Glucocorticoid Receptor Dimerization Is Required for Survival in Septic Shock via Suppression of interleukin-1 in Macrophages

FASEB J. 2012 Feb;26(2):722-9. doi: 10.1096/fj.11-192112. Epub 2011 Oct 31.

Abstract

Sepsis is controlled by endogenous glucocorticoids (GCs). Previous studies provided evidence that crosstalk of the monomeric GC receptor (GR) with proinflammatory transcription factors is the crucial mechanism underlying the suppressive GC effect. Here we demonstrate that mice with a dimerization-deficient GR (GR(dim)) are highly susceptible to sepsis in 2 different models, namely cecal ligation and puncture and lipopolysaccharide (LPS)-induced septic shock. TNF-α is normally regulated in these mice, but down-regulation of IL-6 and IL-1β is diminished. LPS-treated macrophages derived from GR(dim) mice are largely resistant to GC actions in vitro in terms of morphology, surface marker expression, and gene expression. Treatment with recombinant IL-1 receptor antagonist improved survival of GR(dim) mice and mice lacking the GR in macrophages (GR(LysMCre)) mice. This suggests that regulation of IL-1β in macrophages by GCs is pivotal to control sepsis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dexamethasone / pharmacology
  • Dimerization
  • Disease Models, Animal
  • Down-Regulation
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism*
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / toxicity
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Protein Structure, Quaternary
  • RNA / chemistry
  • RNA / genetics
  • RNA / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Glucocorticoid / chemistry*
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Shock, Septic / genetics
  • Shock, Septic / metabolism*
  • Signal Transduction
  • Transcriptome
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Interleukin-1beta
  • Interleukin-6
  • Lipopolysaccharides
  • RNA, Messenger
  • RNA, recombinant
  • Receptors, Glucocorticoid
  • Receptors, Interleukin-1
  • Tumor Necrosis Factor-alpha
  • RNA
  • Dexamethasone