Cell Death In Lymphocytes Research Articles

Poly(ADP-ribose) polymerase inhibitors regulate the mechanism of sulfur mustard-initiated cell death in human lymphocytes†**

Poly(ADP-ribose) polymerase inhibitors regulate the mechanism of sulfur mustard-initiated cell death in human lymphocytes†**

Poly(ADP-ribose) polymerase inhibitors regulate the mechanism of sulfur mustard-initiated cell death in human lymphocytes.

Sulfur mustard (HD) produces slow-healing skin lesions that contain large, tight fluid-filled blisters. These lesions are the result of severe damage to areas of the body exposed to HD and require extensive medical care before complete recovery is achieved. Converting the mechanism of HD-initiated cell death from an inflammatory oncosis (homicide) to benign apoptosis (assisted suicide) may reduce the extent of cellular damage and the time required for healing. HD-exposed human lymphocytes lose cellular function, membrane integrity and viability, and suffer degradation of their nuclear components. The treatment of HD-exposed cells with poly(ADP-ribose) polymerase inhibitors prevents or alters the HD-initiated loss of cell viability, membrane integrity, cellular metabolic constituent (NAD) and cellular energy (ATP), while initiating alterations in nuclear constituents. It is hoped that by preventing or altering these HD-initiated changes we can limit the extent of the injury, decrease the time required for repair and reduce the loss of performance suffered by exposed individuals. The use of poly(ADP-ribose) polymerase inhibitors to assist in initiating apoptosis in affected cells should help to achieve these objectives while preventing the chance of further disease development later in the exposed individuals.

Regulation of TNFRSF6 (Fas) expression in ataxia telangiectasia cells by ionizing radiation.

Several studies have shown that ionizing radiation induces transcription of the TNFRSF6 (Fas) gene, leading to augmented TNFRSF6 protein levels at the surface of irradiated cells. We have examined TNFRSF6 expression in an apparently normal lymphocyte line and in a lymphocyte cell line derived from a patient with ataxia telangiectasia (AT) before and after exposure to radiation (0-10 Gy). Plasma membranes were isolated from normal lymphocytes and AT cells and subjected to Western blot analysis, using a TNFRSF6-specific monoclonal antibody to probe resolved proteins transferred onto nitrocellulose membranes. In both cell types, the presence of a 48-kDa band corresponding to the molecular mass of TNFRSF6 was revealed. Analysis of FITC-conjugated anti-TNFRSF6 antibody-stained normal lymphocytes and AT cells confirmed TNFRSF6 expression in both cell types. In MTT assays, AT cells treated with agonistic anti-TNFRSF6 Ab (CH.11) displayed a 25.9% decrease in cell viability, relative to cells treated with isotype-matched IgM Ab, suggesting the presence of a biologically active TNFRSF6 receptor at the AT cell surface. Exposure to cycloheximide (0-5 microg/ml), a metabolic inhibitor, enhanced sensitivity of AT cells to CH.11. Normal lymphocytes exhibited increased levels of apoptosis (approximately 34% cell death relative to cells treated with isotype-matched IgM Ab) when exposed to CH.11; however, the degree of cell death was not altered significantly with increasing concentrations of cycloheximide. When AT cells were exposed to 0.1, 0.5, 2 and 10 Gy, the activities of caspases 3 and 8 increased in a dose-dependent manner at 24 h postirradiation and reached a plateau by 72 h. A similar trend for activation of caspase 3 and 8 was observed in normal lymphocytes after irradiation. To assess the roles of TNFRSF6 and/or caspase 8 in radiation-induced cell death of AT and normal lymphocytes, and to determine whether hyper-radiosensitivity in AT cells is correlated with increased activity of these two components of the TNFRSF6 pathway, AT and normal lymphocytes were irradiated in the presence of ZB4, an anti-TNFRSF6 blocking antibody, and a caspase 8 inhibitor (Z-IETD-FMK). Apoptosis was determined by Annexin V staining using flow cytometry. Incubation with ZB4 anti-TNFRSF6 antibody did not alter the fraction of apoptotic cells in either AT cells or normal lymphocytes treated with doses of radiation ranging from 0-10 Gy. In contrast, apoptosis was significantly reduced in both cell lines in the presence of Z-IETD-FMK when samples were exposed to low-dose (< or = 2 Gy) radiation. Relative to control samples (those not incubated with Z-IETD-FMK), no difference in the level of apoptosis was observed in AT or normal lymphocytes treated with 10 Gy. These data indicate that: (a) despite radiation-induced up-regulation of TNFRSF6 at the cell surface, the death-promoting receptor does not play a role in radiation-mediated cytotoxicity; (b) apoptosis in lymphocytes irradiated with low (< or = 2 Gy) but not high doses (>2 Gy) proceeds at least in part through activation of caspase 8; and (3) since blocking anti-TNFRSF6 antibody (ZB4) did not reduce levels of apoptosis in irradiated AT cells to those of normal lymphocytes, TNFRSF6 is unlikely to play a significant role in the hyper-radiosensitivity exhibited by cells having the AT phenotype.

