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Received for publication May 13, 2005.
Revised July 7, 2005.
Accepted for publication July 12, 2005.
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 non-specific way. Here, models of bone marrow B cell development were employed 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 previously demonstrated with a non-transformed pro/pre-B cell line, primary pro-B cells cultured on bone marrow stromal cells undergo apoptosis following 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, 
-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 TNF-, TNF-
, LT- or TNFR1, TNFR2, Fas, or DR6 were as susceptible to apoptosis signaling as wildtype cells. These results suggest a complex death receptor-independent B cell apoptosis pathway in which caspase-8 is activated downstream of caspase-3.
Key words:
Apoptosis, Protein targets
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