Thymic alterations induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin are strictly dependent on aryl hydrocarbon receptor activation in hemopoietic cells.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related congeners affect the immune system, causing immunosuppression and thymic atrophy in a variety of animal species. TCDD is believed to exert its effects primarily through the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Although the AhR is found at high levels in both thymocytes and thymic stroma, it is uncertain in which cells TCDD is activating the AhR to cause alterations in the thymus. Some investigators have suggested that stromal elements, primarily epithelial cells, within the thymus are the primary targets for TCDD. Others have suggested that atrophy is due to a direct effect on thymocytes, either by apoptosis or by altering the development of progenitor cells. By producing chimeric mice with TCDD-responsive (AhR[+/+]) stromal components and TCDD-unresponsive (AhR[-/-]) hemopoietic components, or the reverse, we have clarified the role of stromal vs hemopoietic elements in TCDD-induced thymic alterations. Our results show that the targets for TCDD-induced thymic atrophy and phenotypic alterations are strictly in the hemopoietic compartment and that TCDD activation of epithelial cells in the stroma is not required for thymic alterations. Furthermore, changes observed in the putative stem cell populations of these chimeric mice are also dependent on TCDD activation of the AhR in hemopoietic elements.
Staples
J E
JE
Department of Microbiology and Immunology, State University of New York, Health Science Center, Syracuse 13210, USA.
Murante
F G
FG
Fiore
N C
NC
Gasiewicz
T A
TA
Silverstone
A E
AE
D000818:Animals; D001284:Atrophy; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D006410:Hematopoiesis / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011828:Radiation Chimera; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*
D018960:Hyaluronan Receptors; D007166:Immunosuppressive Agents; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D015375:Receptors, Interleukin-2; D019363:Cytochrome P-450 CYP1A1