Bcl-2 Protects Macrophages from Nitric Oxide-induced Apoptosis

Meβmer, Udo K.; Reed, John C.; Brüne, Bernhard

doi:10.1074/jbc.271.33.20192

Cited by 216 publications

(113 citation statements)

References 31 publications

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“…Although little is yet known regarding the functional significance of Bax and Bcl-2 expression in the microglial/macrophage lineage, marked changes in the pattern of their expression are likely to alter the life span of these reactive macrophages. Evidence of the role of Bax/ Bcl-2 families in the apoptotic pathway of macrophages/monocytes has been recently studied in human atherosclerotic plaques, giant cell granulomas and osteopetrosis (35)(36)(37)(38)(39)(40). It is possible that these macrophages, after engulfing the degraded myelins, undergo apoptosis, and apoptotic macrophages may further enhance the development of demyelinating lesions by releasing cytokines.…”

Section: Discussionmentioning

confidence: 99%

Expression of Bax, Bcl-2, and P53 in Progressive Multifocal Leukoencephalopathy

Yang

Prayson

2000

Modern Pathology

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It has been shown in vitro that JC viral protein can form a complex with wild-type p53 protein, which is a key regulator of both cell proliferation and cell death. Cellular factors, Bax and Bcl-2, are two essential downstream elements involved in p53-dependent apoptosis. To determine whether association of JC virus with p53 protein affects the expression of Bax and Bcl-2 in viral-infected cells in progressive multifocal leukoencephalopathy (PML), we studied the expression of Bax, Bcl-2, and p53 in 14 cases from 13 PML patients by using paraffin immunohistochemistry. Seven of 13 patients were known to be HIV positive. Overexpression of p53 was found in viral-infected oligodendrocytes and some astrocytes in all 14 cases. Intense immunostaining of Bax was strongly expressed in viralinfected oligodendrocytes and astrocytes. Bax immunostaining was also found in macrophages in the demyelinating lesions. Bcl-2 was not detected in viral-infected glial cells. The expression pattern of Bax positive/Bcl-2 negative in viral-infected glial cells suggests that the oligodendrocyte may be undergoing apoptosis which may in turn contribute to the demyelinating process in PML. The coexpression of p53 and Bax in the infected glial cells suggests that p53 detected by immunohistochemistry may still maintain its wild-type function.

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Section: Discussionmentioning

confidence: 99%

Expression of Bax, Bcl-2, and P53 in Progressive Multifocal Leukoencephalopathy

Yang

Prayson

2000

Modern Pathology

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“…-mediated apoptosis in RAW 264.7 macrophages (Albina et al, 1996;Messmer et al, 1996b). We observed enforced expression of human Bcl-2 in RAW macrophages, named Rblc2-14, that contained the plasmid pRc/CMVbcl2 (Figure 3a).…”

Section: P53 Acts Upstream Of Bcl-x L and Mitochondrial Cyt C Releasementioning

confidence: 91%

“…p53 antisense transfection and Bcl-2 overexpression in RAW 264.7 macrophages Construction of p53 antisense expressing RAW 264.7 cells (RDp53asn-11) and Bcl-2 overexpressing RAW 264.7 cells (Rbcl2-14) were previously described (Messmer and BruÈ ne, 1996a;Messmer et al, 1996b).…”

Section: Cell Culturementioning

confidence: 99%

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p53 accumulation in apoptotic macrophages is an energy demanding process that precedes cytochrome c release in response to nitric oxide

Brockhaus

Brüne

1999

Oncogene

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Apoptosis in response to stress signals activates e ector caspases known to be regulated by the release of cytochrome c (Cyt c) from mitochondria and the subsequent ATP-dependent activation of the death regulator apoptotic protease-activating factor 1 (Apaf-1). Experiments were carried out to determine whether the release of Cyt c is evoked by NO . in RAW 264.7 macrophages and to position signaling components relative to mitochondria. S-nitrosoglutathione and spermine-NO caused a fast p53 accumulation, followed by Bcl-x L downregulation, Cyt c release, and caspase activation. These alterations were absent in p53 antisense expressing macrophages (RDp53asn-11). In Bcl-2 overexpressing cells (Rbcl2-14) Cyt c relocation and caspase activation were abrogated although p53 accumulation remained intact. The use of caspase inhibitors revealed Cyt c release and decreased Bcl-x L expression to be caspase independent. ATP-depleted cells showed a shift from apoptosis towards necrosis and no p53 accumulation or caspase activation upon NO . addition. Conclusively, NO . -mediated apoptosis in macrophages is entirely controlled by the mitochondrial pathway with the implication that Cyt c relocation demands p53 accumulation. Moreover, pulse-chase-experiments in combination with the ATP-depletion protocol identi®ed p53 accumulation and stabilization as an energy requiring process. This allowed to dissect two ATPdependent steps, one is in association with Apaf-1 formation, while the other resides in p53 accumulation.

