Immune-specific up-regulation of adseverin gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin.
To identify genes that are regulated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and possibly involved in TCDD-induced immunotoxicity, we used the differential display technique to screen for differentially expressed genes in the mouse thymus. Here we show that TCDD increased the expression of adseverin, a Ca(2+)-dependent, actin-severing protein. The induction of adseverin is dose- and time-dependent in parallel with the induction of CYP1A1, which is currently the most frequently used marker for TCDD exposure. A comparison between mouse strains with different TCDD responsiveness indicated that the induction of adseverin is dependent on the aryl hydrocarbon receptor, a transcription factor known to mediate most of TCDD's biological effects. Examination of additional organs revealed that the up-regulation of the adseverin gene expression is immune-specific. Using an anti-adseverin antibody, we confirmed the induction of adseverin by TCDD at the protein level and it was confined to the thymic cortex, which harbors immature thymocytes that are known target cells of TCDD. Considering adseverin's role in actin cytoskeletal reorganization, our observations reveal new mechanistic aspects of how TCDD might exert some of its immunotoxic effects.
Svensson
C
C
Department of Pharmaceutical Biosciences, Division of Toxicology, Biomedical Centre, Uppsala University, Uppsala, Sweden.
Lundberg
K
K
D000199:Actins / Q000378:metabolism; D000818:Animals; D004147:Dioxins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018260:Gelsolin; D005786:Gene Expression Regulation / Q000187:drug effects*; D007109:Immunity; D016906:Interleukin-9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
C092566:2,3,7,8-tetrafluorodibenzodioxin; D000199:Actins; D004147:Dioxins; D018260:Gelsolin; D016906:Interleukin-9; D008840:Microfilament Proteins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C065395:scinderin