DIMETHYLDITHIOCARBAMATE INHIBITS IN-VITRO ACTIVATION OF PRIMARY HUMANCD4(-LYMPHOCYTES() T)

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 complex ity of the DTCs biological activities and are probably due in part to differences in dose, route of exposure, animal species used and/or spe cific compound tested. The studies described herein were undertaken to investigate the immunotoxicity of one member of this family, dimethyl dithiocarbamate (DMDTC). We demonstrate that 0.1-0.5 mu M DMDTC inhibi ts TNF-alpha-induced activation of NF-kappa B in primary human CD4(+) T cells. This inhibition is not accompanied by a loss in viability, an d DMDTC-treated T cells retain other active signaling pathways through out the exposure duration. The inhibition of NF-kappa B is apparently permanent as DMDTC-treated T cells did not regain normal TNF-alpha act ivation, even after 72 h in culture. DMDTC does not appear to alter NF -kappa B directly as pre-incubation of nuclear extracts with DMDTC doe s not diminish binding activity of this protein. We further demonstrat e that 0.1-0.5 mu M DMDTC inhibits intracellular IL-2 production and d ecreases surface expression of CD25 (the alpha subunit of the IL-2 rec eptor) in T cells stimulated with phorbol ester. These data demonstrat e that DMDTC is a potent immunosuppressive compound in vitro. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.