Prevention of nitrogen mustard-induced apoptosis in normal and transformed lymphocytes by ebselen

The alkylating agent, nitrogen mustard (HN2), is thought to cause apoptosis through production of free oxygen radicals. To explore the mechanism of HN2-induced apoptosis, we utilized ebselen, a selenoorganic compound with potent antioxidant activity. We examined whether ebselen would inhibit apoptosis in BALB/c mouse spleen lymphocytes and human MOLT-4 leukemia cells treated with HN2 (2.5 μM) in vitro. Non-toxic concentrations (<50 μM) of ebselen were found to prevent HN2-induced apoptosis of murine lymphocytes in a dose-dependent manner, as measured by cell viability, hypodiploid DNA formation, and phosphatidylserine externalization. However, ebselen was ineffective at preventing spontaneous apoptosis in these cells, pointing to the selectivity of its action. Furthermore, pretreatment with ebselen at 1–10 μM for 72 hr protected MOLT-4 cells from HN2-induced apoptosis and maintained cell viability and proliferation as monitored by the above-mentioned parameters. This was accompanied by the preservation of mitochondrial transmembrane potential and elevated glutathione levels and by a blockage of caspase-3 and -9 activation. In vivo, ebselen also had a marked protective effect against spleen weight loss associated with lymphocyte apoptosis in mice treated by HN2. Therefore, ebselen provides an efficient protection against HN2-induced cell death in normal and tumoral lymphocytes and might prove useful as an antidote against alkylating agents.

Cytokine regulation of apoptosis and Bcl-2 expression in lymphocytes of patients with systemic lupus erythematosus.

Both faulty regulation of apoptosis and the inappropriate expression of several interleukins have been considered important defects of lymphocytes in the human autoimmune disease systemic lupus erythematosus (SLE). We therefore tested the in vitro effect of recombinant interleukin (IL-)-2, 4, 7, and 15 on peripheral blood mononuclear cells from patients with SLE and from healthy volunteers. Intracellular Bcl-2 and Bax expression was measured by fluorocytometry and the rate of apoptosis was determined by the TUNEL technique and propidium iodide staining. IL-2, IL-4, IL-7 and IL-15 led to a significant increase in Bcl-2 and a reduction in cell death rates, which was even more pronounced in SLE. Bax levels remained unchanged. Interestingly, the high ex vivo Bcl-2 content of lymphocytes from some SLE patients was maintained after growth factor withdrawal. Anti-apoptotic cytokine signaling may significantly influence the deregulation of cell death in SLE lymphocytes.

Rapid onset of intestinal epithelial and lymphocyte apoptotic cell death in patients with trauma and shock.

Apoptosis is a cellular suicide program that can be activated by cell injury or stress. Although a number of laboratory studies have shown that ischemia/reperfusion injury can induce apoptosis, few clinical studies have been performed. The purpose of this study was to determine whether apoptosis is a major mechanism of cell death in intestinal epithelial cells and lymphocytes in patients who sustained trauma, shock, and ischemia/ reperfusion injury. Intestinal tissues were obtained intraoperatively from 10 patients with acute traumatic injuries as a result of motor vehicle collisions or gun shot wounds. A control population consisted of six patients who underwent elective bowel resections. Apoptosis was evaluated by conventional light microscopy, laser scanning confocal microscopy using the nuclear staining dye Hoechst 33342, immunohistochemical staining for active caspase-3, and immunohistochemical staining for cytokeratin 18. Academic medical center. Patients with trauma or elective bowel resections. Extensive focal crypt epithelial and lymphocyte apoptosis were demonstrated by multiple methods of examination in the majority of trauma patients. Trauma patients having the highest injury severity score tended to have the most severe apoptosis. Repeat intestinal samples obtained from two of the trauma patients who had a high degree of apoptosis on initial evaluation were negative for apoptosis at the time of the second operation. Tissue lymphocyte apoptosis was associated with a markedly decreased circulating lymphocyte count in 9 of 10 trauma patients. Focal apoptosis of intestinal epithelial and lymphoid tissues occurs extremely rapidly after injury. Apoptotic loss of intestinal epithelial cells may compromise bowel wall integrity and be a mechanism for bacterial or endotoxin translocation into the systemic circulation. Apoptosis of lymphocytes may impair immunologic defenses and predispose to infection.

