TY - JOUR
T1 - Cell-type-specific downregulation of heme oxygenase-1 by lipopolysaccharide via Bach1 in primary human mononuclear cells
AU - Dorresteijn, Mirrin J.
AU - Paine, Ananta
AU - Zilian, Eva
AU - Fenten, Maaike G. E.
AU - Frenzel, Eileen
AU - Janciauskiene, Sabina
AU - Figueiredo, Constanca
AU - Eiz-Vesper, Britta
AU - Blasczyk, Rainer
AU - Dekker, Douwe
AU - Pennings, Bas
AU - Scharstuhl, Alwin
AU - Smits, Paul
AU - Larmann, Jan
AU - Theilmeier, Gregor
AU - van der Hoeven, Johannes G.
AU - Wagener, Frank A. D. T. G.
AU - Pickkers, Peter
AU - Immenschuh, Stephan
PY - 2015/1
Y1 - 2015/1
N2 - 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.
AB - 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.
KW - Bach1
KW - Heme oxygenase-1
KW - Inflammation
KW - Lipopolysaccharide
KW - Mononuclear cells
KW - Toll-like receptor
KW - RAT KUPFFER CELLS
KW - GENE-EXPRESSION
KW - NITRIC-OXIDE
KW - IMMUNE-RESPONSE
KW - INFLAMMATORY RESPONSE
KW - SIGNALING PATHWAY
KW - REPRESSOR BACH1
KW - UP-REGULATION
KW - MONOXIDE
KW - PROTEIN
U2 - 10.1016/j.freeradbiomed.2014.10.579
DO - 10.1016/j.freeradbiomed.2014.10.579
M3 - Article
C2 - 25463280
SN - 0891-5849
VL - 78
SP - 224
EP - 232
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -