Article Text

PDF
Sulfasalazine sensitises human monocytic/macrophage cells for glucocorticoids by upregulation of glucocorticoid receptor α and glucocorticoid induced apoptosis
  1. Ruud Oerlemans1,
  2. Josefien Vink2,
  3. Ben A C Dijkmans1,
  4. Yehuda G Assaraf3,
  5. Marjolein van Miltenburg1,2,
  6. Joost van der Heijden1,
  7. Ilan Ifergan3,
  8. Willem F Lems1,
  9. Rik J Scheper4,
  10. Gertjan J L Kaspers2,
  11. Jacqueline Cloos2,
  12. Gerrit Jansen1
  1. 1
    Department of Rheumatology, VU-Institute for Cancer and Immunology, VU-Medical Center, Amsterdam, The Netherlands
  2. 2
    Department of Pediatric Oncology, VU-Institute for Cancer and Immunology, VU-Medical Center, Amsterdam, The Netherlands
  3. 3
    Department of Biology, The Technion, Haifa, Israel
  4. 4
    Department of Pathology, VU-Institute for Cancer and Immunology, VU-Medical Center, Amsterdam, The Netherlands
  1. Dr G Jansen, Department of Rheumatology, Room 4A42, VU-University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; g.jansen{at}vumc.nl

Abstract

Background: Glucocorticoids (GCs) are commonly used in the treatment of (chronic) inflammatory diseases and cancer, but inherent or acquired resistance to these drugs limits their optimal efficacy. The availability of drugs that could modulate GC resistance is therefore of potential clinical interest.

Objective: To explore the molecular basis of GC sensitisation of GC resistant monocytic/macrophage cells after chronic exposure to sulfasalazine.

Methods: Human monocytic/macrophage THP1 and U937 cells represent a cell line model system characterised by inherent resistance to the GCs dexamethasone and prednisolone. Both cell lines were chronically exposed in vitro to 0.3–0.6 mM sulfasalazine (SSZ) for approximately 3 months, after which they were characterised for GC sensitivity, expression levels of GC receptor and components of the nuclear factor kappa B (NFκB) signalling pathway, and their ability to undergo GC induced apoptosis.

Results: Chronic exposure to SSZ markedly sensitised both U937 and THP1 cells to dexamethasone (781-fold and 1389-fold, respectively) and prednisolone (562-fold and 1220-fold, respectively). Restoration of GC sensitivity in cells exposed to SSZ was provoked via GC induced apoptosis, coinciding with inhibition of NFκB activation. Moreover, western blot analysis revealed a markedly increased expression of glucocorticoid receptor α (GRα) in cells exposed to SSZ. Since GRα mRNA levels were only marginally increased, these results suggest that an altered post-transcriptional mechanism was operable which conferred a stable GRα protein on SSZ exposed cells.

Conclusion: These results suggest that chronic targeting of the NFκB signalling pathway by SSZ may be exploited as a novel strategy to stabilise GRα expression and thereby sensitise primary resistant cells to GCs.

Statistics from Altmetric.com

Footnotes

  • This study was supported by grants from the Dutch Arthritis Association (NRF-03-40) to GJ and the EC (EUGIA:QLG1-CT-2001-01574) to GJLK.

  • Competing interests: None.

  • RO and JV contributed equally to this study.

  • Abbreviations:
    SSZ
    sulfasalazine
    GC
    glucocorticoid
    GR
    glucocorticoid receptor
    NFκB
    nuclear factor kappa B
    IκB
    inhibitor kappa B
    IKK
    inhibitor kappa B kinase
    TNFα
    tumour necrosis factor α

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.