“
“Zinc signals, i.e. a change of the intracellular concentration of free zinc ions in response to receptor stimulation, are involved in signal transduction in several immune cells. Here, the role of zinc signals in T-cell activation by IL-2 was investigated in the murine cytotoxic T-cell line CTLL-2 and

in primary human T cells. Measurements with the fluorescent dyes FluoZin-3 and Zinquin showed that zinc is released from lysosomes into the cytosol in response to stimulation of the IL-2-receptor. Activation of the ERK-pathway was blocked by chelation of free MG-132 mw zinc with N,N,N′,N′-tetrakis-2(pyridyl-methyl)ethylenediamine, whereas zinc was not required for STAT5 phosphorylation. In addition, the key signaling molecules MEK and ERK were

activated in response to elevated free intracellular zinc, induced by incubation with zinc and the ionophore pyrithione. Downstream of ERK activation, ERK-specific gene selleck kinase inhibitor expression of c-fos and IL-2-induced proliferation was found to depend on zinc. Further experiments indicated that inhibition of MEK and ERK-dephosphorylating protein phosphatases is the molecular mechanism for the influence of zinc on this pathway. In conclusion, an increase of cytoplasmic free zinc is required for IL-2-induced ERK signaling and proliferation of T cells. Zinc signals have been observed in different cell types of the immune system, including monocytes, dendritic cells, and mast cells 1. T-cell function is particularly susceptible to zinc deprivation, and zinc signals were suggested to activate protein kinase C in T cells 1, 2. Furthermore, zinc is involved

in the activation of the Src-family kinase Lck by the TCR. Here, zinc ions are required for interactions at two protein/protein interface sites. First, they stabilize the interaction between Lck and CD4 or CD8, recruiting the kinase to the TCR signaling complex 3. Second, zinc ions stabilize homodimerization of Lck, which promotes activating transphosphorylation between two Lck molecules 4. Cellular zinc homeostasis is Fenbendazole mediated by ten members of the ZnT family and 14 members of the Zrt-, Irt-like protein (ZIP) family of zinc transporters 5. Intracellular localization for most of these transporters remains to be determined. So far, no nuclear zinc transporters were identified, even though there is evidence that nuclear and cytoplasmic zinc are differentially regulated 6. In general, ZIP transport zinc into the cytoplasm, whereas ZnT transport zinc out of the cell or into cellular compartments, including different vesicular structures 7. Importantly, zinc accumulates in a lysosomal compartment of T cells, from which it is released by ZIP8 in response to TCR-mediated activation by antibodies against CD2, CD3, and CD28 8.