Regular Article
Glucocorticoid-Mediated Suppression of the Promoter Activity of the Cyclooxygenase-2 Gene Is Modulated by Expression of Its Receptor in Vascular Endothelial Cells

https://doi.org/10.1006/bbrc.1998.9939Get rights and content

Abstract

Cyclooxygenase-2 (COX-2), an inducible isozyme of cyclooxygenase, is expressed selectively in response to various inflammatory stimuli such as lipopolysaccharide (LPS) and its expression is suppressed by the glucocorticoid dexamethasone (DEX) in numerous types of cells. However, LPS-enhanced production of prostacyclin in bovine arterial endothelial cells (BAEC) was not significantly decreased by treatment with DEX but was suppressed by selective COX-2 inhibitors. This is consistent with the finding that DEX was not effective at preventing the expression of LPS-induced COX-2 mRNA. Transient transfection analysis showed that DEX did not suppress the LPS-induced promoter activity of the 5′-flanking region of the human COX-2 gene (nucleotides −327 to +59). Since RNA blot analysis indicated low-level expression of glucocorticoid receptor (GR) mRNA in BAEC, a GR-expression vector was transfected to evaluate the role of the GR in the COX-2 promoter activity. It was found that DEX mediated the suppression of the LPS-induced COX-2 promoter activity in a dose-dependent manner. These results suggest that the DEX-mediated suppression of LPS-induced promoter activity of the COX-2 gene is modulated by expression of the GR, which will be possible to account for a unique expression pattern of the COX-2 gene in BAEC.

References (32)

  • H.R. Herschman

    Biochim. Biophys. Acta

    (1996)
  • H. Inoue et al.

    FEBS Lett.

    (1994)
  • T. Nanayama et al.

    Prostaglandins

    (1995)
  • H. Inoue et al.

    Biochem. Biophys. Res. Commun.

    (1998)
  • H. Inoue et al.

    J. Biol. Chem.

    (1995)
  • D.A. Jones et al.

    J. Biol. Chem.

    (1993)
  • A. Habib et al.

    J. Biol. Chem.

    (1993)
  • C. Jonat et al.

    Cell

    (1990)
  • V.L. Chandler et al.

    Cell

    (1983)
  • D.A. Kujubu et al.

    J. Biol. Chem.

    (1992)
  • W. Xie et al.

    Arch. Biochem. Biophys.

    (1993)
  • D.L. DeWitt et al.

    Arch. Biochem. Biophys.

    (1993)
  • Y. Kamei et al.

    Cell

    (1996)
  • J.R. Vane et al.

    Annu. Rev. Pharmacol. Toxicol.

    (1998)
  • T. Kosaka et al.

    Eur. J. Biochem.

    (1994)
  • Cited by (80)

    • Glucocorticoids and estrogens modulate the NF-κB pathway differently in the micro- and macrovasculature

      2013, Medical Hypotheses
      Citation Excerpt :

      Recent observations indicate that glucocorticoid receptors in the macrovasculature can repress the gene transcription of these inflammatory molecules by interaction with transcription factor such as NF-κB [10]. In addition, glucocorticoids inhibit the expression of COX-2 in ECs stimulated with pro-inflammatory cytokines and LPS [25]. Several studies have demonstrated that glucocorticoids reduce the expression of eNOS and iNOS and consequently the production of NO in human endothelial cells [39].

    • Endothelial cells are a potential site of interaction between estrogens and glucocorticoids

      2009, Bioscience Hypotheses
      Citation Excerpt :

      Recent observations indicate that glucocorticoid receptors in the macrovasculature can repress the gene transcription of these inflammatory molecules by interaction with transcription factors such as AP-1 and NF-kappaB [49]. In addition, glucocorticoids inhibit the expression of COX-2 in endothelial cells stimulated with pro-inflammatory cytokines and LPS [50]. Several studies have demonstrated that glucocorticoids reduce the expression of eNOS and iNOS and consequently the production of NO in human endothelial cells [51].

    • Sulforaphane suppresses lipopolysaccharide-induced cyclooxygenase-2 (COX-2) expression through the modulation of multiple targets in COX-2 gene promoter

      2007, International Immunopharmacology
      Citation Excerpt :

      These findings suggest that the inhibitory effects of sulforaphane on the LPS-induced COX-2 gene expression are due to the suppression of COX-2 mRNA expression. The COX-2 promoter region (− 327/+ 59) contains 3 cis-acting elements, namely, NF-κB binding site, C/EBP binding site, and CREB binding site, all of which have been shown to be involved in the regulation of COX-2 gene transcription [15,16,18]. To identify which cis-acting elements play a critical role in sulforaphane-mediated COX-2 promoter inhibition, mutants of the three cis-acting elements were tested in transfection assay (Fig. 1D).

    View all citing articles on Scopus

    Abbreviations used: PG, prostaglandin; COX, Cyclooxygenase; LPS, lipopolysaccharide; DEX, dexamethasone; BAEC, bovine arterial endothelial cells; GR, glucocorticoid receptor; TPA, 12-O-tetradecanoyl phorbol-13-acetate; CRE, cyclic AMP response element; NF-IL6, nuclear factor for interleukin-6 expression; NF-κB, nuclear factor κB; C/EBP, CCAAT/enhancer binding protein; CREB, CRE binding protein; CBP, CREB binding protein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase

    1

    To whom correspondence should be addressed. Fax: +81-6-872-8092. E-mail:[email protected].

    View full text