Molecular mechanism of 7,12-dimethylbenz[a]anthracene-induced immunosuppression: evidence for action via the interleukin-2 pathway.
Previous studies in this laboratory have demonstrated that exposure of mice to the carcinogenic polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene results in suppression of both humoral and cell-mediated immunity. This suppression is unaccompanied by any significant alteration in splenic lymphocyte subpopulation composition, suggesting that the immune deficit was due to a modulation of lymphocyte function. Additional studies implicated the T helper lymphocyte as the probable target for 7,12-dimethylbenz[a]anthracene-induced immunosuppression, apparently through an inhibition of interleukin 2 production. The purpose of the present study was to examine the mechanism of 7,12-dimethylbenz[a]anthracene-induced T lymphocyte dysfunction at the molecular level and to determine the consequences of 7,12-dimethylbenz[a]anthracene exposure on the interleukin 2 pathway. In vitro exposure of Con A-activated splenocytes to 7,12-dimethylbenz[a]anthracene resulted in suppression of the mitogenic response, suppressed interleukin 2 production, and reduced the expression of the high affinity receptor for interleukin 2. In contrast, expression of the low affinity interleukin 2 receptor was not affected. In addition, interleukin 2-dependent lymphoblasts and long term cultured splenocytes exhibited a dose-dependent decrease in proliferation following in vitro exposure to 7,12-dimethylbenz[a]anthracene. These results suggest that 7,12-dimethylbenz[a]anthracene-induced immunosuppression may be mediated, at least in part, through the interleukin 2/interleukin 2 receptor pathway.
Pallardy
M J
MJ
Department of Cellular and Molecular Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
House
R V
RV
Dean
J H
JH
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology*; D000818:Animals; D003208:Concanavalin A / Q000494:pharmacology; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D015375:Receptors, Interleukin-2 / Q000032:analysis
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D003208:Concanavalin A; D015127:9,10-Dimethyl-1,2-benzanthracene