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  • Title: Cell proliferation arrest within intrathymic lymphocyte progenitor cells causes thymic atrophy mediated by the aryl hydrocarbon receptor.
    Author: Laiosa MD, Wyman A, Murante FG, Fiore NC, Staples JE, Gasiewicz TA, Silverstone AE.
    Journal: J Immunol; 2003 Nov 01; 171(9):4582-91. PubMed ID: 14568932.
    Abstract:
    Activation of the aryl hydrocarbon receptor (AHR), a basic helix-loop-helix transcription factor, in lymphocytes by the immunosuppressive environmental contaminant 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to cause thymic atrophy in every species studied. We set out to identify the specific hemopoietic cellular populations in which the AHR was activated to lead to thymic atrophy and to determine the effect of AHR activation in those cellular populations. Initially, we examined whether AHR activation in intrathymic dendritic cells could mediate TCDD-induced thymic atrophy. It was found that thymic atrophy occurred only when the AHR could be activated in the thymocytes but not hemopoietic-derived dendritic cells or other APCs. We next analyzed the effect of TCDD on the proliferation of thymocytes in vivo. There was a significant increase in the percentage of thymocytes in the G(1) phase of the cell cycle and a significant decrease in the percentage of S plus G(2)/M thymocytes, especially in the CD4(-)CD8(-)CD3(-) triple-negative intrathymic progenitor cell population 24 h after exposure to 30 micro g/kg TCDD. Furthermore, by 12 h after exposure to TCDD, we observed approximately 60% reduction of 5-bromo-2'-deoxyuridine incorporation in specific intrathymic progenitor cell populations. This reduction persisted for at least 6 days. These data indicate that intrathymic progenitor cells are direct targets of TCDD in the thymus and suggest that TCDD causes thymic atrophy by reducing entrance into cell cycle in these populations.
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