Dimethyldithiocarbamate inhibits in vitro activation of primary human CD4+ T lymphocytes.
Dithiocarbamates (DTC), a diverse group of industrial and therapeutic chemicals, have been reported to inhibit, enhance or have no effect on the immune system. These apparent inconsistencies reflect the complexity of the DTCs biological activities and are probably due in part to differences in dose, route of exposure, animal species used and/or specific compound tested. The studies described herein were undertaken to investigate the immunotoxicity of one member of this family, dimethyldithiocarbamate (DMDTC). We demonstrate that 0.1-0.5 microM DMDTC inhibits TNF-alpha-induced activation of NF-kappaB in primary human CD4+ T cells. This inhibition is not accompanied by a loss in viability, and DMDTC-treated T cells retain other active signaling pathways throughout the exposure duration. The inhibition of NF-kappaB is apparently permanent as DMDTC-treated T cells did not regain normal TNF-alpha activation, even after 72 h in culture. DMDTC does not appear to alter NF-kappaB directly as pre-incubation of nuclear extracts with DMDTC does not diminish binding activity of this protein. We further demonstrate that 0.1-0.5 microM DMDTC inhibits intracellular IL-2 production and decreases surface expression of CD25 (the alpha subunit of the IL-2 receptor) in T cells stimulated with phorbol ester. These data demonstrate that DMDTC is a potent immunosuppressive compound in vitro.
Pyatt
D W
DW
Molecular Toxicology and Environmental Health Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA.
Gruntmeir
J
J
Stillman
W S
WS
Irons
R D
RD
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D004125:Dimethyldithiocarbamate / Q000633:toxicity*; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004125:Dimethyldithiocarbamate; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016328:NF-kappa B; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D013755:Tetradecanoylphorbol Acetate