Glucocorticoid receptor represses proinflammatory genes at distinct steps of the transcription cycle

Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14616-21. doi: 10.1073/pnas.1309898110. Epub 2013 Aug 15.

Abstract

Widespread anti-inflammatory actions of glucocorticoid hormones are mediated by the glucocorticoid receptor (GR), a ligand-dependent transcription factor of the nuclear receptor superfamily. In conjunction with its corepressor GR-interacting protein-1 (GRIP1), GR tethers to the DNA-bound activator protein-1 and NF-κB and represses transcription of their target proinflammatory cytokine genes. However, these target genes fall into distinct classes depending on the step of the transcription cycle that is rate-limiting for their activation: Some are controlled through RNA polymerase II (PolII) recruitment and initiation, whereas others undergo signal-induced release of paused elongation complexes into productive RNA synthesis. Whether these genes are differentially regulated by GR is unknown. Here we report that, at the initiation-controlled inflammatory genes in primary macrophages, GR inhibited LPS-induced PolII occupancy. In contrast, at the elongation-controlled genes, GR did not affect PolII recruitment or transcription initiation but promoted, in a GRIP1-dependent manner, the accumulation of the pause-inducing negative elongation factor. Consistently, GR-dependent repression of elongation-controlled genes was abolished specifically in negative elongation factor-deficient macrophages. Thus, GR:GRIP1 use distinct mechanisms to repress inflammatory genes at different stages of the transcription cycle.

Keywords: NELF and P-TEFb complex; inflammation; initiation and elongation; transcriptional repression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Cells, Cultured
  • Cytokines / genetics*
  • Dexamethasone / pharmacology
  • Gene Expression Regulation*
  • Immunoblotting
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / pharmacology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Positive Transcriptional Elongation Factor B / genetics
  • Positive Transcriptional Elongation Factor B / metabolism
  • RNA Polymerase II / metabolism
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic / genetics*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Grip1 protein, mouse
  • Inflammation Mediators
  • Lipopolysaccharides
  • NF-kappa B
  • Nerve Tissue Proteins
  • Receptors, Glucocorticoid
  • Transcription Factors
  • negative elongation factor
  • Dexamethasone
  • Positive Transcriptional Elongation Factor B
  • RNA Polymerase II