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Immunobiology. 2017 Jun;222(6):846-857. doi: 10.1016/j.imbio.2017.05.006. Epub 2017 May 31.

Reprint of: Heme oxygenase 1 affects granulopoiesis in mice through control of myelocyte proliferation.

Author information

1
Department of Medical Biotechnology, Faculty Of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Department of Clinical Immunology and Transplantology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.
2
Department of Medical Biotechnology, Faculty Of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
3
AGH University of Science and Technology, Faculty of Metal Engineering and Industrial Computer Science, Department of Heat Engineering and Environment Protection, Poland.
4
Department of Radioligands, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
5
Department of Clinical Immunology and Transplantology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.
6
Department of Medical Biotechnology, Faculty Of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. Electronic address: alicja.jozkowicz@uj.edu.pl.

Abstract

Heme oxygenase-1 (HO-1) is stress-inducible, cytoprotective enzyme degrading heme to carbon monoxide (CO), biliverdin and Fe2+. We showed that HO-1 knock-out mice (HO-1-/-) have a twofold higher level of granulocytes than wild type (WT) mice, despite decreased concentration of granulocyte colony-stimulating factor (G-CSF) in the blood and reduced surface expression of G-CSF receptor on the hematopoietic precursors. This suggests the effect of HO-1 on granulopoiesis. Here we aimed to determine the stage of granulopoiesis regulated by HO-1. The earliest stages of hematopoiesis were not biased toward myeloid differentiation in HO-1-/- mice. Within committed granulocytic compartment, in WT mice, HO-1 was up-regulated starting from myelocyte stage. This was concomitant with up-regulation of miR-155, which targets Bach1, the HO-1 repressor. In HO-1-/- mice granulopoiesis was accelerated between myelocyte and metamyelocyte stage. There was a higher fraction of proliferating myelocytes, with increased nuclear expression of pro-proliferative C/EBPβ (CCAAT/enhancer binding protein beta) protein, especially its active LAP (liver-enriched activator proteins) isoform. Also our mathematical model confirmed shortening the myelocyte cyclic-time and prolonged mitotic expansion in absence of HO-1. It seems that changes in C/EBPβ expression and activity in HO-1-/- myelocytes can be associated with reduced level of its direct repressor miR-155 or with decreased concentration of CO, known to reduce nuclear translocation of C/EBPs. Mature HO-1-/- granulocytes were functionally competent as determined by oxidative burst capacity. In conclusion, HO-1 influences granulopoiesis through regulation of myelocyte proliferation. It is accompanied by changes in expression of transcriptionally active C/EBPβ protein. As HO-1 expression vary in human and is up-regulated in response to chemotherapy, it can potentially influence chemotherapy-induced neutropenia.

KEYWORDS:

C/EBPβ; Carbon monoxide; Granulocyte colony-stimulating factor; Granulopoiesis; Heme oxygenase 1

PMID:
28576353
DOI:
10.1016/j.imbio.2017.05.006
[Indexed for MEDLINE]

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