ToxSci Advance Access originally published online on September 26, 2003
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Toxicological Sciences 76, 357-365 (2003)
Copyright © 2003 by the Society of Toxicology
IMMUNOTOXICOLOGY |
Bone Marrow Stromal-B Cell Interactions in Polycyclic Aromatic Hydrocarbon-Induced Pro/Pre-B Cell Apoptosis
* Department of Environmental Health,
Department of Microbiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts;
Lady Davis Institute for Medical Research, Montreal, Canada; and
The Burdock Group, Vero Beach, Florida
Environmental polycyclic aromatic hydrocarbons (PAH) and related halogenated hydrocarbons are immunotoxic in a variety of systems. In a model system of B lymphopoiesis, PAH exposure rapidly induces apoptosis in CD43- pre-B and CD43+ pro/pre-B cells. Apoptosis induction by 7,12-dimethylbenzo[a]anthracene (DMBA) is dependent upon AhR+ bone marrow stromal cells and likely involves DMBA metabolism within the stromal cell. However, it is not known if PAH-treated stromal cells release free metabolites or soluble factors that may directly induce B cell death or if the effector death signal is delivered by stromal cell-B cell contact. Here, we demonstrate that supernatants from DMBA-treated bone marrow stromal cells contain an activity capable of inducing apoptosis in pro/pre-B cells cocultured with stromal cells. This activity (1) is not produced when stromal cells are cotreated with DMBA and 
-naphthoflavone (-NF), an aryl hydrocarbon receptor (AhR) and cytochrome P-450 inhibitor, (2) is 
50 kDa, (3) is trypsin and heat sensitive, and (4) is dependent on AhR+ stromal cells, which in turn deliver the effector death signal to pro/pre-B cells. The results (1) argue against a role for a soluble, stromal cell-derived cytokine as the effector of PAH-induced pro/pre-B cell death, (2) exclude the possibility of a free metabolite acting directly on AhR- pro/pre-B cell targets, and (3) suggest the elaboration by stromal cells of a relatively stable, DMBA metabolite-protein complex capable of acting on other stromal cells at some distance. Collectively, these studies suggest that, while stromal cell products, e.g., metabolite-protein complexes, may affect the function of distant stromal cells, the effector death signal delivered by stromal cells to bone marrow B cells is mediated by cell–cell contact.
Key Words: polycyclic aromatic hydrocarbon; B cell apoptosis; stromal cells.
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