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Medical Institute of Environmental Hygiene,
Heinrich-Heine-University of Düsseldorf, Germany
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) binds and
activates the aryl hydrocarbon receptor (Ah-R), an endogenous
transcription factor that is expressed in the thymus. TCDD exposure
leads, among other effects, to thymus atrophy and immunosuppression. We
previously analyzed the interference of TCDD with differentiation
processes in fetal thymus organ cultures and found that in the presence of TCDD, the proliferation rate of immature
(CD4
CD8 and
CD4CD8+ HSA+) thymocytes is
inhibited, whereas the maturation along the CD4/CD8 path is
accelerated. Moreover, the differentiation of thymocytes is skewed by
TCDD at 
40% (compared with ~15% without TCDD) of the CD8
single-positive subset of future cytotoxic T cells, and apparently more
cells audition for and pass positive selection. The fetal murine thymus
expresses functional Ah-R mRNA, as shown by reverse
transcription-polymerase chain reaction and TCDD-inducible CYP1A1 and
CYP1B1 expression. Because the differentiation of thymocytes is to a
considerable extent controlled by cytokines and many cytokine genes are
potential targets of the Ah-R due to Ah-R-binding elements (xenobiotic
response elements) in their promoters, we analyzed the cytokine
expression in fetal thymus organ culture exposed to TCDD. Fetal thymi
were cultured from gestation day 15 for 8 days, thus covering
ex vivo the period after population of the thymus anlage
until birth. We show with semiquantitative reverse transcription-polymerase chain reaction that more interleukin (IL)-1
, IL-2, IL-6, tumor growth factor (TGF)-3, and tumor
necrosis factor-
are produced in TCDD-exposed thymi, whereas other
cytokines (e.g., TGF-1, PAI-2, or IL-4) are only slightly up- and
down-modulated during the culture period or not modulated at all (e.g.,
IL-1, IL-7, interferon-
, and TGF-2).
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