Hydroquinone inhibits PMA-induced activation of NFkappaB in primary human CD19+ B lymphocytes.
Hydroquinone (HQ), a reactive metabolite of benzene, is known to inhibit mitogen-stimulated activation of both T and B lymphocytes. Despite extensive study, the underlying mechanism for the immunotoxicity of the HQ is not clear. We have previously demonstrated that 1 micromol/L HQ inhibits TNF-induced activation of NFkappaB in CD4+ T cells, resulting in decreased IL-2 production. NFkappaB, known to be important in T lymphocytes, also plays a critical role in normal B cell development and activation. We therefore hypothesized that alterations in NFkappaB might be involved in HQ-induced B cell immunosuppression as well. In this study, we demonstrate that 1-10 micromol/L HQ inhibits PMA/ionomycin-induced activation of NFkappaB in primary human CD19+ B cells. Inhibition of NFkappaB is accompanied by a dose-dependent decrease in PMA-stimulated production of TNF with no corresponding loss in viability or increased apoptosis. HQ also does not appear to alter NFkappaB directly, as preincubation of B cell nuclear extracts with HQ does not diminish DNA binding activity of this protein. In contrast to T cells, inhibition of NFkappaB by HQ in B cells is not reversible after 72 h in culture, suggesting a long-term functional suppression. These data support our original findings in T cells and indicate that NFkappaB is particularly susceptible to inhibition by HQ. We further hypothesize that inhibition of NFkappaB in lymphocytes, and perhaps other cell types as well, may play a significant role in the observed toxicity of HQ.
Pyatt
D W
DW
Molecular Toxicology and Environmental Health Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA.
Yang
Y
Y
Stillman
W S
WS
Cano
L L
LL
Irons
R D
RD
D000328:Adult; D018941:Antigens, CD19 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018941:Antigens, CD19; D006873:Hydroquinones; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate; C031927:hydroquinone