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Functions of mononuclear phagocytes in mice exposed to diethylstilbestrol: a model of aberrant macrophage development
Abstract:
Administration of the synthetic estrogen diethylstilbestrol (DES) lowers the systemic resistance of mice to challenge with either tumor cells or the facultative intracellular parasite Listeria monocytogenes. To assess the potential role of impaired mononuclear phagocyte system (MPS) function in this depression of host resistance, we addressed the question of systemic perturbations of the MPS induced by administration of DES. A panel of objective quantitative markers which have been previously shown to identify and characterize macrophages in the several stages of development of activation was employed. DES perturbed the resident population of peritoneal macrophages by increasing their number approximately twofold and by enhancing their competence for phagocytosis, cytostasis of tumor cells, and secretion of plasminogen activator. When we examined the competence of the MPS in DES-treated mice to respond to challenge with activating stimuli, we found that DES systemically suppressed the development of macrophages, in response to either pyran copolymer or BCG, to develop tumoricidal function and to gain competence for secretion of reactive oxygen intermediates such as H2O2. Since these data suggested that DES inhibited the development of macrophages from a precursor stage (i.e., responsive macrophages) to activated macrophages in vivo, we tested this possibility directly by applying known activating signals in vitro to responsive macrophages. Responsive macrophages from DES-treated mice did not become activated in response to the application of two known potent activating signals (i.e., MAF + LPS). Taken together, the data indicate that DES systemically perturbs the MPS and does so by enhancing development of the early stages of maturation and suppressing subsequent development.
Insights
Synthetic estrogen diethylstilbestrol (DES) impairs host resistance by disrupting the mononuclear phagocyte system (MPS). DES enhances early macrophage maturation but suppresses their ability to become fully activated and tumoricidal.
Area of Science:
- Immunology
- Endocrinology
- Pharmacology
Background:
- Diethylstilbestrol (DES) is a synthetic estrogen known to suppress host resistance.
- The mononuclear phagocyte system (MPS) plays a crucial role in host defense against infections and tumors.
- Understanding how DES affects MPS function is vital for comprehending its immunomodulatory effects.
Purpose of the Study:
- To investigate the systemic effects of DES administration on the function of the mononuclear phagocyte system (MPS) in mice.
- To determine if impaired MPS function contributes to the reduced host resistance observed after DES exposure.
- To characterize the specific stages of macrophage development and activation affected by DES.
Main Methods:
- Mice were treated with DES, and their peritoneal macrophages were analyzed using quantitative markers.
- Macrophage functions including phagocytosis, cytostasis, and mediator secretion were assessed.
- The response of macrophages to in vivo and in vitro activating stimuli (pyran copolymer, BCG, MAF + LPS) was evaluated.
Main Results:
- DES administration increased peritoneal macrophage numbers and enhanced their phagocytic and tumoricidal precursor functions.
- However, DES suppressed the development of fully activated, tumoricidal macrophages in response to immune stimuli.
- Macrophages from DES-treated mice failed to activate properly in vitro when exposed to potent activating signals.
Conclusions:
- DES causes systemic perturbations in the MPS by altering macrophage maturation.
- The synthetic estrogen enhances early macrophage development but inhibits their progression to a fully activated state.
- This dual effect of DES on macrophage activation likely contributes to the observed depression of host resistance.