title: Glucocorticoid-induced leucine zipper: a critical factor in macrophage endotoxin tolerance.
abstract: Induction of glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a key role in their anti-inflammatory action. In activated macrophages, GILZ levels are downregulated via tristetraprolin-mediated GILZ mRNA destabilization. To assess the functional significance of GILZ downregulation, we generated myeloid-specific GILZ knockout (KO) mice. GILZ-deficient macrophages displayed a higher responsiveness toward LPS, as indicated by increased TNF-α and IL-1β expression. This effect was due to an activation of ERK, which was significantly amplified in GILZ KO cells. The LPS-induced activation of macrophages is attenuated upon pretreatment of macrophages with low-dose LPS, an effect termed endotoxin tolerance. In LPS-tolerant macrophages, GILZ mRNA was stabilized, whereas ERK activation was strongly decreased. In contrast, GILZ KO macrophages exhibited a strongly reduced desensitization. To explore the contribution of GILZ expression in macrophages to endotoxin tolerance in vivo, we treated GILZ KO mice with repeated i.p. injections of low-dose LPS followed by treatment with high-dose LPS. LPS pretreatment resulted in reduced proinflammatory mediator expression upon high-dose LPS treatment in serum and tissues. In contrast, cytokine induction was preserved in tolerized GILZ KO animals. In summary, our data suggest that GILZ is a key regulator of macrophage functions.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany;
authors.forename: Jessica
authors.initials: J
authors.lastname: Hoppstädter
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany;
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Kessler
authors.affiliation: Section of Pharmacology, Department of Medicine, University of Perugia, 06100 Perugia, Italy; and.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bruscoli
authors.affiliation: Department of Cardiothoracic Surgery, Völklingen Heart Centre, 66333 Völklingen, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Huwer
authors.affiliation: Section of Pharmacology, Department of Medicine, University of Perugia, 06100 Perugia, Italy; and.
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, 66041 Saarbrücken, Germany; pharm.bio.kiemer@mx.uni-saarland.de.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Kiemer
mesh_terms: D000818:Animals; D002460:Cell Line; D004731:Endotoxins / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
chemical_list: C498608:Dsip1 protein, mouse; D004731:Endotoxins; D008070:Lipopolysaccharides; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases