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TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment
BACKGROUND: Secondary bone marrow (BM) myelodysplastic syndromes (MDS) are increasingly common, as a result of radio or chemotherapy administered to a majority of cancer patients. Patients with secondary MDS have increased BM cell apoptosis, which results in BM dysfunction (cytopenias), and an incre...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813873/ https://www.ncbi.nlm.nih.gov/pubmed/20126546 http://dx.doi.org/10.1371/journal.pone.0008980 |
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author | Cachaço, Ana Sofia Carvalho, Tânia Santos, Ana Cristina Igreja, Cátia Fragoso, Rita Osório, Catarina Ferreira, Manuela Serpa, Jacinta Correia, Sofia Pinto-do-Ó, Perpétua Dias, Sérgio |
author_facet | Cachaço, Ana Sofia Carvalho, Tânia Santos, Ana Cristina Igreja, Cátia Fragoso, Rita Osório, Catarina Ferreira, Manuela Serpa, Jacinta Correia, Sofia Pinto-do-Ó, Perpétua Dias, Sérgio |
author_sort | Cachaço, Ana Sofia |
collection | PubMed |
description | BACKGROUND: Secondary bone marrow (BM) myelodysplastic syndromes (MDS) are increasingly common, as a result of radio or chemotherapy administered to a majority of cancer patients. Patients with secondary MDS have increased BM cell apoptosis, which results in BM dysfunction (cytopenias), and an increased risk of developing fatal acute leukemias. In the present study we asked whether TNF-α, known to regulate cell apoptosis, could modulate the onset of secondary MDS. PRINCIPAL FINDINGS: We show that TNF-α is induced by irradiation and regulates BM cells apoptosis in vitro and in vivo. In contrast to irradiated wild type (WT) mice, TNF-α deficient (TNF-α KO) mice or WT mice treated with a TNF-α-neutralizing antibody were partially protected from the apoptotic effects of irradiation. Next we established a 3-cycle irradiation protocol, in which mice were sub-lethally irradiated once monthly over a 3 month period. In this model, irradiated WT mice presented loss of microsatellite markers on BM cells, low white blood cell (WBC) counts, reduced megakaryocyte (MK) and platelet levels (thrombocytopenia) and macrocytic anemia, phenoypes that suggest the irradiation protocol resulted in BM dysfunction with clinical features of MDS. In contrast, TNF-α KO mice were protected from the irradiation effects: BM cell apoptosis following irradiation was significantly reduced, concomitant with sustained BM MK numbers and absence of other cytopenias. Moreover, irradiated WT mice with long term (≥5 months) BM dysfunction had increased BM angiogenesis, MMPs and VEGF and NFkB p65, suggestive of disease progression. CONCLUSION: Taken together, our data shows that TNF-α induction following irradiation modulates BM cell apoptosis and is a crucial event in BM dysfunction, secondary MDS onset and progression. |
format | Text |
id | pubmed-2813873 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-28138732010-02-02 TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment Cachaço, Ana Sofia Carvalho, Tânia Santos, Ana Cristina Igreja, Cátia Fragoso, Rita Osório, Catarina Ferreira, Manuela Serpa, Jacinta Correia, Sofia Pinto-do-Ó, Perpétua Dias, Sérgio PLoS One Research Article BACKGROUND: Secondary bone marrow (BM) myelodysplastic syndromes (MDS) are increasingly common, as a result of radio or chemotherapy administered to a majority of cancer patients. Patients with secondary MDS have increased BM cell apoptosis, which results in BM dysfunction (cytopenias), and an increased risk of developing fatal acute leukemias. In the present study we asked whether TNF-α, known to regulate cell apoptosis, could modulate the onset of secondary MDS. PRINCIPAL FINDINGS: We show that TNF-α is induced by irradiation and regulates BM cells apoptosis in vitro and in vivo. In contrast to irradiated wild type (WT) mice, TNF-α deficient (TNF-α KO) mice or WT mice treated with a TNF-α-neutralizing antibody were partially protected from the apoptotic effects of irradiation. Next we established a 3-cycle irradiation protocol, in which mice were sub-lethally irradiated once monthly over a 3 month period. In this model, irradiated WT mice presented loss of microsatellite markers on BM cells, low white blood cell (WBC) counts, reduced megakaryocyte (MK) and platelet levels (thrombocytopenia) and macrocytic anemia, phenoypes that suggest the irradiation protocol resulted in BM dysfunction with clinical features of MDS. In contrast, TNF-α KO mice were protected from the irradiation effects: BM cell apoptosis following irradiation was significantly reduced, concomitant with sustained BM MK numbers and absence of other cytopenias. Moreover, irradiated WT mice with long term (≥5 months) BM dysfunction had increased BM angiogenesis, MMPs and VEGF and NFkB p65, suggestive of disease progression. CONCLUSION: Taken together, our data shows that TNF-α induction following irradiation modulates BM cell apoptosis and is a crucial event in BM dysfunction, secondary MDS onset and progression. Public Library of Science 2010-02-01 /pmc/articles/PMC2813873/ /pubmed/20126546 http://dx.doi.org/10.1371/journal.pone.0008980 Text en Cachaço et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Cachaço, Ana Sofia Carvalho, Tânia Santos, Ana Cristina Igreja, Cátia Fragoso, Rita Osório, Catarina Ferreira, Manuela Serpa, Jacinta Correia, Sofia Pinto-do-Ó, Perpétua Dias, Sérgio TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment |
title | TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment |
title_full | TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment |
title_fullStr | TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment |
title_full_unstemmed | TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment |
title_short | TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment |
title_sort | tnf-α regulates the effects of irradiation in the mouse bone marrow microenvironment |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813873/ https://www.ncbi.nlm.nih.gov/pubmed/20126546 http://dx.doi.org/10.1371/journal.pone.0008980 |
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