Histone H2AX phosphorylation as a measure of DNA double-strand breaks and a marker of environmental stress and disease activity in lupus
| Autor: | Paul Renauer, Amr H. Sawalha, Mikhail Ognenovski, Rajaie Namas, Pei-Suen Tsou |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Immunology Cell medicine.disease_cause Peripheral blood mononuclear cell Flow cytometry 03 medical and health sciences chemistry.chemical_compound Double strand breaks medicine Propidium iodide Systemic lupus erythematosus medicine.diagnostic_test business.industry Biomarker Studies General Medicine medicine.disease 030104 developmental biology medicine.anatomical_structure chemistry Oxidative stress Apoptosis Cancer research biological phenomena cell phenomena and immunity business H2AX phosphorylation CD8 |
| Zdroj: | Lupus Science & Medicine |
| ISSN: | 2053-8790 |
| DOI: | 10.1136/lupus-2016-000148 |
| Popis: | Objective Defective or inefficient DNA double-strand break (DSB) repair results in failure to preserve genomic integrity leading to apoptotic cell death, a hallmark of systemic lupus erythematosus (SLE). Compelling evidence linked environmental factors that increase oxidative stress with SLE risk and the formation of DSBs. In this study, we sought to further explore genotoxic stress sensitivity in SLE by investigating DSB accumulation as a marker linking the effect of environmental stressors and the chromatin microenvironment. Methods DSBs were quantified in peripheral blood mononuclear cell subsets from patients with SLE, healthy controls, and patients with rheumatoid arthritis (RA) by measuring phosphorylated H2AX (phospho-H2AX) levels with flow cytometry. Phospho-H2AX levels were assessed in G0/G1, S and G2 cell-cycle phases using propidium iodide staining, and after oxidative stress using 0.5 µM hydrogen peroxide exposure for 0, 2, 5, 10, 30 and 60 min. Results DSB levels were significantly increased in CD4+ T cells, CD8+ T cells and monocytes in SLE compared with healthy controls (p=2.16×10−4, 1.68×10−3 and 4.74×10−3, respectively) and RA (p=1.05×10−3, 1.78×10−3 and 2.43×10−2, respectively). This increase in DSBs in SLE was independent of the cell-cycle phase, and correlated with disease activity. In CD4+ T cells, CD8+ T cells and monocytes, oxidative stress exposure induced significantly higher DSB accumulation in SLE compared with healthy controls (60 min; p=1.64×10−6, 8.11×10−7 and 2.04×10−3, respectively). Conclusions Our data indicate that SLE T cells and monocytes have increased baseline DSB levels and an increased sensitivity to acquiring DSBs in response to oxidative stress. Although the mechanism underlying DSB sensitivity in SLE requires further investigation, accumulation of DSB may serve a biomarker for disease activity in SLE and help explain increased apoptotic cell accumulation in this disease. |
| Databáze: | OpenAIRE |
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