Cell-type-specific downregulation of heme oxygenase-1 by lipopolysaccharide via Bach1 in primary human mononuclear cells
Dorresteijn, Mirrin J.; Paine, Ananta; Zilian, Eva; Fenten, Maaike G. E.; Frenzel, Eileen; Janciauskiene, Sabina; Figueiredo, Constanca; Eiz-Vesper, Britta; Blasczyk, Rainer; Dekker, Douwe; Pennings, Bas; Scharstuhl, Alwin; Smits, Paul; Larmann, Jan; Theilmeier, Gregor; van der Hoeven, Johannes G.; Wagener, Frank A. D. T. G.; Pickkers, Peter; Immenschuh, Stephan
(2015) Free Radical Biology and Medicine, volume 78, pp. 224 - 232
(Article)
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)
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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.
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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, Journal Article, Research Support, Non-U.S. Gov't
ISSN: 0891-5849
Publisher: Elsevier Inc.
(Peer reviewed)