Role of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids.

TitleRole of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids.
Publication TypeJournal Article
Year of Publication2012
AuthorsChinenov Y, Gupte R, Dobrovolna J, Flammer JR, Liu B, Michelassi FE, Rogatsky I
JournalProc Natl Acad Sci U S A
Volume109
Issue29
Pagination11776-81
Date Published2012 Jul 17
ISSN1091-6490
KeywordsAdaptor Proteins, Signal Transducing, Animals, Anti-Inflammatory Agents, Cells, Cultured, Chromatin Immunoprecipitation, Cytokines, Gene Expression Profiling, Gene Expression Regulation, Glucocorticoids, Immunoblotting, Macrophages, Mice, Mice, Transgenic, Nerve Tissue Proteins, Real-Time Polymerase Chain Reaction, Receptors, Glucocorticoid, Sequence Analysis, RNA, Survival Analysis, Transcription Factor RelA
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.

DOI10.1073/pnas.1206059109
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID22753499
PubMed Central IDPMC3406827

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