title: Anti-allergic effects of mapracorat, a novel selective glucocorticoid receptor agonist, in human conjunctival fibroblasts and epithelial cells.
abstract: OBJECTIVE
  To determine the ocular anti-allergic effects of mapracorat, a novel selective glucocorticoid receptor agonist (SEGRA) in primary human conjunctival fibroblasts and epithelial cells.
  
  
  METHODS
  Two primary human conjunctival cell types, human conjunctival epithelial cells (HConEpiC) and human conjunctival fibroblasts (HConF), were challenged with interleukin-4 (IL-4) or IL-13 plus tumor necrosis factor-alpha (TNF-α). Luminex technology was used to profile the resulting inflammatory response. The effects of mapracorat on the release of eotaxin and regulated on activation, normal T cell expressed and secreted (RANTES), two allergy-related chemokines, as well as proinflammatory cytokines and intercellular adhesion molecule 1 (ICAM-1) were then determined. Small interfering RNA was used to determine whether the effects of mapracorat were mediated via the glucocorticoid receptor (GR). Dexamethasone was used as the control.
  
  
  RESULTS
  IL-13 or IL-4 plus TNF-α in the HConF or HConEpiC significantly increased eotaxin-1 (HConF only), eotaxin-3, RANTES, multiple proinflammatory cytokines, and ICAM-1. Synergistic effects of IL-13 or IL-4 plus TNF-α were observed in the HConEpiC for RANTES and monocyte chemoattractant protein-1, and in the HConF for eotaxin-1, eotaxin-3, and RANTES. Mapracorat significantly reduced IL-4 or IL-13 plus TNF-α-induced cytokine release and ICAM-1 protein in a dose-dependent manner in both cell types, with comparable efficacy to dexamethasone. These effects were mediated through the glucocorticoid receptor (GR), as demonstrated by the reversal of inhibitory effects after silencing of glucocorticoid receptor expression.
  
  
  CONCLUSIONS
  Data from these in vitro models indicate that mapracorat is efficacious and potent in reducing IL-4 or IL-13 plus TNF-α-induced release of allergy-related and proinflammatory cytokines from the HConF and the HConEpiC, supporting clinical evaluation of the compound in reducing allergic and inflammatory reactions in allergic conjunctivitis.
authors.affiliation: Global Pharmaceutical R&D, Bausch & Lomb Inc., Rochester, NY 14609, USA. Megan.Cavet@bausch.com
authors.forename: Megan E
authors.initials: ME
authors.lastname: Cavet
authors.forename: Stepan
authors.initials: S
authors.lastname: Volhejn
authors.forename: Karen L
authors.initials: KL
authors.lastname: Harrington
authors.forename: Jin-Zhong
authors.initials: JZ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology*; D002417:Cattle; D003228:Conjunctiva / Q000473:pathology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D000439:Pentanols / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D001572:Benzofurans; D018793:Interleukin-13; 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; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D015847:Interleukin-4