Role of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids Academic Article uri icon

Overview

MeSH Major

  • Adaptor Proteins, Signal Transducing
  • Anti-Inflammatory Agents
  • Cytokines
  • Gene Expression Regulation
  • Glucocorticoids
  • Nerve Tissue Proteins
  • Receptors, Glucocorticoid

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.

publication date

  • July 17, 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3406827

Digital Object Identifier (DOI)

  • 10.1073/pnas.1206059109

PubMed ID

  • 22753499

Additional Document Info

start page

  • 11776

end page

  • 81

volume

  • 109

number

  • 29