title: Glucocorticoid-induced leucine zipper is downregulated in human alveolar macrophages upon Toll-like receptor activation.
abstract: Induction of the glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a role in their antiinflammatory action, whereas GILZ expression is reduced under inflammatory conditions. The mechanisms regulating GILZ expression during inflammation, however, have not yet been characterized. Here, we investigated GILZ expression in human alveolar macrophages (AMs) following Toll-like receptor (TLR) activation. Macrophages were shown to predominantly express GILZ transcript variant 2. Lipopolysaccharide-treated AMs, THP-1 cells, and lungs of lipopolysaccharide-exposed mice displayed decreased GILZ protein and mRNA levels. The effect was strictly dependent on the adapter molecule MyD88, as shown by using specific ligands or a knockdown strategy. Investigations on the functional significance of GILZ downregulation performed by GILZ knockdown revealed a proinflammatory response, as indicated by increased cytokine expression and NF-κB activity. We found that TLR activation reduced GILZ mRNA stability, which was mediated via the GILZ 3'-untranslated region. Finally, involvement of the mRNA-binding protein tristetraprolin (TTP) is suggested, since TTP overexpression or knockdown modulated GILZ expression and TTP was induced in a MyD88-dependent fashion. Taken together, our data show a MyD88- and TTP-dependent GILZ downreg-ulation in human macrophages upon TLR activation. Suppression of GILZ is mediated by mRNA destabilization, which might represent a regulatory mechanism in macrophage activation.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hoppstädter
authors.forename: Britta
authors.initials: B
authors.lastname: Diesel
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Eifler
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmid
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Kiemer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008262:Macrophage Activation / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000276:immunology; D051816:Tristetraprolin / Q000378:metabolism
chemical_list: D016207:Cytokines; C498608:Dsip1 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C499045:TIRAP protein, mouse; C404226:TSC22D3 protein, human; D051193:Toll-Like Receptors; D014157:Transcription Factors; D051816:Tristetraprolin; C497552:ZFP36 protein, human; C497553:Zfp36 protein, mouse