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“…[25][26][27] It has been reported that NO is directly involved in apoptosis of cells via several mechanisms, including inhibition of mitochondrial respiration, inhibition of DNA synthesis and initiation of DNA strand breaks. 28,29 Our experiments revealed that when S-nitrosoacetylpenicillamine (SNAP), an NO donor, was added into the SCCVII culture in vitro, the apoptosis of the SCCVII cells was induced. Furthermore, apoptotic tumor cells adjacent to iNOS-positive immune cells in vivo were observed.…”

Section: Discussionmentioning

confidence: 99%

TX‐1877, a bifunctional hypoxic cell radiosensitizer, enhances anticancer host response: Immune cell migration and nitric oxide production

Oshikawa

Okamoto

Ahmed

et al. 2005

Intl Journal of Cancer

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We investigated in the current study the effect of TX-1877, a bifunctional hypoxic cell radiosensitizer, in augmenting anticancer host response. In the syngeneic squamous cell carcinoma-bearing mouse model, a single administration of TX-1877 significantly inhibited the primary tumor growth as well as lung metastasis. TX-1877 administration resulted in a significant infiltration of immune cells, such as CD4 1 T, CD8 1 T cells, macrophages and dendritic cells (DCs), and an increased expression of chemokines for cytotoxic T lymphocytes (CTLs), helper T-cell 1 (Th1) cells, monocytes/macrophages and DCs, in tumor tissues. Nitric oxide (NO) production and the expression of inducible NO synthase (iNOS) and interferon-g, a major Th1 cytokine that plays a major role in anticancer immunity, were also enhanced. Furthermore, neutralization of NO by N-monomethyl-L-arginine acetate resulted in a marked inhibition of the antitumor effect of TX-1877. In tumor-draining lymph nodes, MHC class I-restricted CD8 1 memory CTLs specific for inoculated cancer cells were induced by TX-1877. In in vitro experiments, TX-1877 induced chemokines and iNOS/NO in several types of culture cells. These findings strongly suggested that TX-1877 induces migration of CD8 1 CTLs, CD4 1 Th1 cells, macrophage/monocytes and dendritic cells into the tumor site, and that this migration is mediated by chemokine induction. In addition, it was suggested that NO produced by several types of cells stimulated by TX-1877 in the tumor sites plays a major role in the anticancer effect of TX-1877. TX-1877 was thus shown to be an effective immunopotentiator as well as a hypoxic cell radiosensitizer. ' 2005 Wiley-Liss, Inc.Key words: radiosensitizer; anticancer immunity; chemokine; nitric oxide; cytotoxic T lymphocyte Hypoxic cell radiosensitizers, as electron-affinic compounds, have oxygen-mimic effects to tumor hypoxic cells on fixing the radiation-induced damage in DNA or other molecules. 1,2 Misonidasole (1-methoxy-3-(2-nitro-1 H-imidazolyl)-2-propanol) is a well-known 2-nitroimidazole radiosensitizer. Tested in clinical trials, its development was discontinued because of its dose-limiting side effects, such as neurotoxicity. 3 Etanidazole (N1-(2-hydroxyethyl)-2-(2-nitro-1 H-imidazolyl)acetamide) was found to be 3-4 times less toxic than Misonidasole, but to have radiosensitizing activity comparable to Misonidasole. However, a phase 3 randomized trial of radiotherapy of head and neck cancer with or without etanidazole has failed. 4 Recently, hypoxic cell radiosensitizers have been designated not to improve radiosensitizing activities and hydrophilicities but to have chemical and biologic activities by introducing additional functional groups, such as alkylating groups or enzyme chelating groups, to their side-chain moieties. [5][6][7] We have previously reported that a hypoxic cell radiosensitizer developed in our laboratories, haloacetylcarbamoyl-2-(2-nitro-1 H-1imidazolyl) acetamide, showed strong antiangiogenic activity in chicken embryo chorioallantoic membra...

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Bcl-2 Protects Macrophages from Nitric Oxide-induced Apoptosis

Cited by 216 publications

References 31 publications

Expression of Bax, Bcl-2, and P53 in Progressive Multifocal Leukoencephalopathy

Expression of Bax, Bcl-2, and P53 in Progressive Multifocal Leukoencephalopathy

p53 accumulation in apoptotic macrophages is an energy demanding process that precedes cytochrome c release in response to nitric oxide

TX‐1877, a bifunctional hypoxic cell radiosensitizer, enhances anticancer host response: Immune cell migration and nitric oxide production

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