title: Glucocorticoid augments lipopolysaccharide-induced activation of the IκBζ-dependent genes encoding the anti-microbial glycoproteins lipocalin 2 and pentraxin 3.
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.
authors.affiliation: Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan; Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; and Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan syamaz@mailserver.med.kyushu-u.ac.jp.
authors.forename: Soh
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan; Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; and Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan; Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; and Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan; Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; and Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan hsumi@med.kyushu-u.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Sumimoto
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics*; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000235:genetics*; D002460:Cell Line; D005938:Glucocorticoids / Q000494:pharmacology*; D051550:I-kappa B Kinase / Q000235:genetics*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D000099153:Pentraxins
chemical_list: D000209:Acute-Phase Proteins; D000890:Anti-Infective Agents; D002097:C-Reactive Protein; D005938:Glucocorticoids; D051550:I-kappa B Kinase; D000071068:Lipocalin-2; D054834:Lipocalins; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D000099153:Pentraxins; C071332:Lcn2 protein, mouse
keywords: dexamethasone; glucocorticoid; lipocalin 2; pentraxin 3; signal transduction