Sulfasalazine sensitizes human monocytic/macrophage cells for glucocorticoids by up-regulation of glucocorticoid receptor and glucocorticoid- induced apoptosis

Ruud Oerlemans ¹, Josefien Vink ¹, Ben A.C. Dijkmans ¹, Yehuda G. Assaraf ², Marjolein Van Miltenburg ¹, Joost W. Van der Heijden ¹, Ilan Ifergan ², Willem F. Lems ¹, Rik J. Scheper ¹, Gertjan LK Kaspers ¹, Jacqueline Cloos ¹ and Gerrit Jansen ^1*

¹ VU University Medical Ctr, Amsterdam, Netherlands
² The Technion-Israel Institute of Technology, Haifa, Israel

^* To whom correspondence should be addressed. E-mail: g.jansen{at}vumc.nl.

Accepted 21 January 2007

Abstract

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

Objective: To explore the molecular basis of glucocorticoid (GC) sensitization 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 characterized by inherent resistance to the GCs dexamethasone and prednisolone. Both cell lines were chronically exposed in vitro to (0.3-0.6mM) sulfasalazine (SSZ) for & [approx] 3 months, after which they were characterized for GC-sensitivity, expression levels of GC-receptor and components of the NFB signaling pathway, and their ability to undergo GC-induced apoptosis.

Results: Chronic exposure to SSZ markedly sensitized both U937 and THP1 cells to dexamethasone (781- and 1,389-fold, respectively) and prednisolone (562- and 1,220-fold, respectively). Restoration of GC- sensitivity in SSZ-exposed cells was provoked via GC- induced apoptosis, coinciding with inhibition of NF& [kappa]B activation. Moreover, western blot analysis revealed a markedly increased expression of glucocorticoid receptor (GR) in SSZ- exposed cells. Since GR mRNA levels were only marginally increased, these results suggested that an altered post-transcriptional mechanism was operable which conferred upon SSZ-exposed cells a stable GR& [alpha] protein.

Conclusion: These results suggest that chronic targeting of the NFB signaling pathway by SSZ may be exploited as a novel strategy to stabilize GR& [alpha] expression and thereby sensitize primary resistant cells to GCs.

Keywords: NFkB, glucocorticoid receptor, glucocorticoids, rheumatoid arthritis, sulfasalazine

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