Regulation of preB cell apoptosis by aryl hydrocarbon receptor transcription factor-expressing stromal adherent cells
Regulation of preB cell apoptosis by aryl hydrocarbon receptor transcription factor-expressing stromal adherent cells
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DOI：
10.1046/j.1525-1373.1999.d01-82.x
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发表时间：
1999-07-01
影响因子：
--
通讯作者：
Sherr, DH
中科院分区：
文献类型：
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作者：
Near, RI;Matulka, RA;Sherr, DH
多环芳烃（PAH）是介导免疫抑制的环境化学物质。在长期骨髓B细胞淋巴细胞生成模型中，PAH诱导未成熟（preB）淋巴细胞凋亡。由于PAH的生物学功能通常由芳烃受体/转录因子（AhR）介导，因此评估AhR或AhR调节基因在前B细胞凋亡中的作用。具体地，将骨髓来源的前B细胞系（BU-11）在AhR（+）骨髓来源的基质细胞系BMS 2的单层上培养，表达不同水平AhR活性的肝癌亚系（Hepa-1c 1c 7和变体）、AhR（+）胸腺上皮细胞和来自野生型或AhR（-/-）小鼠的原代骨髓基质细胞。培养物用两种原型PAH，7，12-二甲基-苯并[a]蒽（DMBA）或苯并[a]芘（B[a]P）中的一种处理，并测量经历凋亡的细胞的百分比。数据表明：1）骨髓和肝源性基质/贴壁细胞支持前B细胞生长并调节DMBA或B[a]P诱导的细胞凋亡; 2）当前B细胞维持在Hepa-1c 1c 7单层上时，B[a]P比DMBA更有效，而不是维持在BMS 2单层上; 3）当前B细胞在BMS 2单层上培养时，DMBA比B[a]P更有效; 4）AhR拮抗剂和细胞色素P-450抑制剂α-萘酚酮阻断BU-11/Hepa-1c 1c 7和BU-11/BMS 2培养物中的preB细胞凋亡; 5）尽管前B细胞在Hepa-1c 1c 7或BMS 2上清液中生长良好，在没有肝或骨髓来源的贴壁细胞的情况下加入PAH不会导致前B细胞凋亡; 6）前B细胞凋亡依赖于贴壁的肝或骨髓来源的基质细胞中的AhR活性;和7）当preB细胞维持在来自野生型而不是来自AhR（-/-）小鼠的原代骨髓基质细胞单层上时，DMBA诱导凋亡。总的来说，这些数据表明，造血微环境中的AhR调节活动影响未成熟淋巴细胞对低剂量PAH暴露的敏感性。
Polycyclic aromatic hydrocarbons (PAH) are environmental chemicals that mediate immunosuppression. In long-term bone marrow B-cell lymphopoiesis models, PAH induce apoptosis in immature (preB) lymphocytes. Since the biologic function of PAH is often mediated by the aryl hydrocarbon receptor/transcription factor (AhR), the role of the AhR or AhR-regulated genes was assessed in preB cell apoptosis, Specifically, a bone marrow-derived preB cell line (BU-11) was cultured on monolayers of the AhR(+) bone marrow-derived stromal cell line BMS2, hepatoma sublines that express various levels of AhR activity (Hepa-1c1c7 and variants), AhR(+) thymic epithelial cells, and primary bone marrow stromal cells from wildtype or AhR(-/-) mice. Cultures were treated with one of two prototypic PAH, 7,12-dimethyl-benz[a]anthracene (DMBA) or benz[a]pyrene (B[a]P), and the percentage of cells undergoing apoptosis measured. The data demonstrated that: 1) bone marrow- and hepatic-derived stromal/adherent cells support preB cell growth and regulate apoptosis induced by DMBA or B[a]P; 2) B[a]P is more effective than DMBA when preB cells are maintained on Hepa-1c1c7 monolayers than when maintained on BMS2 monolayers; 3) DMBA is more effective than B[a]P when preB cells are cultured on BMS2 monolayers; 4) alpha-naphthoflavone, an AhR antagonist and cytochrome P-450 inhibitor, blocks preB cell apoptosis in both BU-11/Hepa-1c1c7 and BU-11/BMS2 cultures; 5) although preB cells grow well in Hepa-1c1c7 or BMS2 supernatants, addition of PAH in the absence of hepatic- or bone marrow-derived adherent cells does not result in preB cell apoptosis; 6) preB cell apoptosis is dependent on AhR activity in adherent hepatic- or bone marrow-derived stromal cells; and 7) apoptosis is induced by DMBA when preB cells are maintained on primary bone marrow stromal cell monolayers from wildtype but not from AhR(-/-) mice. Collectively, the data indicated that AhR-regulated activities in the hematopoietic microenvironment influence the susceptibility of immature lymphocytes to low-dose PAH exposure.