RT Journal Article
SR Electronic
T1 Environmental Chemical-Induced Bone Marrow B Cell Apoptosis: Death Receptor-Independent Activation of a Caspase-3 to Caspase-8 Pathway
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1087
OP 1096
DO 10.1124/mol.105.014712
VO 68
IS 4
A1 Ryu, Heui-Young
A1 Emberley, Jessica K.
A1 Schlezinger, Jennifer J.
A1 Allan, Lenka L.
A1 Na, Songqing
A1 Sherr, David H.
YR 2005
UL http://molpharm.aspetjournals.org/content/68/4/1087.abstract
AB 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, α-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)-α, TNF-β, lymphotoxin-β, 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.