title: Cell-type-specific downregulation of heme oxygenase-1 by lipopolysaccharide via Bach1 in primary human mononuclear cells.
abstract: Heme oxygenase (HO)-1 is the inducible isoform of the heme-degrading enzyme HO, which is upregulated by multiple stress stimuli. HO-1 has major immunomodulatory and anti-inflammatory effects via its cell-type-specific functions in mononuclear cells. Contradictory findings have been reported on HO-1 regulation by the Toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS) in these cells. Therefore, we reinvestigated the effects of LPS on HO-1 gene expression in human and murine mononuclear cells in vitro and in vivo. Remarkably, LPS downregulated HO-1 in primary human peripheral blood mononuclear cells (PBMCs), CD14(+) monocytes, macrophages, dendritic cells, and granulocytes, but upregulated this enzyme in primary murine macrophages and human monocytic leukemia cell lines. Furthermore, experiments with human CD14(+) monocytes revealed that activation of other TLRs including TLR1, -2, -5, -6, -8, and -9 decreased HO-1 mRNA expression. LPS-dependent downregulation of HO-1 was specific, because expression of cyclooxygenase-2, NADP(H)-quinone oxidoreductase-1, and peroxiredoxin-1 was increased under the same experimental conditions. Notably, LPS upregulated expression of Bach1, a critical transcriptional repressor of HO-1. Moreover, knockdown of this nuclear factor enhanced basal and LPS-dependent HO-1 expression in mononuclear cells. Finally, downregulation of HO-1 in response to LPS was confirmed in PBMCs from human individuals subjected to experimental endotoxemia. In conclusion, LPS downregulates HO-1 expression in primary human mononuclear cells via a Bach1-mediated pathway. As LPS-dependent HO-1 regulation is cell-type- and species-specific, experimental findings in cell lines and animal models need careful interpretation.
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Department of Pharmacology and Toxicology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Mirrin J
authors.initials: MJ
authors.lastname: Dorresteijn
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Ananta
authors.initials: A
authors.lastname: Paine
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Zilian
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Department of Pharmacology and Toxicology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Maaike G E
authors.initials: MG
authors.lastname: Fenten
authors.affiliation: Department of Internal Medicine-Respiratory Medicine, Hannover Medical School, 30635 Hannover, Germany.
authors.forename: Eileen
authors.initials: E
authors.lastname: Frenzel
authors.affiliation: Department of Internal Medicine-Respiratory Medicine, Hannover Medical School, 30635 Hannover, Germany.
authors.forename: Sabina
authors.initials: S
authors.lastname: Janciauskiene
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Constanca
authors.initials: C
authors.lastname: Figueiredo
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Eiz-Vesper
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Blasczyk
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Douwe
authors.initials: D
authors.lastname: Dekker
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 Nijmegen, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Pennings
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Alwin
authors.initials: A
authors.lastname: Scharstuhl
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Smits
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Larmann
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Theilmeier
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Nijmegen Center for Infectious Diseases, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.affiliation: Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 Nijmegen, The Netherlands.
authors.forename: Frank A D T G
authors.initials: FA
authors.lastname: Wagener
authors.affiliation: Department of Intensive Care Medicine, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; Nijmegen Center for Infectious Diseases, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany. Electronic address: Immenschuh.Stephan@mh-hannover.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Immenschuh
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015536:Down-Regulation; D019446:Endotoxemia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051547:Heme Oxygenase-1
keywords: Bach1; Heme oxygenase-1; Inflammation; Lipopolysaccharide; Mononuclear cells; Toll-like receptor