Age-related changes of apoptotic cell death in human lymphocytes

Apoptosis seems to be involved in immunosenescence associated with aging. Moreover, in lymphocytes (PBL) of patients with Alzheimer’s disease, an increased susceptibility to the apoptotic pathway has been described possibly due to impaired protection of oxidative stress. Accordingly, it seemed to be of particular interest to investigate the contribution of normal aging to the susceptibility from human lymphocytes to programmed cell death. We could show that PBL from elderly individuals (>60 years) accumulate apoptosing cells to a significant higher extent in spontaneous and activation-induced cell death compared to younger controls (<35 years). Treatment with the oxidative stressor 2-deoxy- d-ribose or with agonistic-CD95-antibody pronounced this effect even more implicating a higher sensitivity to reactive oxygen species and a higher functional CD95 expression, respectively. In addition, expression of the activation markers HLA-DR and CD95 was significantly increased in CD3 +-cells of aged subjects, while expression of CD25 did not seem to be affected by age. Expression of Bcl-2 was increased in aging and correlated with the number of apoptotic cells.

Homodimerization via a Leucine Zipper Motif Is Required for Enzymatic Activity of Quiescent Cell Proline Dipeptidase

Homodimerization via a Leucine Zipper Motif Is Required for Enzymatic Activity of Quiescent Cell Proline Dipeptidase

A novel immunocytolytic factor secreted by pancreatic adenocarcinoma.

We have observed a putative immunocytolytic factor secreted by several pancreatic adenocarcinoma cell lines that mediates a potent cytolytic effect on lymphocytes. We sought to investigate its mechanism of action and determine if it is Fas ligand (FasL)-mediated. Coincubation assays with murine splenocytes and supernatants from various species of pancreatic adenocarcinoma cell lines were performed. The mechanism of lymphocytic cell death was evaluated by the TUNEL assay. Pancreatic adenocarcinoma supernatant was coincubated with Fas-sensitive Jurkat cells and Western blotting for FasL was performed. A marked reduction in the viability (%/control) of target splenocytes was observed after incubation with the conditioned media from hamster PAN-1 (14.7%), PC 1.0 (21.7%), Taka-1 p70 (12.4%), Taka-1 p79 (7.6%), murine PANCO2 (16.1%), and human Capan-1 (14.0%) pancreatic adenocarcinoma cell lines. FACS analysis demonstrated significant lymphoid apoptosis at 16 h. The cytolytic effect appeared to be specific for lymphocytes and was not observed with the conditioned media of other tumor cells or normal pancreatic ductal cells. Pancreatic adenocarcinoma supernatant had no killing effect on Jurkat cells compared with control supernatant of TC-248 cells (87% vs 15%) and immunoblotting did not demonstrate soluble FasL. These findings demonstrate that pancreatic adenocarcinoma cells secrete a potent cytolytic factor that induces apoptosis of lymphocytes and is not FasL-mediated.

Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells

Mutations in the Wiskott-Aldrich syndrome protein (WASP) have been hypothesized to cause defective actin cytoskeletal function. This resultant dysfunction of the actin cytoskeleton has been implicated in the pathogenesis of Wiskott-Aldrich syndrome (WAS). In contrast, it was found that stimulated actin polymerization is kinetically normal in the hematopoietic lineages affected in WAS. It was also found that the actin cytoskeleton in WAS platelets is capable of producing the hallmark cytoarchitectural features associated with activation. Further analysis revealed accelerated cell death in WAS lymphocytes as evidenced by increased caspase-3 activity. This increased activity resulted in accelerated apoptosis of these cells. CD95 expression was also increased in these cells, suggesting an up-regulation in the FAS pathway in WAS lymphocytes. Additionally, inhibition of actin polymerization in lymphocytes using cytochalasin B did not accelerate apoptosis in these cells. This suggests that the accelerated apoptosis observed in WAS lymphocytes was not secondary to an underlying defect in actin polymerization caused by mutation of the WAS gene. These data indicate that WASP does not play a universal role in signaling actin polymerization, but does play a role in delaying cell death. Therefore, the principal consequence of mutations in the WAS gene is to accelerate lymphocyte apoptosis, potentially through up-regulation of the FAS-mediated cell death pathway. This accelerated apoptosis may ultimately give rise to the clinical manifestations observed in WAS. (Blood. 2000;95:1283-1292)

