| Title | TNF-α regulates the effects of irradiation in the mouse bone marrow microenvironment |
| Publication Type | Journal Article |
| 2010 |
| Authors | Cachaço, AS, Carvalho, T, Santos, AC, Igreja, C, Fragoso, R, Rio, CO, Ferreira, M, Serpa, J, Correia, S, Pinto-Do-Ó, P, Dias, S |
| Journal | PLoS ONEPLoS ONE |
| Volume | 5 |
| Issue | 2 |
| Date Published | 2010/// |
| 19326203 (ISSN) |
| angiogenesis, animal, animal cell, animal experiment, animal model, animal tissue, Animals, Antibodies, Neutralizing, apoptosis, article, Blood, blood cell count, Blotting, Western, bone marrow, bone marrow cell, Bone Marrow Cells, C57BL mouse, Cell Line, clinical feature, controlled study, cytokine production, disease course, drug effect, Enzyme Activation, flow cytometry, genetics, immunology, in vitro study, in vivo study, irradiation, leukocyte, leukocyte count, Leukocytes, macrocytic anemia, male, matrix metalloproteinase, Matrix Metalloproteinases, megakaryocyte, Megakaryocytes, metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, microenvironment, microsatellite marker, mouse, mouse mutant, Mus, myelodysplastic syndrome, neovascularization (pathology), Neovascularization, Pathologic, neutralizing antibody, nonhuman, Pathology, phenotype, protein expression, radiation dose, radiation exposure, Reverse Transcriptase Polymerase Chain Reaction, reverse transcription polymerase chain reaction, thrombocytopenia, transcription factor RelA, tumor necrosis factor alpha, tumor necrosis factor alpha antibody, Tumor Necrosis Factor-alpha, Vascular Endothelial Growth Factor A, vascularization, vasculotropin, vasculotropin A, Western blotting, zymography |
| 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. © 2010 Cachaço et al. |
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