Regulation of preB cell apoptosis by aryl hydrocarbon receptor/transcription factor-expressing stromal/adherent cells.
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-dimethylbenz[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.
Department of Environmental Health, Boston University Schools of Medicine and Public Health, Boston, Massachusetts 02118, USA. rocket1@bu.edu
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D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000633:toxicity; D001571:Benzoflavones / Q000494:pharmacology; D001854:Bone Marrow Cells; D002460:Cell Line; D053938:DNA Fragmentation / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D006410:Hematopoiesis; D008099:Liver / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D017154:Stromal Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*
D001571:Benzoflavones; D011084:Polycyclic Aromatic Hydrocarbons; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D001564:Benzo(a)pyrene; D015127:9,10-Dimethyl-1,2-benzanthracene; C011512:alpha-naphthoflavone