title: Glucocorticoids suppress hypoxia-induced COX-2 and hypoxia inducible factor-1α expression through the induction of glucocorticoid-induced leucine zipper.
abstract: OBJECTIVE
  The COX-2/PGE2 pathway in hypoxic cancer cells has important implications for stimulation of inflammation and tumourigenesis. However, the mechanism by which glucocorticoid receptors (GRs) inhibit COX-2 during hypoxia has not been elucidated. Hence, we explored the mechanisms underlying glucocorticoid-mediated inhibition of hypoxia-induced COX-2 in human distal lung epithelial A549 cells.
  
  
  METHODS
  The expressions of COX-2 and glucocorticoid-induced leucine zipper (GILZ) in A549 cells were determined by Western blot and/or quantitative real time-PCR respectively. The anti-invasive effect of GILZ on A549 cells was evaluated using the matrigel invasion assay.
  
  
  RESULTS
  The hypoxia-induced increase in COX-2 protein and mRNA levels and promoter activity were suppressed by dexamethasone, and this effect of dexamethasone was antagonized by the GR antagonist RU486. Overexpression of GILZ in A549 cells also inhibited hypoxia-induced COX-2 expression levels and knockdown of GILZ reduced the glucocorticoid-mediated inhibition of hypoxia-induced COX-2 expression, indicating that the inhibitory effects of dexamethasone on hypoxia-induced COX-2 are mediated by GILZ. GILZ suppressed the expression of hypoxia inducible factor (HIF)-1α at the protein level and affected its signalling pathway. Hypoxia-induced cell invasion was also dramatically reduced by GILZ expression.
  
  
  CONCLUSIONS
  Dexamethasone-induced upregulation of GILZ not only inhibits the hypoxic-evoked induction of COX-2 expression and cell invasion but further blocks the HIF-1 pathway by destabilizing HIF-1α expression. Taken together, these findings suggest that the suppression of hypoxia-induced COX-2 by glucocorticoids is mediated by GILZ. Hence, GILZ is a potential key therapeutic target for suppression of inflammation under hypoxia.
authors.affiliation: Department of Bioscience and Biotechnology, College of Life Science, Institute of Biotechnology, Sejong University, Seoul, Korea.
authors.forename: Wonchung
authors.initials: W
authors.lastname: Lim
authors.forename: Choa
authors.initials: C
authors.lastname: Park
authors.forename: Myeong Kuk
authors.initials: MK
authors.lastname: Shim
authors.forename: Yong Hee
authors.initials: YH
authors.lastname: Lee
authors.forename: You Mie
authors.initials: YM
authors.lastname: Lee
authors.forename: YoungJoo
authors.initials: Y
authors.lastname: Lee
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015687:Cell Hypoxia; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter / Q000187:drug effects; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D034622:RNA Interference; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005938:Glucocorticoids; C497442:HIF1A protein, human; D006727:Hormone Antagonists; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011965:Receptors, Glucocorticoid; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D003907:Dexamethasone; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: cyclooxygenase-2; glucocorticoid receptor; glucocorticoid-induced leucine zipper; hypoxia; hypoxia-inducible factor-1