Heme oxygenase 1 affects granulopoiesis in mice through control of myelocyte proliferation.
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.
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.
Karolina
K
Bukowska-Strakova
Department of Medical Biotechnology, Faculty Of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Maciej
M
Ciesla
Department of Medical Biotechnology, Faculty Of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Krzysztof
K
Szade
Department of Medical Biotechnology, Faculty Of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Witold Norbert
WN
Nowak
AGH University of Science and Technology, Faculty of Metal Engineering and Industrial Computer Science, Department of Heat Engineering and Environment Protection, Poland.
Robert
R
Straka
Department of Medical Biotechnology, Faculty Of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Agata
A
Szade
Department of Radioligands, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
Malgorzata
M
Tyszka-Czochara
Department of Medical Biotechnology, Faculty Of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Karolina
K
Najder
Department of Medical Biotechnology, Faculty Of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Anna
A
Konturek
Department of Clinical Immunology and Transplantology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.
Maciej
M
Siedlar
Department of Medical Biotechnology, Faculty Of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Jozef
J
Dulak
Department of Medical Biotechnology, Faculty Of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. Electronic address: alicja.jozkowicz@uj.edu.pl.
Alicja
A
Jozkowicz
D000818:Animals; D015415:Biomarkers; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000378:metabolism; D042381:Granulocyte Precursor Cells / Q000166:cytology* / Q000378:metabolism*; D006098:Granulocytes / Q000166:cytology* / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D016130:Immunophenotyping; D007958:Leukocyte Count; D051379:Mice; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism
D015415:Biomarkers; D022762:CCAAT-Enhancer-Binding Proteins; D017382:Reactive Oxygen Species; D016179:Granulocyte Colony-Stimulating Factor; D051547:Heme Oxygenase-1
C/EBPβ; Carbon monoxide; Granulocyte colony-stimulating factor; Granulopoiesis; Heme oxygenase 1