Die Rolle von Zink in der Signaltransduktion von T-Zellen

  • The role of zinc in signal transduction of T cells

Hönscheid, Andrea; Rink, Lothar (Thesis advisor); Slusarenko, Alan (Thesis advisor)

Aachen : Publikationsserver der RWTH Aachen University (2010, 2011)
Dissertation / PhD Thesis

Aachen, Techn. Hochsch., Diss., 2010

Abstract

Zinc is an essential trace element with a variety of cellular functions in all organ systems. Disturbance of the cellular zinc availability by zinc deficiency leads to multiple disorders. Predominantly the cell-mediated immune response is influenced by zinc deprivation, and here in particular T-cell mediated functions. For example, the Th1/Th2 balance is disturbed leading to a reduced production of Th1 cytokines such as IFN-gamma and IL-2. Zinc supplementation in vivo causes reconstitution of Th1-mediated responses. To achieve a broad picture about the role of zinc in T-cell signal transduction, phosphorylation of several effector kinases in primary human T-cells and in the human T-cell line Jurkat was investigated. CD3-mediated activation and stimulation by zinc and the ionophore pyrithione led to differential activation of kinase Lck, MAPK p38, JNK1/2 and ERK1/2. Experiments showed that CD3-stimulated T-cells release intracellular zinc which has no effect on signal transduction itself. However, if cells were stimulated with zinc and pyrithione, the kinases Lck and p38 were activated, while CD3-induced ERK1/2 phosphorylation was reduced. To elucidate this differential zinc effect, several known zinc-mediated signalling mechanisms were investigated for their validity in T-cells. Lck is influenced by zinc in its activity at different levels. Experiments with Lck-negative cells showed that activation after stimulation with zinc and pyrithione additionally depends on protein tyrosine phosphatase CD45. Furthermore the observed zinc effect is independent from CD3 signalling and represents an intracellular event. MAPK phosphatase inhibition by zinc could be excluded as one possible explanation for p38 activation. Zinc induced phosphorylation of p38 by alternative activation mediated by Lck and ZAP70 could be also eliminated by inhibitor studies and the use of Lck and ZAP70 deficient cell lines. Further on, the involvement of the PKA signalling pathway was no explanation for the observed differential zinc effect, confirmed by the use of different inhibitors and activators. After verification of several signalling pathways, the molecular pathway of the observed zinc effect in T-cells seems to differ from established pathways in other cells. Although the mechanism could not be elucidated, it could be demonstrated that there is a connection between the induction of Th1 answers and the activation of p38/CREB cascade. For the first time the impact of zinc on Th1 cells could be linked to p38 activation. Further work on the molecular mechanism could have an influence on the treatment of T-cell mediated diseases and could open up new therapy perspectives.

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