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A plant-derived glucocorticoid receptor modulator attenuates inflammation without provoking ligand-induced resistance
  1. Valerie Gossye (valerie.gossye{at}
  1. Ghent University, Belgium
    1. Dirk Elewaut (dirk.elewaut{at}
    1. Ghent University Hospital, Belgium
      1. Katrien Van Beneden (katrien.vanbeneden{at}
      1. Ghent University Hospital, Belgium
        1. Pieter Dewint (pieter.dewint{at}
        1. Ghent University Hospital, Belgium
          1. Guy Haegeman (guy.haegeman{at}
          1. Ghent University, Belgium
            1. Karolien De Bosscher (karolien.debosscher{at}
            1. Ghent University, Belgium


              Background: Acquired resistance to glucocorticoids (GCs) constitutes a major clinical challenge, often overlooked in the search for improved alternatives to classical steroids. We sought to unravel how two glucocorticoid receptor (GR) activating compounds, Dexamethasone (DEX) and CompoundA (CpdA), influence GR levels and how this can be correlated to their gene regulatory potential.

              Methods: CpdA and DEX were applied in a short-term and in a long-term treatment protocol. Via Q-PCR analysis in fibroblast-like synoviocytes (FLS) the gene regulatory potential of both compounds in the two experimental conditions was analysed. A parallel Western blot assay revealed the GR protein levels in both conditions (ex vivo). Additionally, we examined the effect of systemic administration of DEX and CpdA, in concentrations effective to inhibit collagen-induced arthritis (CIA), in DBA/1 mice on GR levels (in vivo).

              Results: CpdA does not induce a homologous down-regulation of GR in vivo and ex vivo, thereby retaining its anti-inflammatory effects after prolonged treatment in FLS. This is in sharp contrast to DEX, showing a direct link between prolonged DEX treatment, decreasing GR levels, and the abolishment of inflammatory gene repression in FLS. We additionally observed that the acquired low receptor levels after prolonged DEX treatment are still sufficient to sustain the transactivation of endogenous GRE-driven genes in FLS, a mechanism partially held accountable for the metabolic side effects.

              Conclusion CpdA is less likely to evoke therapy resistance, as it does not lead to homologous GR down-regulation, which is in contrast to classical GCs.

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