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Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin‐1 in macrophages
Author(s) -
Kleiman Anna,
Hübner Sabine,
Parkitna Jan M. Rodriguez,
Neumann Anita,
Hofer Stefan,
Weigand Markus A.,
Bauer Michael,
Schmid Wolfgang,
Schütz Gunter,
Libert Claude,
Reichardt Holger M.,
Tuckermann Jan P.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-192112
Subject(s) - septic shock , glucocorticoid receptor , lipopolysaccharide , sepsis , proinflammatory cytokine , receptor , interleukin , glucocorticoid , immunology , biology , chemistry , microbiology and biotechnology , inflammation , medicine , cytokine
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.—Kleiman, A., Hübner, S., Rodriguez Parkitna, J. M., Neumann, A., Hofer, S., Weigand, M. A., Bauer, M., Schmid, W., Schütz, G., Libert, C., Reichardt, H. M., Tuckermann, J. P. Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin‐1 in macrophages. FASEB J. 26, 722–729 (2012). www.fasebj.org