Involvement of peripheral benzodiazepine receptors in the protection of hematopoietic cells against oxygen radical damage

Abstract

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 confocal 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 H202 cytotoxicity and their level of PBR expression. Demonstration of the role of PBR in the protection against H202 was obtained by transfecting JURKAT cells with the human PBR cDNA. Transfected cells exhibited increased resistance to H202 compared with wild-type cells, suggesting that PBR may prevent mitochondria from radical damages and thereby modulate apoptosis in the hematopoietic system.

Treatment with Dehydroepiandrosterone Increases Peripheral Benzodiazepine Receptors of Mitochondria from Cerebral Cortex in d‐Galactose‐Induced Aged Rats

“…Such a loss has been reported in amnesia mice induced by d-galactose [14]. In the haematopoietic system, it has been demonstrated that peripheral benzodiazepine receptors participate in an antioxidant pathway, preventing mitochondria from radical damages and modulate apoptosis [11]. We assume that the peripheral benzodiazepine receptor decline induced by dgalactose in our experiment may cause decreases in antioxidant ability in cerebral cortex.…”

Axonal injury‐dependent induction of the peripheral benzodiazepine receptor in small‐diameter adult rat primary sensory neurons

“…PBR ligands might also have an indirect beneficial effect on injured neurons through their actions on glia and immune cells (Zavala et al, 1990;Waterfield et al, 1999;Torres et al, 2000). PBR ligand binding modulates the mitochondrial transmembrane potential (Chelli et al, 2001;Tanimoto et al, 1999) and protects cells from damage by reactive oxygen species (Carayon et al, 1996). These two actions help prevent apoptotic death by inhibiting cytochrome-c release from mitochondria and subsequent caspase activation (Bono et al, 1999;Stoebner et al, 2001;Ferzaz et al, 2002;Strohmeier et al, 2002).…”

Expression of the peripheral benzodiazepine receptor is decreased in skin cancers in comparison with normal skin

“…However, given the proposed protective role of PBR against reactive oxygen species 41 and UV radiation, 42 both of which may contribute to carcinogenesis, cells underexpressing PBR (particularly in skin exposed to UV radiation), being less protected, could have a predisposition for neoplastic selection. Thus cells expressing PBR at the low end of the normal distribution might be more susceptible to transformation, and only later, during growth and differentiation, start to express the more heterogeneous distribution observed in this study.…”