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Vol. 59, Issue 2, 302-309, February 2001

The Role of NF-kappa B as a Survival Factor in Environmental Chemical-Induced Pre-B Cell Apoptosis

Koren K. Mann, Stefan Doerre, Jennifer J. Schlezinger, David H. Sherr, and Shafat Quadri

Boston University Schools of Public Health and Medicine, Department of Environmental Health (K.K.M., J.J.S., D.H.S., S.Q.) and Boston University School of Medicine, Department of Microbiology (S.D.), Boston, Massachusetts

Polycyclic aromatic hydrocarbons (PAH) are ubiquitous environmental chemicals that suppress the immune system at multiple levels, including at the level of B cell development in the bone marrow microenvironment. Specifically, PAH induce preB cell apoptosis in primary bone marrow cultures and in cocultures of an early preB cell line (BU-11) and a bone marrow stromal cell line (BMS2). Previous studies focused on the molecular mechanisms through which PAH induce stromal cells to deliver an apoptosis signal to adjacent preB cells. Apoptosis signaling within the preB cell itself was not investigated. Here, the role of NF-kappa B, a lymphocyte survival factor, in PAH-induced preB cell apoptosis was assessed. Analysis of DNA-binding proteins extracted from the nuclei of untreated BU-11 cells indicated DNA-binding complexes comprising NF-kappa B subunits p50, c-Rel, and/or Rel A. NF-kappa B down-regulation with previously described inhibitors induced BU-11 cell apoptosis, demonstrating that the default apoptosis pathway blocked by NF-kappa B is functional at this early stage in B cell development. Similarly, exposure of BU-11/BMS2 cocultures to 7,12-dimethylbenz[a]anthracene (DMBA), a prototypic PAH, down-regulated nuclear Rel A and c-Rel before overt apoptosis. Finally, ectopic expression of Rel A or c-Rel rescued BU-11 cells from DMBA-induced apoptosis. These results extend previous observations by demonstrating that 1) NF-kappa B is a survival factor at an earlier stage of B cell development than previously appreciated and 2) NF-kappa B down-regulation is likely to be part of the molecular mechanism resulting in PAH-induced preB cell apoptosis. These results suggest nonclonally restricted, PAH-mediated suppression of B lymphopoiesis.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics