Adseverin – An Immune-Specific Target of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

Sammanfattning: The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces thymus atrophy and immunosuppression in all animal species examined and these effects constitute a potential risk to humans. TCDD can via binding to the intracellular aryl hydrocarbon receptor (AhR), modulate transcription of a number of genes and the aim of this thesis has been to identify such genes, which may explain the mechanisms behind TCDD-mediated immunotoxicity. The differential display polymerase chain reaction (PCR) technique was applied to screen for TCDD-responsive genes in the thymus of C57BL/6 mice. The major finding was that TCDD up-regulates the level of adseverin, an actin-severing protein. The induction of adseverin by TCDD was dose-dependent and could be detected before any signs of thymus atrophy were apparent. Reverse transcription-PCR analysis of the levels of adseverin in different tissues revealed that the up-regulation was restricted to lymphoid tissues with hematopoietic activity. Adseverin was not induced in lymph nodes indicating that peripheral resting T cells are refractory to TCDD exposure. Within the thymus, the induction of adseverin was shown to be a direct AhR-mediated effect on thymocytes, which are known target cells of TCDD. In contrast, no adseverin induction was observed in thymic stroma although TCDD clearly reached these cells, as they up regulated CYP1A1, a marker for TCDD exposure. By sorting the different maturation stages of thymocytes it was demonstrated that adseverin under normal conditions is expressed at high levels during early differentiation stages and then gradually down regulated as the thymocytes differentiate. Interestingly, TCDD exposure counteracted the down regulation of adseverin by inducing adseverin at all stages of thymocyte differentiation. This may explain previous observations that TCDD affects many different stages of thymocyte maturation.It is suggested that overexpression of adseverin leads to increased depolymerisation of the actin cytoskeleton. This may be detrimental for normal thymocyte/T cell activities such as migration and activation that are dependent on strictly controlled actin reorganisation. Thus, adseverin may be a critical target for TCDD and be involved in TCDD-induced immunotoxicity.