Aminodipeptidase inhibitor-induced cell death in quiescent lymphocytes: a review.

We recently isolated and cloned an intracellular post-proline cleaving aminodipeptidase, quiescent cell proline dipeptidase (QPP), which has a substrate specificity very similar to that of dipeptidyl peptidase IV (CD26/DPPIV). Highly specific inhibitors of proline aminodipeptidases activate a novel apoptotic pathway in quiescent lymphocytes. The target of these inhibitors is not CD26/DPPIV, but appears to be QPP. The apoptosis pathway induced by the aminodipeptidase inhibitors is unusual in that it is restricted to quiescent lymphocytes, but not activated or transformed lymphocytes. The caspases activated in this apoptotic pathway are different from those activated in Fas or gamma-irradiation mediated cell death pathways, and furthermore, the proteasome appears to play a role in this death pathway. A large number of signal molecules including chemokines and cytokines have a highly conserved X-Pro motif on the N-terminus, rendering them potential substrates of QPP and players in the survival of resting lymphocytes.

Induction of Apoptosis in Rat Peripheral Blood Lymphocytes by the Anticancer Drug CI-994 (Acetyldinaline)(*).

CI-994 (acetyldinaline) is an investigational anticancer drug currently in clinical trials. In preclinical safety studies in rats and dogs, CI-994 resulted in significant toxicity to bone marrow and lymphoid tissue. To determine if apoptosis was involved in CI-994 toxicity, peripheral blood lymphocytes were isolated from untreated male Wistar rats and exposed to CI-994 (1, 3, 10, or 30 μM) in vitro for up to 24 hours. Morphological and biochemical features of apoptosis were evaluated using several techniques, and lactate dehydrogenase (LDH) release was measured as an indicator of cell necrosis. No evidence of apoptosis or necrosis was detected in lymphocytes exposed to CI-994 for 4 hours. After 24 hours, concentration-dependent increases in apoptosis characterized by DNA condensation, DNA fragmentation, and/or externalization of phosphatidyl serine were seen at CI-994 concentrations as low as 1 μM and were statistically significant beginning at 10 μM. Ultrastructural analysis confirmed the presence of DNA condensation, DNA fragmentation, cell shrinkage, and membrane blebbing in cells exposed to 30 μM CI-994. After 24 hours, the percent of maximum LDH release from lymphocytes treated with 10 and 30 μM CI-994 was 7% and 15%, respectively, compared with 0% in the controls. In comparison, morphological changes of apoptosis detected by fluorescent microscopy were observed in 79% of the lymphocytes at these two concentrations. Additionally, apoptosis was seen in more than 24% of lymphocytes exposed to 1 and 3 μM CI-994, whereas maximum LDH release was less than or equal to 1% at these concentrations. These results show that apoptosis is the primary mode of cell death in rat lymphocytes exposed to CI-994 in vitro.

Caspases -2, -3, -6, and -9, but not caspase-1, are activated in sepsis-induced thymocyte apoptosis.

Sepsis induces extensive lymphocyte cell death that may contribute to immune depression and morbidity/mortality in the disorder. bcl-2 is a member of a new class of oncogenes that prevents cell death from an array of noxious stimuli. Transgenic mice that overexpress BCL-2 in T lymphocytes are resistant to sepsis-induced T cell apoptosis, and mortality was decreased in sepsis. The purpose of this study was to identify key initiator and executioner "caspases" involved in sepsis-induced lymphocyte apoptosis and to determine if BCL-2 acts prior to caspase activation. Thymi were removed 5-22 h post-cecal ligation and puncture (CLP) or sham surgery. Apoptosis was evaluated in thymocytes by annexin-V FITC labeling and flow cytometry. Caspase-1 activity was determined by western blot analysis of the procaspase protein and p20 subunit of the activated caspase; activities of caspases -2, -6, and -9 were determined by colorimetric assays using specific substrates conjugated to a color reporter molecule. Caspase-3 activity was determined both by western blot and by a fluorogenic assay in which a fluorescent compound was generated. Thymocytes from CLP mice had markedly increased apoptosis and activation of caspases -2, -3, -6, and -9 in comparison with thymocytes of sham-operated mice. Caspase-1 was not activated. BCL-2 prevented sepsis-induced thymocyte apoptosis and inhibited activation of all caspases. We conclude that sepsis causes activation of multiple caspases and that BCL-2 acts upstream as an inhibitor of caspase activation. The pattern of caspase activation suggests a mitochondrial mediated pathway.

Prevention of lymphocyte cell death in sepsis improves survival in mice.

Sepsis induces extensive lymphocyte apoptosis, a process which may be beneficial to host survival by down-regulating the inflammatory response or, alternatively, harmful by impairing host defenses. To determine the beneficial vs. adverse effects of lymphocyte apoptosis in sepsis, we blocked lymphocyte apoptosis either by N-benzyloxycarbonyl-Val-Ala-Asp(O-methyl) fluoromethyl ketone (z-VAD), a broad-spectrum caspase inhibitor, or by use of Bcl-2 Ig transgenic mice that selectively overexpress the antiapoptotic protein Bcl-2 in a lymphoid pattern. Both z-VAD and Bcl-2 prevented lymphocyte apoptosis and resulted in a marked improvement in survival. z-VAD did not decrease lymphocyte tumor necrosis factor-alpha production. Considered together, these two studies employing different methods of blocking lymphocyte apoptosis provide compelling evidence that immunodepression resulting from the loss of lymphocytes is a central pathogenic event in sepsis, and they challenge the current paradigm that regards sepsis as a disorder resulting from an uncontrolled inflammatory response. Caspase inhibitors may represent a treatment strategy in this highly lethal disorder.

Cholangiocarcinomas express Fas ligand and disable the Fas receptor.

Cholangiocarcinoma is a highly-malignant adenocarcinoma originating from cholangiocytes. Current concepts support escape from immune surveillance using aberrant expression of Fas ligand (FasL) and dysregulation of receptor (FasR) signaling as a potential mechanism for tumor progression. Our aims were to determine if altered expression of FasR and FasL or changes in expression of FLICE inhibitor (I-FLICE) allow cholangiocarcinoma cells to escape immune surveillance. Human cholangiocarcinoma cell lines were evaluated for the functional expression of FasR and FasL by (1) quantitating apoptosis after incubation of cells with agonistic antibodies and (2) an in vitro cell death assay involving coculture of cholangiocarcinoma cells with Fas-sensitive thymocytes. I-FLICE antisense treatment was performed by stable transfection with complementary DNA (cDNA) for I-FLICE in the reverse orientation. We found that normal cholangiocytes in vivo express FasL. Human cholangiocarcinoma cell lines express both FasL and FasR and I-FLICE. FasL expressed by cholangiocarcinomas in vitro induced lymphocyte cell death (70% after 24 hours). Despite the expression of FasR, exposure of the cells to agonistic antibodies (500 ng/mL) induced only minimal apoptosis in the Jurkat cells. Antisense treatment of cholangiocarcinomas in vitro with I-FLICE reduced protein expression of I-FLICE by 90% to 95% and increased Fas-mediated apoptosis 2-fold. We concluded that cholangiocarcinomas escape immune surveillance either by disabling FasR signaling through the expression of I-FLICE and/or increased FasL expression to induce apoptosis of invading T cells. Reduction of I-FLICE expression in cholangiocarcinoma cells restored Fas-mediated apoptosis. Therapeutic maneuvers to inhibit expression of I-FLICE may aid in the treatment of cholangiocarcinoma.

Oxidative cell membrane alteration. Evidence for surfactant-mediated sealing.

Exposure to very intense ionizing irradiation produces acute tissue sequelae including inflammation, pain, and swelling that often results in tissue fibrosis and/or necrosis. Acute tissue necrosis occurs in hours when sufficiently rapid damage to membrane lipids and proteins leads to altered membrane structure, disrupting the vital electrochemical diffusion barrier necessary for cell survival. This damage mechanism is thought to underlie the interphase death of lethally irradiated postmitotic cells such as neurons, but it has also been implicated in the rapid cell death of lymphocytes and acute vascular changes due to capillary epithelium dysfunction. It is not known whether sealing of radiation-permeabilized cell membranes will prolong survival of lethally irradiated cells or perhaps lead to repair of damaged nucleic acids. The purpose of this study is to begin to address the first question.

