Environmental chemical-induced pro/pre-B cell apoptosis: analysis of c-Myc, p27Kip1, and p21WAF1 reveals a death pathway distinct from clonal deletion.
J Immunol
; 170(10): 4897-904, 2003 May 15.
Article
em En
| MEDLINE
| ID: mdl-12734332
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
/
Subpopulações de Linfócitos B
/
Proteínas Proto-Oncogênicas c-myc
/
Apoptose
/
Ciclinas
/
Deleção Clonal
/
Proteínas de Ciclo Celular
/
Proteínas Supressoras de Tumor
/
9,10-Dimetil-1,2-benzantraceno
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2003
Tipo de documento:
Article