Cell-type-specific downregulation of heme oxygenase-1 by lipopolysaccharide via Bach1 in primary human mononuclear cells

Mirrin J. Dorresteijn, Ananta Paine, Eva Zilian, Maaike G. E. Fenten, Eileen Frenzel, Sabina Janciauskiene, Constanca Figueiredo, Britta Eiz-Vesper, Rainer Blasczyk, Douwe Dekker, Bas Pennings, Alwin Scharstuhl, Paul Smits, Jan Larmann, Gregor Theilmeier, Johannes G. van der Hoeven, Frank A. D. T. G. Wagener, Peter Pickkers, Stephan Immenschuh*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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. (C) 2014 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)224-232
Number of pages9
JournalFree Radical Biology and Medicine
Volume78
DOIs
Publication statusPublished - Jan 2015

Keywords

  • Bach1
  • Heme oxygenase-1
  • Inflammation
  • Lipopolysaccharide
  • Mononuclear cells
  • Toll-like receptor
  • RAT KUPFFER CELLS
  • GENE-EXPRESSION
  • NITRIC-OXIDE
  • IMMUNE-RESPONSE
  • INFLAMMATORY RESPONSE
  • SIGNALING PATHWAY
  • REPRESSOR BACH1
  • UP-REGULATION
  • MONOXIDE
  • PROTEIN

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