title: Role of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids.
abstract: Inhibition of cytokine gene expression by the hormone-activated glucocorticoid receptor (GR) is the key component of the anti-inflammatory actions of glucocorticoids, yet the underlying molecular mechanisms remain obscure. Here we report that glucocorticoid repression of cytokine genes in primary macrophages is mediated by GR-interacting protein (GRIP)1, a transcriptional coregulator of the p160 family, which is recruited to the p65-occupied genomic NFκB-binding sites in conjunction with liganded GR. We created a mouse strain enabling a conditional hematopoietic cell-restricted deletion of GRIP1 in adult animals. In this model, GRIP1 depletion in macrophages attenuated in a dose-dependent manner repression of NFκB target genes by GR irrespective of the upstream Toll-like receptor pathway responsible for their activation. Furthermore, genome-wide transcriptome analysis revealed a broad derepression of lipopolysaccharide (LPS)-induced glucocorticoid-sensitive targets in GRIP1-depleted macrophages without affecting their activation by LPS. Consistently, conditional GRIP1-deficient mice were sensitized, relative to the wild type, to a systemic inflammatory challenge developing characteristic signs of LPS-induced shock. Thus, by serving as a GR corepressor, GRIP1 facilitates the anti-inflammatory effects of glucocorticoids in vivo.
authors: Hospital for Special Surgery Research Division, New York, NY 10021, USA.
authors: Yurii
authors: Y
authors: Chinenov
authors: Rebecca
authors: R
authors: Gupte
authors: Jana
authors: J
authors: Dobrovolna
authors: Jamie R
authors: JR
authors: Flammer
authors: Bill
authors: B
authors: Liu
authors: Francesco E
authors: FE
authors: Michelassi
authors: Inez
authors: I
authors: Rogatsky
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000037:antagonists & inhibitors*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D005938:Glucocorticoids / Q000276:immunology*; D015151:Immunoblotting; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000276:immunology*; D017423:Sequence Analysis, RNA; D016019:Survival Analysis; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005938:Glucocorticoids; C491309:Grip1 protein, mouse; D009419:Nerve Tissue Proteins; D011965:Receptors, Glucocorticoid; D051996:Transcription Factor RelA