A plant-derived glucocorticoid receptor modulator attenuates inflammation without provoking ligand-induced resistance.
BACKGROUND
Acquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for improved alternatives to classic steroids. We sought to unravel how two glucocorticoid receptor-activating compounds, dexamethasone and Compound A, influence glucocorticoid receptor levels and how this can be correlated to their gene regulatory potential.


METHODS
Compound A and dexamethasone were applied in a short-term and long-term treatment protocol. By quantitative 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 glucocorticoid receptor protein levels in both conditions (ex vivo). In addition, this study examined the effect of systemic administration of dexamethasone and Compound A, in concentrations effective to inhibit collagen-induced arthritis, in DBA/1 mice on glucocorticoid receptor levels (in vivo).


RESULTS
Compound A does not induce a homologous downregulation of glucocorticoid receptor in vivo and ex vivo, thereby retaining its anti-inflammatory effects after prolonged treatment in FLS. This is in sharp contrast to dexamethasone, showing a direct link between prolonged dexamethasone treatment, decreasing glucocorticoid receptor levels, and the abolishment of inflammatory gene repression in FLS. It was also observed that the acquired low receptor levels after prolonged dexamethasone treatment are still sufficient to sustain the transactivation of endogenous glucocorticoid-responsive element-driven genes in FLS, a mechanism partly held accountable for the metabolic side-effects.


CONCLUSIONS
Compound A is less likely to evoke therapy resistance, as it does not lead to homologous glucocorticoid receptor downregulation, which is in contrast to classic glucocorticoids.
Gossye
V
V
Ghent University, Department of Physiology, Laboratory for Eukaryotic Gene Expression and Signal Transduction, B-9000 Gent, Belgium.
Elewaut
D
D
Van Beneden
K
K
Dewint
P
P
Haegeman
G
G
De Bosscher
K
K
D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000378:metabolism / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004351:Drug Resistance; D005021:Ethylamines / Q000494:pharmacology / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000187:drug effects / Q000502:physiology; D014439:Tyramine / Q000031:analogs & derivatives
C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; D000085:Acetates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005021:Ethylamines; D005938:Glucocorticoids; D018836:Inflammation Mediators; D008024:Ligands; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D014439:Tyramine