The role of NF-kappa B as a survival factor in environmental chemical-induced pre-B cell apoptosis

Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental chemica ls that suppress the immune system at multiple levels, including at the lev el of B cell development in the bone marrow microenvironment. Specifically, PAH induce preB cell apoptosis in primary bone marrow cultures and in cocu ltures of an early preB cell line (BU-11) and a bone marrow stromal cell li ne (BMS2). Previous studies focused on the molecular mechanisms through whi ch PAH induce stromal cells to deliver an apoptosis signal to adjacent preB cells. Apoptosis signaling within the preB cell itself was not investigate d. Here, the role of NF-kappaB, a lymphocyte survival factor, in PAH-induce d preB cell apoptosis was assessed. Analysis of DNA-binding proteins extrac ted from the nuclei of untreated BU-11 cells indicated DNA-binding complexe s comprising NF-kappaB subunits p50, c-Rel, and/or Rel A. NF-kappaB down-re gulation with previously described inhibitors induced BU-11 cell apoptosis, demonstrating that the default apoptosis pathway blocked by NF-kappaB is f unctional at this early stage in B cell development. Similarly, exposure of BU-11/BMS2 cocultures to 7,12-dimethylbenz[a]anthracene (DMBA), a prototyp ic PAH, down-regulated nuclear Rel A and c-Rel before overt apoptosis. Fina lly, ectopic expression of Rel A or c-Rel rescued BU-11 cells from DMBA-ind uced apoptosis. These results extend previous observations by demonstrating that 1) NF-kappaB is a survival factor at an earlier stage of B cell devel opment than previously appreciated and 2) NF-kappaB down-regulation is like ly to be part of the molecular mechanism resulting in PAH-induced preB cell apoptosis. These results suggest nonclonally restricted, PAH-mediated supp ression of B lymphopoiesis.