Environmental chemical-induced bone marrow B cell apoptosis: death receptor-independent activation of a caspase-3 to caspase-8 pathway.
Programmed cell death is a critical process in B lymphocyte development. Premature apoptosis in developing B cells could affect the repertoire and number of mature B cells produced. Of particular concern is the ability of environmentally ubiquitous polycyclic aromatic hydrocarbons (PAH) to induce B cell apoptosis within the bone marrow microenvironment in a clonally nonspecific way. Here, models of bone marrow B cell development were used to assess the role of the "extrinsic" apoptosis pathway in PAH-induced apoptosis and to compare PAH-induced apoptosis with that induced during clonal deletion. As demonstrated previously with a nontransformed pro-/pre-B cell line, primary pro-B cells cultured on bone marrow stromal cells underwent apoptosis after exposure to a prototypic PAH, 7,12-dimethylbenz[a]anthracene (DMBA). Apoptosis was preceded by cleavage of caspase-3 (4-6 h) and caspase-8 (6-8 h) and their respective substrates, alpha-fodrin and Bid. Inhibition of caspase-3 blocked caspase-8 activation and apoptosis. Furthermore, a pan-caspase inhibitor blocked apoptosis and activation of both caspases-3 and -8. Cells from mice defective in tumor necrosis factor (TNF)-alpha, TNF-beta, lymphotoxin-beta, or TNFR1, TNFR2, Fas, or death receptor 6 were as susceptible to apoptosis signaling as wild-type cells. These results suggest a complex death receptor-independent B cell apoptosis pathway in which caspase-8 is activated downstream of caspase-3.
Ryu
Heui-Young
HY
Boston University School of Public Health, Dept. of Environmental Health, MA 02118, USA.
Emberley
Jessica K
JK
Schlezinger
Jennifer J
JJ
Allan
Lenka L
LL
Na
Songqing
S
Sherr
David H
DH
D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D017931:DNA Primers; D004785:Environmental Pollutants / Q000633:toxicity*; D004789:Enzyme Activation; D006801:Humans; D011083:Polycyclic Compounds / Q000633:toxicity*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*
D017931:DNA Primers; D004785:Environmental Pollutants; D011083:Polycyclic Compounds; D018124:Receptors, Tumor Necrosis Factor; C114109:TNFRSF21 protein, human; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases