Einfluss von Zink auf die Zytokingenregulation

  • Influence of zinc on cytokine gene regulation

Kloubert, Veronika; Rink, Lothar (Thesis advisor); Slusarenko, A. J. (Thesis advisor)

Aachen (2018)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2018

Abstract

Zinc deficiency in T cells is associated with decreased interleukin (IL)-2 production. The underlying molecular mechanisms leading to reduced IL-2 production are so far not completely elucidated. Here, a new molecular link, connecting zinc deficiency with decreased IL-2 production in T cells, was identified. This link is presented by the transcription factor cAMP responsive element modulator (CREM)α. After zinc deficiency, CREMα expression is increased on RNA and protein levels. An association between zinc, IL-2 and CREMα was confirmed in vitro as well as in vivo. In vivo, increased IL-2 production was associated with decreased CREMα production upon zinc supplementation of pigs. It is likely that increased amounts of CREMα in T cells, caused by increased protein phosphatase (PP)2A activity, lead to enhanced recruitment of histone deacetylase (HDAC)1. Here, it was shown that zinc leads to inhibited HDAC1 activity. Under zinc deficiency, HDAC1 is more active, which in turn causes increased histone deacetylation, resulting in a more condensed DNA state followed by reduced transcription. The half-maximal concentration of zinc on HDAC1 was determined with a value of 0.26 nM, correlating the intracellular amount of zinc in zinc adequate Jurkat cells. Moreover, zinc deficiency caused increased deacetylation of H3K9. Proper zinc homeostasis is ensured by regulation of zinc transporters. Here, significant up-regulation of Zip10 expression was observed in contrast to significant down-regulation of ZnT1, ZnT3 and ZnT8 transporter expression. Participation of the transcription factor metal-responsive transcription factor (MTF)-1 as an additional regulator of IL-2 expression could be excluded as well as differential methylation of the IL2 gene after zinc deficiency. To summarize, a molecular link was found with CREMα, connecting zinc with altered IL-2 production in T cells. One possible future approach might be to beneficially influence impaired IL-2 production due to zinc supplementation, ensuring proper immune responses. Apart from that, the use of zinc as an HDAC1 inhibitor might be applied in different illnesses.