Bone Marrow Stromal-B Cell Interactions in Polycyclic Aromatic Hydrocarbon-Induced Pro/Pre-B Cell Apoptosis

• Published in: Toxicological sciences 2003-12, Vol.76 (2), p.357-365
• Main Authors: Allan, Lenka L., Mann, Koren K., Matulka, Raymond A., Ryu, Heui-Young, Schlezinger, Jennifer J., Sherr, David H.
• Format: Article
• Language: English
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - metabolism; 9,10-Dimethyl-1,2-benzanthracene - pharmacology; Animals; Apoptosis - drug effects; B cell apoptosis; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Benzoflavones - pharmacology; Biological and medical sciences; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Cell Line, Tumor; Chemical and industrial products toxicology. Toxic occupational diseases; Culture Media, Conditioned - chemistry; Culture Media, Conditioned - pharmacology; Environmental Pollutants - metabolism; Environmental Pollutants - pharmacology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; polycyclic aromatic hydrocarbon; Receptors, Aryl Hydrocarbon - antagonists & inhibitors; Receptors, Aryl Hydrocarbon - metabolism; stromal cells; Stromal Cells - drug effects; Stromal Cells - metabolism; Stromal Cells - pathology; Toxicology; Various organic compounds
• ISSN: 1096-6080; 1096-0929; 1096-0929
• DOI: 10.1093/toxsci/kfg239

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 α-naphthoflavone (α-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.