title: Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells.
abstract: Despite several side effects, glucocorticoids (GCs) have been widely used for 60 y to treat rheumatoid arthritis on the basis of their antiinflammatory effects. However, the cells targeted by GCs and the transcriptional mechanisms underlying their actions through the glucocorticoid receptor (GR) in steroid therapy remain poorly defined. Using cell type-specific GR-deficient mice subjected to antigen-induced arthritis (AIA) as a model of human rheumatoid arthritis, we show that GC action on T cells but not myeloid cells is critical for therapeutic intervention in AIA. Furthermore, the resistance of mice expressing a DNA binding-defective GR (GR(dim)) to GC treatment reveals that dimerization of the GR is indispensable for the antiinflammatory effects. In these mice, the GC-induced suppression of T(H)1 and T(H)17 cell-derived proinflammatory cytokines is impaired. Our finding that IL-17A(-/-) mice are resistant to GC therapy, whereas IFN-γ(-/-) mice respond as efficiently as WT mice implies that IL-17-producing T cells and not IFN-γ-producing T cells are the most important targets for an efficient GC therapy. The present study's identification of the critical cell type and the mode of GR action in steroid therapy of AIA significantly advances our understanding of steroid therapy and should lead to therapies with greater efficiency and fewer side effects.
authors.affiliation: Tissue Specific Hormone Action,  Leibniz Institute for Age Research-Fritz Lipmann Institute, 07745 Jena,  Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Baschant
authors.forename: Lucien
authors.initials: L
authors.lastname: Frappart
authors.forename: Una
authors.initials: U
authors.lastname: Rauchhaus
authors.forename: Lisa
authors.initials: L
authors.lastname: Bruns
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
authors.forename: Thomas
authors.initials: T
authors.lastname: Kamradt
authors.forename: Rolf
authors.initials: R
authors.lastname: Bräuer
authors.forename: Jan P
authors.initials: JP
authors.lastname: Tuckermann
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy*; D016207:Cytokines / Q000097:blood; D019281:Dimerization; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D005620:Freund's Adjuvant / Q000633:toxicity; D005938:Glucocorticoids / Q000378:metabolism / Q000627:therapeutic use*; D005956:Glucose-6-Phosphate Isomerase / Q000633:toxicity; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D007596:Joints / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000633:toxicity; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D016207:Cytokines; D005938:Glucocorticoids; D020381:Interleukin-17; D011965:Receptors, Glucocorticoid; D012710:Serum Albumin, Bovine; D007371:Interferon-gamma; D005620:Freund's Adjuvant; D005956:Glucose-6-Phosphate Isomerase; D016650:Fluorescein-5-isothiocyanate
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