Environmental chemical-induced pro/pre-B cell apoptosis: analysis of c-Myc, p27Kip1, and p21WAF1 reveals a death pathway distinct from clonal deletion.
Polycyclic aromatic hydrocarbons (PAH) are common environmental pollutants that suppress the immune system in part by inducing pro/pre-B cell apoptosis. The PAH-induced death signaling pathway resembles the signaling cascade activated during clonal deletion and modeled by B cell receptor cross-linking or by dexamethasone exposure of immature surface Ig(+) B cells in that apoptosis is mediated by NF-kappa B down-regulation. Because a PAH-induced, clonally nonrestricted deletion of B cells would have important implications for B cell repertoire development, the nature of the PAH-induced intracellular death signal was studied further. Particular emphasis was placed on the roles of growth arrest and c-Myc, p27(Kip1), and p21(WAF1) expression, because all of these elements contribute to clonal deletion. As in clonal deletion models, and as predicted by the down-regulation of NF-kappa B, PAH-induced death of pro/pre-B cells was at least partially dependent on c-Myc down-regulation. Furthermore, whereas dexamethasone induced a G(0)/G(1) cell cycle arrest, PAH had no effect on pro/pre-B cell growth, indicating that growth arrest and apoptosis occur by separable signaling pathways in this early phase of B cell development. Finally, in contrast to clonal deletion, PAH-induced pro/pre-B cell death was not dependent on p27(Kip1) or p21(WAF1) up-regulation but did coincide with p53 induction. These results distinguish the PAH-induced apoptosis pathway from that activated during clonal deletion and indicate that signaling cascades leading to growth arrest and/or apoptosis in pro/pre-B cells differ from those active at later B cell developmental stages.
Ryu
Heui-Young
HY
Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA.
Mann
Koren K
KK
Schlezinger
Jennifer J
JJ
Jensen
Brenda
B
Sherr
David H
DH
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000502:physiology*; D002460:Cell Line; D017637:Clonal Deletion / Q000187:drug effects*; D018920:Coculture Techniques; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004785:Environmental Pollutants / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004785:Environmental Pollutants; D006131:Growth Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015127:9,10-Dimethyl-1,2-benzanthracene; D003907:Dexamethasone