title: Cell type-dependent divergence of transactivation by glucocorticoid receptor ligand.
abstract: The glucocorticoid receptor regulates gene expression mainly by two mechanisms; transactivation and trans-repression. A ligand with strong transrepression and weak transactivation activity is predicted to be a beneficial agent with potent anti-inflammatory activity and minor adverse effects. Recently, the profile of a synthetic steroid, RU24858, has been reported to fulfill this condition in vitro, but others have reported no dissociation between the anti-inflammatory activity and side effects in vivo. To gain further information on the profile of this compound, we evaluated its transactivation ability using a reporter gene analysis both in vitro and in vivo. In the in vitro analysis, RU24858 demonstrated only a weak transactivation activity in HeLa cells, when compared with prednisolone. In CV-1 cells, however, these two glucocorticoids exhibited equivalent transactivation activities. This behavior is independent of whether the reporter gene is regulated by mouse mammary tumor virus promoter or multiple copies of glucocorticoid response element. When the reporter plasmid was inoculated into mouse abdominal skin using a gene gun, followed by orally administration of glucocorticoids, RU24858 induced significantly higher reporter enzyme activity than prednisolone. These results suggest that the profile of RU24858 is divergent and its transactivation ability is comparable to prednisolone depending on the cell-type both in vitro and in vivo.
authors.affiliation: Pharmacobioregulation Research Laboratory, Taiho Pharmaceutical Co, Ltd, Hanno, Saitama, Japan. k-tanigawa@taiho.co.jp
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Tanigawa
authors.forename: Katsunao
authors.initials: K
authors.lastname: Tanaka
authors.forename: Hideki
authors.initials: H
authors.lastname: Nagase
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Miyake
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kiniwa
authors.forename: Koichi
authors.initials: K
authors.lastname: Ikizawa
mesh_terms: D000818:Animals; D019470:Biolistics; D003899:Desoximetasone / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D006889:Hydroxycorticosteroids; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010957:Plasmids / Q000008:administration & dosage; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D005938:Glucocorticoids; D006889:Hydroxycorticosteroids; D008024:Ligands; C000589029:RU24858; D011965:Receptors, Glucocorticoid; D003899:Desoximetasone