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Molecular mechanism of 7,12-dimethylbenz[a]anthracene-induced immunosuppression: evidence for action via the
M J Pallardy1, R V House, J H Dean
1Department of Cellular and Molecular Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
Abstract:
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.
Insights
The polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene suppresses immune function by disrupting the interleukin 2 pathway. This impacts T lymphocyte function and proliferation, contributing to immunosuppression.
Area of Science:
- Immunology
- Toxicology
- Molecular Biology
Background:
- Previous studies show 7,12-dimethylbenz[a]anthracene (DMBA) suppresses humoral and cell-mediated immunity in mice.
- DMBA-induced immunosuppression appears to target T helper lymphocytes, potentially via inhibiting interleukin 2 (IL-2) production.
Purpose of the Study:
- To investigate the molecular mechanisms of DMBA-induced T lymphocyte dysfunction.
- To determine the effects of DMBA exposure on the interleukin 2 (IL-2) pathway.
Main Methods:
- In vitro exposure of Concanavalin A (Con A)-activated splenocytes to DMBA.
- Assessing mitogenic response, IL-2 production, and IL-2 receptor expression.
- Evaluating proliferation of IL-2-dependent lymphoblasts and cultured splenocytes post-DMBA exposure.
Main Results:
- DMBA suppressed splenocyte mitogenic response and IL-2 production.
- DMBA reduced high-affinity IL-2 receptor expression, but not low-affinity receptors.
- DMBA exposure led to a dose-dependent decrease in proliferation of IL-2-dependent cells.
Conclusions:
- DMBA-induced immunosuppression is partly mediated through the interleukin 2 (IL-2)/IL-2 receptor pathway.
- DMBA disrupts critical components of T lymphocyte activation and proliferation.
- Understanding these molecular effects is crucial for addressing DMBA toxicity.