Involvement of Peripheral Benzodiazepine Receptors in the Protection of Hematopoietic Cells Against Oxygen Radical Damage

• Published in: Blood Vol. 87; no. 8; pp. 3170 - 3178
• Main Authors: Carayon, P., Portier, M., Dussossoy, D., Bord, A., Petitprêtre, G., Canat, X., Fur, G.Le, Casellas, P.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-04-1996; The Americain Society of Hematology
• Subjects: Adult; Biological and medical sciences; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Child, Preschool; Female; Fundamental and applied biological sciences. Psychology; Hematopoiesis; Humans; Hydrogen Peroxide - pharmacology; Infant; Leukemia - pathology; Lymphoid Tissue - cytology; Lymphoid Tissue - drug effects; Lymphoid Tissue - metabolism; Male; Mitochondria - metabolism; Molecular and cellular biology; Oxidative Stress; Porphyrins - biosynthesis; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species - pharmacology; Receptors, GABA-A - drug effects; Receptors, GABA-A - physiology; Tumor Cells, Cultured; Human; Mitochondria; Oxygen; Membrane receptor; Hematopoiesis; Established cell line; Hematopoietic cell; Benzodiazepine derivatives; Antioxidant; Protection; Free radical
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V87.8.3170.bloodjournal8783170

Several putative functions have been attributed to the peripheral benzodiazepine receptor (PBR), but its precise physiologic role has not been elucidated. In the present study, we investigated PBR function by quantifying this receptor in leukocyte subsets from healthy donors and in leukemic blasts from lymphoid and myeloid lineages. Using a monoclonal antibody (MoAb) directed against the human PBR and a quantitative flow cytometric assay, we found that phagocytic cells from healthy donors displayed a higher level of PBRs than lymphocytes or natural killer (NK) cells. Among the lymphoid lineage, thymocytes and IgD-negative B cells expressed the lowest levels. However, because of the wide heterogeneity of PBR levels among 42 acute or chronic lymphoid and myeloid leukemias, it was not possible to assign PBR expression to a stage of maturation or a cell lineage. Although the PBR displayed a mitochondrial subcellular localization, its expression was not correlated with the mitochondrial content, suggesting a modulation of PBR density at the level of the mitochondria. This modulation was confirmed when we studied in detail the PBR expression during T-cell development by both flow cytometry and con-focal microscopy. We found that the PBR was expressed with a bimodal profile during T-cell development, identical to the one observed with the proto-oncogene, Bcl-2. The high similarity in the expression of both the PBR and the Bcl-2 proto-oncogene in T-cell and B-cell subsets, their common mitochondrial localization, and the observation of high quantities of PBR in phagocytic cells, which are known to produce high levels of radical oxygen species, suggested that PBRs may participate in an antioxidant pathway. Indeed, a strong correlation was established between the ability of hematopoietic cell lines to resist H2O2 cytotoxicity and their level of PBR expression. Demonstration of the role of PBR in the protection against H2O2 was obtained by transfecting JURKAT cells with the human PBR cDNA. Transfected cells exhibited increased resistance to H2O2 compared with wild-type cells, suggesting that PBR may prevent mitochondria from radical damages and thereby modulate apoptosis in the hematopoietic system.