Inhibition of NF-kappaB by hydroquinone sensitizes human bone marrow progenitor cells to TNF-alpha-induced apoptosis.
Suppression of hematopoiesis is an important mechanism governing blood cell formation. Factors such as tumor necrosis factor alpha (TNF-alpha) inhibit proliferation and colony-forming activity of bone marrow cells and activate nuclear factor kappa B (NF-kappaB) in multiple cell types. Activated NF-kappaB is required for many cells to escape apoptosis, including hematopoietic progenitor cells (HPC). The benzene metabolite hydroquinone (HQ) alters cytokine response and induces cell death in HPC, and inhibits NF-kappaB activation in T and B cells. Therefore, we studied the potential role of HQ-induced NF-kappaB inhibition in a hematopoietic cell line (TF-1) and primary HPC in rendering these cells susceptible to TNF-alpha-induced apoptosis. We demonstrate in both cell types that TNF-alpha activates NF-kappaB, and HQ exposure inhibits activation of NF-kappaB by TNF-alpha in a dose dependent manner. We further investigated the ability of HQ to potentiate TNF-alpha-induced apoptosis in these cells, and found that HQ sensitized the cells to the pro-apoptotic effect of TNF-alpha. These results suggest that NF-kappaB plays a key role in HPC survival, and that HQ-induced inhibition of NF-kappaB leaves these cells susceptible to cytokine-induced apoptosis. These effects may play a role in the suppression of hematopoiesis seen in some benzene exposed individuals.
Kerzic
Patrick J
PJ
Molecular Toxicology and Environmental Health Sciences Program, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box C238, Denver 80262, USA.
Pyatt
David W
DW
Zheng
Jia Hua
JH
Gross
Sherilyn A
SA
Le
Anh
A
Irons
Richard D
RD
D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D006873:Hydroquinones; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C031927:hydroquinone