RRC ID 34921
Author Yamazaki S, Akira S, Sumimoto H.
Title Glucocorticoid augments lipopolysaccharide-induced activation of the IκBζ-dependent genes encoding the anti-microbial glycoproteins lipocalin 2 and pentraxin 3.
Journal J Biochem
Abstract Bacterial lipopolysaccharide (LPS), one of the most potent inducers of inflammation, activates the transcription factor NF-κB to induce expression of both proinflammatory mediators and anti-microbial glycoproteins such as lipocalin 2 (Lcn2) and pentraxin 3 (PTX3) in macrophages. Glucocorticoids are known to inhibit LPS-induced expression of proinflammatory cytokines via glucocorticoid receptor (GR)-mediated transrepression of NF-κB, whereas their effect on induction of anti-microbial effectors has remained to be elucidated. Here we show that the synthetic glucocorticoid dexamethasone (Dex) strongly enhances LPS-induced transcription of Lcn2 and Ptx3, although Dex by itself fails to trigger their transcription. In macrophages deficient in IκBζ (an inducible coactivator of NF-κB), Lcn2 and Ptx3 are not activated by LPS either alone or in combination with Dex. Association of GR as well as Brg1 (a subunit of the chromatin remodelling Swi/Snf complex) with a functional glucocorticoid response element in Lcn2 requires both the costimulation with LPS and the presence of IκBζ. Although Ptx3 does not contain the element, LPS induces recruitment of Dex-liganded GR to NF-κB-binding sites in regulatory regions of Ptx3, an event that does not occur in IκBζ-deficient macrophages. Thus glucocorticoids likely regulate infection-induced inflammation by increasing anti-microbial effectors in an IκBζ-dependent manner, while repressing proinflammatory genes.
Volume 157(5)
Pages 399-410
Published 2015-5-1
DOI 10.1093/jb/mvu086
PII mvu086
PMID 25552549
MeSH Acute-Phase Proteins / genetics* Animals Anti-Infective Agents / pharmacology* C-Reactive Protein / genetics* Cell Line Glucocorticoids / pharmacology* I-kappa B Kinase / genetics* Lipocalin-2 Lipocalins / genetics* Lipopolysaccharides / pharmacology* Mice Nerve Tissue Proteins / genetics* Oncogene Proteins / genetics*
IF 2.476
Times Cited 8
DNA material Lcn2 promoter (RDB13670) Lcn2 CEBP mutant promoter (RDB13671) Lcn2 NF kappa B mutant promoter (RDB13672) Lcn2 GRE-1 mutant promoter (RDB13673) Lcn2 GRE-2 mutant promoter (RDB13674) Lcn2 GRE-3 mutant promoter (RDB13675) Ptx3 promoter (RDB13676) Ptx3 NF kappa B-1 mutant promoter (RDB13677) Ptx3 GRE-1 mutant promoter (RDB13678) Ptx3 CEBP-1 mutant promoter (RDB13679) Ptx3 GRE-2 mutant promoter (RDB13680) Ptx3 CEBP-2 mutant promoter (RDB13681) Ptx3 CEBP-3 mutant promoter (RDB13682) Ptx3 NF kappa B-2 mutant promoter (RDB13683).