Zinc signals are utilized by several immune cell receptors. One is TLR4, which causes an increase of free zinc ions (Zn2+) that is required for the MyD88-dependent expression of inflammatory cytokines. This study investigates the role of Zn2+ on Toll/IL-1R domain–containing adapter inducing IFN-β (TRIF)–dependent signals, the other major intracellular pathway activated by TLR4. Chelation of Zn2+ with the membrane-permeable chelator N,N,N’,N’-Tetrakis(2-pyridylmethyl)ethylenediamine augmented TLR4-mediated production of IFN-β and subsequent synthesis of inducible NO synthase and production of NO. The effect is based on Zn2+ acting as a negative regulator of the TRIF pathway via reducing IFN regulatory factor 3 activation. This was also observed with TLR3, the only TLR that signals exclusively via TRIF, but not MyD88, and does not trigger a zinc signal. In contrast, IFN-γ–induced NO production was unaffected by N,N,N’,N’-Tetrakis(2-pyridylmethyl)ethylenediamine. Taken together, Zn2+ is specifically involved in TLR signaling, where it differentially regulates MyD88 and TRIF signaling via a zinc signal or via basal Zn2+ levels, respectively.

No abstract

Free zinc ions (Zn(2+)) participate in several signaling pathways. The aim of the present study was to investigate a potential involvement of Zn(2+) in the PI3K/Akt pathway of interleukin (IL)-2 signaling in T-cells. The IL-2 receptor triggers three major pathways, ERK1/2, JAK/STAT5, and PI3K/Akt. We have previously shown that an IL-2-mediated release of lysosomal Zn(2+) into the cytoplasm activates ERK1/2, but not STAT5. In the present study, Akt phosphorylation in response to IL-2 was abrogated by the Zn(2+) chelator N,N,N',N'-tetrakis-2(pyridyl-methyl)ethylenediamine, and was induced by treatment with Zn(2+) and the ionophore pyrithione. The latter were ineffective in cells that were treated with siRNA against the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a phosphatase that degrades the lipid second messenger PI(3,4,5)P3, which is produced by PI3K and leads to activation of Akt. Inhibition of recombinant PTEN by Zn(2+)in vitro yielded an IC50 of 0.59 nM. Considering a resting free cytoplasmic Zn(2+) level of 0.2 nM in the T-cell line CTLL-2, this seems ideally suited for dynamic regulation by cellular Zn(2+). Oxidation with H2O2 and supplementation with Zn(2+) led to similar changes in the CD spectrum of PTEN. Moreover, Zn(2+) partially prevented the oxidation of cysteines 71 and 124. Hence, we hypothesize that zinc signals affect the IL-2-dependent PI3K/Akt pathway by inhibiting the negative regulator PTEN through binding with a sub-nanomolar affinity to cysteine residues that are essential for its catalytic activity.

No abstract

No abstract