title: BAY 11-7085 induces glucocorticoid receptor activation and autophagy that collaborate with apoptosis to induce human synovial fibroblast cell death.
abstract: Inhibition of proapoptotic pathways in synovial fibroblasts is one of the major causes of synovial proliferation and hyperplasia in rheumatic diseases. We have shown previously that NF-κB inhibitor BAY 11-7085, through inactivation of PPAR-γ, induces apoptosis in human synovial fibroblasts. In this work we showed that BAY 11-7085 induced autophagy that preceded BAY 11-7085-induced apoptosis. Of interest, BAY 11-7085 induced Serine 211 phosphorylation and degradation of glucocorticoid receptor (GR). Glucocorticoid prednisolone induced both activation and degradation of GR, as well as autophagy in synovial fibroblasts. BAY 11-7085-induced cell death was significantly decreased with glucocorticoid inhibitor mifepristone and with inhibitors of autophagy. Both BAY 11-7085-induced autophagy and GR activation were down regulated with PPAR-γ agonist, 15d-PGJ2 and MEK/ERK inhibitor UO126. Inhibition of autophagy markedly decreased endogenous and BAY 11-7085-induced ERK phosphorylation, suggesting a positive feed back loop between ERK activation and autophagy in synovial fibroblasts. Co-transfection of MEK1 with PPAR-γ1 in HEK293 cells caused known inhibitory phosphorylation of PPAR-γ1 (Serine 112) and enhanced GR degradation, in the absence or presence of prednisolone. Furthermore, GR was both phosphorylated on Serine 211 and down regulated in synovial fibroblasts during serum starvation induced autophagy. These results showed that GR activation and PPAR-γ inactivation mediated BAY 11-7085-induced autophagy.
authors.affiliation: Department of Rheumatology, GIGA Research, University Hospital Sart-Tilman, Liege, Belgium.
authors.forename: Biserka
authors.initials: B
authors.lastname: Relic
authors.affiliation: Department of Rheumatology, GIGA Research, University Hospital Sart-Tilman, Liege, Belgium.
authors.forename: Edith
authors.initials: E
authors.lastname: Charlier
authors.affiliation: Department of Rheumatology, GIGA Research, University Hospital Sart-Tilman, Liege, Belgium.
authors.forename: Celine
authors.initials: C
authors.lastname: Deroyer
authors.affiliation: Department of Rheumatology, GIGA Research, University Hospital Sart-Tilman, Liege, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Malaise
authors.affiliation: Department of Rheumatology, GIGA Research, University Hospital Sart-Tilman, Liege, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Neuville
authors.affiliation: Department of Rheumatology, GIGA Research, University Hospital Sart-Tilman, Liege, Belgium.
authors.forename: Aline
authors.initials: A
authors.lastname: Desoroux
authors.affiliation: Department of Orthopedic Surgery, University Hospital Sart-Tilman, Liege, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gillet
authors.affiliation: Department of Rheumatology, GIGA Research, University Hospital Sart-Tilman, Liege, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: de Seny
authors.affiliation: Department of Rheumatology, GIGA Research, University Hospital Sart-Tilman, Liege, Belgium.
authors.forename: Michel G
authors.initials: MG
authors.lastname: Malaise
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: C416282:BAY 11-7085; D016328:NF-kappa B; D009570:Nitriles; D047495:PPAR gamma; D011965:Receptors, Glucocorticoid; D013450:Sulfones
keywords: BAY 11-7085; PPAR-γ; autophagy; cell death; glucocorticoid receptor