The C. elegans Cell Death Specification Gene ces-1 Encodes a Snail Family Zinc Finger Protein

The ces-1 and ces-2 genes of C. elegans control the programmed deaths of specific neurons. Genetic evidence suggests that ces-2 functions to kill these neurons by negatively regulating the protective activity of ces-1. ces-2 encodes a protein closely related to the vertebrate PAR family of bZIP transcription factors, and a ces-2/ces-1-like pathway may play a role in regulating programmed cell death in mammalian lymphocytes. Here we show that ces-1 encodes a Snail family zinc finger protein, most similar in sequence to the Drosophila neuronal differentiation protein Scratch. We define an element important for ces-1 regulation and provide evidence that CES-2 can bind to a site within this element and thus may directly repress ces-1 transcription. Our results suggest that a transcriptional cascade controls the deaths of specific cells in C. elegans.

An unusual regressive germinal center, the 'FDC-only lymphoid follicle,' in lymph nodes of organ transplant recipients.

Follicular lesions include germinal center (GC) hyperplasia, regressive transformation of GCs, and follicle lysis. The present histologic, electron microscopic, and immunohistochemical study of six autopsy cases after organ transplantation accompanied by the administration of immunosuppressive drugs revealed a peculiar regression of lymph node GCs in two cases, which has not been noted previously. The histologic findings of the regressive GCs were classified into three patterns. In pattern A, the GCs had few or no lymphocytes and were surrounded by a poorly developed mantle zone-like structure. Apoptotic cell death of GC lymphocytes was found in a few GCs, but most GCs lacked tingible body macrophages. In pattern B, the GC lymphocytes and tingible body macrophages were absent, showing crowded follicular dendritic cells (FDCs) in a corpuscular shape. In pattern C, the lymphocytic mantle was absent. The GCs were smaller than those in the other patterns, and the shape was irregular because of disintegration of FDCs. The immunostaining for FDC markers revealed dispersed growth of FDCs. On electron microscopy, the lesions were composed of a dense mass of elliptical and oval cells without prominent cytoplasmic processes, a labyrinthlike structure, and emperipolesis of lymphocytes. The distinct desmosomelike adhesive junctions, specific electron microscopic features of FDCs, were evident. We propose to call these follicular lesions "FDC-only lymphoid follicles." It is speculated that this follicle may be evoked after preceding follicular hyperplasia with a complicated mechanism including increased apoptosis of GC lymphocytes and decreased lymphocyte migration to lymph node GCs caused by immunosuppressive drugs.

Effects of thyroid hormones on apoptotic cell death of human lymphocytes.

Apoptosis plays a critical role in the development and homeostasis of tissues, especially those with high cell turnover such as the lymphoid system. We have examined the effects of thyroid hormones, TSH and TRH, on apoptosis of human T lymphocytes. We found that T lymphocytes cultured with T3 and T4, but not TSH nor TRH, in vitro showed enhanced apoptosis, evidenced by DNA ladder formation and characteristic morphological changes. In addition, prolonged cultivation with thyroid hormones of the lymphocytes further enhanced the extent of apoptosis. We also found that treatment with thyroid hormones of T lymphocytes induced reduction of mitochondrial transmembrane potential (delta psi) and production of reactive oxygen species, both of which are intimately associated with apoptotic cell death. In addition, cellular expression of antiapoptotic Bcl-2 protein was clearly reduced by the treatment of lymphocytes with thyroid hormones in vitro. Thus, T lymphocytes treated with thyroid hormones accompany reduction of Bcl-2 protein expression, production of reactive oxygen species, and reduction of mitochondrial delta psi, resulting in apoptotic lymphocyte death. Moreover, we found that lymphocytes in patients with Graves' disease showed enhanced apoptosis compared with those in normal individuals. These results suggest that thyroid hormones have the potential to induce apoptotic cell death of human lymphocytes in vivo and in vitro.

Effects of Thyroid Hormones on Apoptotic Cell Death of Human Lymphocytes

Effects of Thyroid Hormones on Apoptotic Cell Death of Human Lymphocytes