A plant-derived ligand favoring monomeric glucocorticoid receptor conformation with impaired transactivation potential attenuates collagen-induced arthritis.
The glucocorticoid receptor (GR) is a transcription factor regulating its target genes either positively, through direct binding to the promoter of target genes, or negatively by the interference with the activity of transcription factors involved in proinflammatory gene expression. The well-known adverse effects of glucocorticoids are believed to be mainly caused by their GR-mediated gene-activating properties. Although dimerization of GR is thought to be essential for gene-activating properties, no compound has yet been described which selectively imposes GR monomer formation and interference with other transcription factors. In the present study, we report on a GR-binding, plant-derived compound with marked dissociative properties in rheumatoid arthritis fibroblast-like synoviocytes, which are important effector cells in inflammation and matrix degradation in rheumatoid arthritis. In addition, these findings could be extended in vivo in murine collagen-induced arthritis, in which joint inflammation was markedly inhibited without inducing hyperinsulinemia. Therefore, we conclude that GR monomers are sufficient for inhibition of inflammation in vivo.
Dewint
Pieter
P
Department of Rheumatology, Ghent University Hospital, De Pintelaan 185, Ghent, Belgium.
Gossye
Valerie
V
De Bosscher
Karolien
K
Vanden Berghe
Wim
W
Van Beneden
Katrien
K
Deforce
Dieter
D
Van Calenbergh
Serge
S
Müller-Ladner
Ulf
U
Vander Cruyssen
Bert
B
Verbruggen
Gust
G
Haegeman
Guy
G
Elewaut
Dirk
D
D000085:Acetates / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D024043:Collagen Type II / Q000633:toxicity; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D019281:Dimerization; D005021:Ethylamines / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010936:Plant Extracts / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000502:physiology; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D031248:Salsola; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D014439:Tyramine / Q000031:analogs & derivatives
C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; D000085:Acetates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D024043:Collagen Type II; D005021:Ethylamines; D008024:Ligands; D010936:Plant Extracts; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D003907:Dexamethasone; D014439:Tyramine