Proximal events in 7,12-dimethylbenz[a]anthracene-induced, stromal cell-dependent bone marrow B cell apoptosis: stromal cell-B cell communication and apoptosis signaling.
Intercellular communication is an essential process in stimulating lymphocyte development and in activating and shaping an immune response. B cell development requires cell-to-cell contact with and cytokine production by bone marrow stromal cells. However, this intimate relationship also may be responsible for the transfer of death-inducing molecules to the B cells. 7,12-Dimethylbenz[a]anthracene (DMBA), a prototypical polycyclic aromatic hydrocarbon, activates caspase-3 in pro/pre-B cells in a bone marrow stromal cell-dependent manner, resulting in apoptosis. These studies were designed to examine the hypothesis that an intrinsic apoptotic pathway is activated by DMBA and that the ultimate death signal is a DMBA metabolite generated by the stromal cells and transferred to the B cells. Although a loss of mitochondrial membrane potential did not occur in the DMBA/stromal cell-induced pathway, cytochrome c release was stimulated in B cells. Caspase-9 was activated, and formation of the apoptosome was required to support apoptosis, as demonstrated by the suppression of death in Apaf-1(fog) mutant pro-B cells. Investigation of signaling upstream of the mitochondria demonstrated an essential role for p53. Furthermore, DMBA-3,4-dihydrodiol-1,2-epoxide, a DNA-reactive metabolite of DMBA, was sufficient to upregulate p53, induce caspase-9 cleavage, and initiate B cell apoptosis in the absence of stromal cells, suggesting that production of this metabolite by the stromal cells and transfer to the B cells are proximal events in triggering apoptosis. Indeed, we provide evidence that metabolite transfer from bone marrow stromal cells occurs through membrane exchange, which may represent a novel communication mechanism between developing B cells and stromal cells.
Teague
Jessica E
JE
Department of Microbiology, School of Medicine, Boston University, Boston, MA 02118, USA.
Ryu
Heui-Young
HY
Kirber
Michael
M
Sherr
David H
DH
Schlezinger
Jennifer J
JJ
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology*; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D018920:Coculture Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D015127:9,10-Dimethyl-1,2-benzanthracene