Bone Marrow Stromal Cell Cytochrome P4501B1 Is Required for Pre-B Cell Apoptosis Induced by 7,12-Dimethylbenz[a]anthracene

Heidel, Shawn M.; Holston, Karrie; Buters, Jeroen; Gonzalez, Frank J.; Jefcoate, Colin R.; Czupyrynski, Charles J.

doi:10.1124/mol.56.6.1317

Cited by 50 publications

(48 citation statements)

References 35 publications

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“…Recent reports showed that AHR activation of bone marrow stromal cells was necessary for benz[a]pyrene-or DMBA-induced pre-B-cell apoptosis (7,8,13). In contrast to these reports, Heidel et al showed that the metabolic activation of DMBA in bone marrow stromal cells is required for pre-B-cell apoptosis (35,36). We also examined DMBA-induced lymphoid cytotoxicity using Ah-nonresponsive mice, mEH-null mice and the wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of 7,12-Dimethylbenz[a]anthracene-Induced Immunotoxicity: Role of Metabolic Activation at the Target Organ

Miyata

Furukawa

Takahashi

et al. 2001

Japanese Journal of Pharmacology

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118

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ABSTRACT-The polycyclic aromatic hydrocarbon, 7,12-dimethylbenz [a]anthracene (DMBA), is an immunosuppressor as well as a potent organ-specific carcinogen. To understand the organ-specific mechanism of DMBA-induced lymphoid toxicity, aryl hydrocarbon-nonresponsive mice and microsomal epoxide hydrolase (mEH)-null mice were analyzed. DMBA caused a dose-dependent decrease in spleen weights, but not the thymus weights in aryl hydrocarbon-nonresponsive mice. On the other hand, both spleen and thymus weights were decreased to less than a half in wild-type mice exposed to 30 mg/kg of DMBA. In contrast, no decrease was detected in spleen weights of mEH-null mice exposed to up to 100 mg/ kg of DMBA, while thymus weights were markedly lower. Responses to the B-cell mitogen lipopolysaccharide and to T-cell mitogen phytohemagglutinin were nearly completely abolished in splenocytes isolated from wild-type mice treated with 100 mg/kg of DMBA. These responses were decreased, but maintained in splenocytes isolated from mEH-null mice treated with DMBA. Two DMBA metabolites dependent on mEH including DMBA-3,4-diol were detected in an HPLC chromatogram of spleen microsomes isolated from wild-type mice, but not those from mEH-null mice. These results suggest the involvement of mEH in splenic activation of DMBA for immunotoxicity and the difference for the DMBA-induced lymphoid toxicity between spleen and thymus.

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Section: Discussionmentioning

confidence: 99%

Mechanism of 7,12-Dimethylbenz[a]anthracene-Induced Immunotoxicity: Role of Metabolic Activation at the Target Organ

Miyata

Furukawa

Takahashi

et al. 2001

Japanese Journal of Pharmacology

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118

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“…In our laboratory, and others, it has been observed that PAHs must be metabolically activated to be immunotoxic (White et al, 1985;Heidel et al, 1999Heidel et al, , 2000Mann et al, 1999). Apoptosis does not occur in pre-B (70Z/3) cells incubated with DMBA in the absence of stromal (BMS2) cells.…”

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confidence: 99%

7,12-Dimethylbenz[a]anthracene Induces Apoptosis in Murine Pre-B Cells through a Caspase-8–Dependent Pathway

Page

O'Brien

Jefcoate

et al. 2002

Molecular Pharmacology

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Polycyclic aromatic hydrocarbons (PAHs) have been demonstrated to cause a variety of tumors and immunosuppressive effects. Our laboratory, and others, have demonstrated that coculture of progenitor B lymphocytes (pre-B cells) with bone marrow stromal cells and the model PAH 7,12-dimethylbenz[a]anthracene (DMBA) results in pre-B cell apoptosis. In this study we investigated the molecular events that precede apoptosis in DMBA-treated 70Z/3 cells, a pre-B cell line. Using caspase activity assays and immunoblotting techniques, we determined the temporal pattern of caspase expression in the pre-B cells. Using caspase inhibitors, we demonstrated that DMBA-mediated pre-B cell apoptosis is dependent on activation of caspase-8, whereas caspase-9 activation is essential for maximal apoptosis. We also demonstrated that DMBA activated PKR, an interferon-inducible protein kinase, in pre-B cells. PKR in turn can activate caspase-8 independently of death receptor ligation. As a result of these studies, we propose a novel PKR-dependent pathway for activation of apoptosis in DMBA-treated pre-B cells.

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“…7). This up-regulation may reflect a DNA damage response subsequent to formation of DMBA metabolite-DNA adducts (54). Similarly, p21 WAF1 appears not to play a part in the growth arrest observed following dexamethasone treatment of BU-11 cells, despite its contribution to dexamethasone-induced growth arrest in lung alveolar epithelial cells (55).…”

Section: Figurementioning

confidence: 99%

Environmental Chemical-Induced Pro/Pre-B Cell Apoptosis: Analysis of c-Myc, p27Kip1, and p21WAF1 Reveals a Death Pathway Distinct from Clonal Deletion

Ryu

Mann

Schlezinger

et al. 2003

The Journal of Immunology

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Polycyclic aromatic hydrocarbons (PAH) are common environmental pollutants that suppress the immune system in part by inducing pro/pre-B cell apoptosis. The PAH-induced death signaling pathway resembles the signaling cascade activated during clonal deletion and modeled by B cell receptor cross-linking or by dexamethasone exposure of immature surface Ig+ B cells in that apoptosis is mediated by NF-κB down-regulation. Because a PAH-induced, clonally nonrestricted deletion of B cells would have important implications for B cell repertoire development, the nature of the PAH-induced intracellular death signal was studied further. Particular emphasis was placed on the roles of growth arrest and c-Myc, p27Kip1, and p21WAF1 expression, because all of these elements contribute to clonal deletion. As in clonal deletion models, and as predicted by the down-regulation of NF-κB, PAH-induced death of pro/pre-B cells was at least partially dependent on c-Myc down-regulation. Furthermore, whereas dexamethasone induced a G0/G1 cell cycle arrest, PAH had no effect on pro/pre-B cell growth, indicating that growth arrest and apoptosis occur by separable signaling pathways in this early phase of B cell development. Finally, in contrast to clonal deletion, PAH-induced pro/pre-B cell death was not dependent on p27Kip1 or p21WAF1 up-regulation but did coincide with p53 induction. These results distinguish the PAH-induced apoptosis pathway from that activated during clonal deletion and indicate that signaling cascades leading to growth arrest and/or apoptosis in pro/pre-B cells differ from those active at later B cell developmental stages.

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Bone Marrow Stromal Cell Cytochrome P4501B1 Is Required for Pre-B Cell Apoptosis Induced by 7,12-Dimethylbenz[a]anthracene

Cited by 50 publications

References 35 publications

Mechanism of 7,12-Dimethylbenz[a]anthracene-Induced Immunotoxicity: Role of Metabolic Activation at the Target Organ

Mechanism of 7,12-Dimethylbenz[a]anthracene-Induced Immunotoxicity: Role of Metabolic Activation at the Target Organ

7,12-Dimethylbenz[a]anthracene Induces Apoptosis in Murine Pre-B Cells through a Caspase-8–Dependent Pathway

Environmental Chemical-Induced Pro/Pre-B Cell Apoptosis: Analysis of c-Myc, p27Kip1, and p21WAF1 Reveals a Death Pathway Distinct from Clonal Deletion

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