title: Glucocorticoid dexamethasone down-regulates basal and vitamin D3 induced cathelicidin expression in human monocytes and bronchial epithelial cell line.
abstract: Glucocorticoids (GCs) have been extensively used as the mainstream treatment for chronic inflammatory disorders. The persistent use of steroids in the past decades and the association with secondary infections warrants for detailed investigation into their effects on the innate immune system and the therapeutic outcome. In this study, we analyse the effect of GCs on antimicrobial polypeptide (AMP) expression. We hypothesize that GC related side effects, including secondary infections are a result of compromised innate immune responses. Here, we show that treatment with dexamethasone (Dex) inhibits basal mRNA expression of the following AMPs; human cathelicidin, human beta defensin 1, lysozyme and secretory leukocyte peptidase 1 in the THP-1 monocytic cell-line (THP-1 monocytes). Furthermore, pre-treatment with Dex inhibits vitamin D3 induced cathelicidin expression in THP-1 monocytes, primary monocytes and in the human bronchial epithelial cell line BCi NS 1.1. We also demonstrate that treatment with the glucocorticoid receptor (GR) inhibitor RU486 counteracts Dex mediated down-regulation of basal and vitamin D3 induced cathelicidin expression in THP-1 monocytes. Moreover, we confirmed the anti-inflammatory effect of Dex. Pre-treatment with Dex inhibits dsRNA mimic poly IC induction of the inflammatory chemokine IP10 (CXCL10) and cytokine IL1B mRNA expression in THP-1 monocytes. These results suggest that GCs inhibit innate immune responses, in addition to exerting beneficial anti-inflammatory effects.
authors.affiliation: Biomedical Center and Department of Life and Environmental Sciences, University of Iceland, Reykjavík, Iceland.
authors.forename: Nikhil Nitin
authors.initials: NN
authors.lastname: Kulkarni
authors.affiliation: Biomedical Center and Department of Life and Environmental Sciences, University of Iceland, Reykjavík, Iceland.
authors.forename: Hörður Ingi
authors.initials: HI
authors.lastname: Gunnarsson
authors.affiliation: Biomedical Center and Department of Life and Environmental Sciences, University of Iceland, Reykjavík, Iceland.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Yi
authors.affiliation: Faculty of Medicine, School of Health Sciences, Department of Anatomy, Biomedical Center, University of Iceland, Reykjavik, Iceland.
authors.forename: Steinunn
authors.initials: S
authors.lastname: Gudmundsdottir
authors.affiliation: Biomedical Center and Department of Life and Environmental Sciences, University of Iceland, Reykjavík, Iceland; The Blood Bank, Landspitali University Hospital, Reykjavik, Iceland; Institute of Biomedical and Neural Engineering, School of Science and Engineering, Reykjavik University, Reykjavik, Iceland.
authors.forename: Olafur E
authors.initials: OE
authors.lastname: Sigurjonsson
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology Karolinska University Hospital, Karolinska Institutet, Huddinge, Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Agerberth
authors.affiliation: Biomedical Center and Department of Life and Environmental Sciences, University of Iceland, Reykjavík, Iceland. Electronic address: ghrafn@hi.is.
authors.forename: Gudmundur H
authors.initials: GH
authors.lastname: Gudmundsson
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D002454:Cell Differentiation; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology; D002762:Cholecalciferol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D015735:Mifepristone / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009113:Muramidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction; D023083:beta-Defensins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C406407:DEFB1 protein, human; D005938:Glucocorticoids; D053583:Interleukin-1beta; D011965:Receptors, Glucocorticoid; D023083:beta-Defensins; D002762:Cholecalciferol; D015735:Mifepristone; D003907:Dexamethasone; D009113:Muramidase; D011070:Poly I-C; D054804:Cathelicidins
keywords: Anti-inflammatory; Antimicrobial polypeptides; CAMP gene; Glucocorticoid Receptor; LL-37