CYTOKINE GENE-EXPRESSION DURING ONTOGENY IN MURINE THYMUS ON ACTIVATION OF THE ARYL-HYDROCARBON RECEPTOR BY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) binds and activates the ary l 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 i nterference of TCDD with differentiation processes in fetal thymus org an cultures and found that in the presence of TCDD, the proliferation rate of immature (CD4(-)CD8(-) and CD4(-)CD8(+) HSA(+)) thymocytes is inhibited, whereas the maturation along the CD4/ CD8 path is accelerat ed. Moreover, the differentiation of thymocytes is skewed by TCDD at l ess than or equal to 40% (compared with similar to 15% without TCDD) o f the CD8 single-positive subset of future cytotoxic T cells, and appa rently more cells audition for and pass positive selection, The fetal murine thymus expresses functional Ah-R mRNA, as shown by reverse tran scription-polymerase chain reaction and TCDD-inducible CYP1A1 and CYP1 B1 expression. Because the differentiation of thymocytes is to a consi derable extent controlled by cytokines and many cytokine genes are pot ential targets of the Ah-R due to Ah-R-binding elements (xenobiotic re sponse elements) in their promoters, we analyzed the cytokine expressi on in fetal thymus organ culture exposed to TCDD. Fetal thymi were cul tured from gestation day 15 for less than or equal to 8 days, thus cov ering ex vivo the period after population of the thymus anlage until b irth. We show with semiquantitative reverse transcription-polymerase c hain reaction that more interleukin (IL)-1 beta, IL-2, IL-6, tumor gro wth factor (TGF)-beta 3, and tumor necrosis factor-alpha are produced in TCDD-exposed thymi, whereas other cytokines (e.g., TGF-beta 1, PA1- 2, or IL-4) are only slightly up- and down-modulated during the cultur e period or not modulated at all (e.g., IL-1 beta, IL-7, interferon-ga mma, and TGF-beta 2).