title: Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin-1 in macrophages.
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.
authors: Tissue-Specific Hormone Action, Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors: Anna
authors: A
authors: Kleiman
authors: Sabine
authors: S
authors: Hübner
authors: Jan M
authors: JM
authors: Rodriguez Parkitna
authors: Anita
authors: A
authors: Neumann
authors: Stefan
authors: S
authors: Hofer
authors: Markus A
authors: MA
authors: Weigand
authors: Michael
authors: M
authors: Bauer
authors: Wolfgang
authors: W
authors: Schmid
authors: Günter
authors: G
authors: Schütz
authors: Claude
authors: C
authors: Libert
authors: Holger M
authors: HM
authors: Reichardt
authors: Jan P
authors: JP
authors: Tuckermann
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D019281:Dimerization; D004195:Disease Models, Animal; D015536:Down-Regulation; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D020836:Protein Structure, Quaternary; D012313:RNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D012772:Shock, Septic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C039919:RNA, recombinant; D011965:Receptors, Glucocorticoid; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D003907:Dexamethasone