compound A (CpdA), a novel non-steroidal GR ligand, does not promote GR dimerization and TA, retains anti-inflammatory potential but induces fewer metabolic side effects compared to classical glucocorticoids when used systemically. As topical effects of CpdA have not been well studied, this work goal was to compare the anti-inflammatory and side effects of topical CpdA and glucocorticoids and to assess their effect on GR TA and TR in keratinocytes.
  
  
  METHODS
  We used murine immortalized keratinocytes and F1 C57BlxDBA mice. Effect of glucocorticoid fluocinolone acetonide (FA) and CpdA on gene expression in keratinocytes in vitro and in vivo was evaluated by reverse transcription-PCR. The anti-inflammatory effects were assessed in the model of tumor promoter 12-O-tertradecanoyl-acetate (TPA)-induced dermatitis and in croton oil-induced ear edema test. Skin atrophy was assessed by analysis of epidermal thickness, keratinocyte proliferation, subcutaneous adipose hypoplasia, and dermal changes after chronic treatment with FA and CpdA.
  
  
  RESULTS
  In mouse keratinocytes in vitro and in vivo, CpdA did not activate GR-dependent genes but mimicked closely the inhibitory effect of glucocorticoid FA on the expression of inflammatory cytokines and matrix metalloproteinases. When applied topically, CpdA inhibited TPA-induced skin inflammation and hyperplasia. Unlike glucocorticoids, CpdA itself did not induce skin atrophy which correlated with lack of induction of atrophogene regulated in development and DNA damage response 1 (REDD1) causatively involved in skin and muscle steroid-induced atrophy.
  
  
  CONCLUSIONS
  Overall, our results suggest that CpdA and its derivatives represent novel promising class of anti-inflammatory compounds with reduced topical side effects.
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, IL, USA; Bacteriophage Laboratory, Institute of Immunology and Experimental Therapy, Wrocław, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Klopot
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, IL, USA.
authors.forename: Gleb
authors.initials: G
authors.lastname: Baida
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, IL, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Bhalla
authors.affiliation: Department of Clinical Chemistry, Chulalonkorn University, Bangkok, Thailand.
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, IL, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Budunova
keywords: Atrophy; Glucocorticoid receptors; Inflammation; Selective glucocorticoid receptor activator; Skin