Repletion of zinc in zinc-deficient cells strongly up-regulates IL-1β-induced IL-2 production in T-cells

Abstract

Mild zinc deficiency in humans negatively affects IL-2 production resulting in declined percentages of cytolytic T cells and decreased NK cell lytic activity, which enhances the susceptibility to infections and malignancies. T-cell activation is critically regulated by zinc and the normal physiological zinc level in T-cells slightly lies below the optimal concentration for T-cell functions. A further reduction in zinc level leads to T-cell dysfunction and autoreactivity, whereas high zinc concentrations (100 μM) were shown to inhibit interleukin-1 (IL-1)-induced IL-1 receptor kinase (IRAK) activation. In this study, we investigated the molecular mechanism by which zinc regulates the IL-1β-induced IL-2 expression in T-cells. Zinc supplementation to zinc-deficient T-cells increased intracellular zinc levels by altering the expression of zinc transporters, particularly Zip10 and Zip12. A zinc signal was observed in the murine T-cell line EL-4 6.1 after 1 h of stimulation with IL-1β, measured by specific zinc sensors FluoZin-3 and ZinPyr-1. This signal is required for the phosphorylation of MAPK p38 and NF-κB subunit p65, which triggers the transcription of IL-2 and strongly increases its production. These results indicate that short-term zinc supplementation to zinc-deficient T-cells leads to a fast rise in zinc levels which subsequently enhance cytokine production. In conclusion, low and excessive zinc levels might be equally problematic for zinc-deficient subjects, and stabilized zinc levels seem to be essential to avoid negative concentration-dependent zinc effects on T-cell activation.

Parameters Influencing Zinc in Experimental Systems in Vivo and in Vitro

“…Once it is added to cell cultures, it rapidly loses its activity because of biological degradation, shown by the increasing concentration of intracellular zinc after prior depletion (Figure 3). An upregulation of zinc importers due to prior zinc depletion might be an explanation for higher zinc concentrations in TPEN-treated cells after an incubation time exceeding 24 h compared to the control cells [27]. Depending on their structure, chelators work at different cellular sites, which needs to be considered: TPEN, for example, chelates intracellular zinc, whereas DTPA does not.…”

Zip6 Transporter Is an Essential Component of the Lymphocyte Activation Machinery

“…Moreover, zinc influx from the extracellular compartment has been shown to fine-tune the TCR machinery, including Lck binding and phosphorylation of ZAP70 (16,17). Nevertheless, the latter aspect remains controversial because different studies have shown conflicting results regarding the influence of zinc in IL-2 production, an important early activation marker in T cells (16,18,19). Based on expression analysis, several Zip transporters have been suggested to participate in T cell physiology, including Zip6, Zip8, Zip10, and Zip12 (15,16,19,20).…”

Inhibition of interleukin‐1β‐mediated interleukin‐1 receptor‐associated kinase 4 phosphorylation by zinc leads to repression of memory T helper type 17 response in humans

“…Our previous studies showed that TCR‐mediated zinc influx is significantly influenced by the extracellular zinc concentration as the mean fluorescence intensity of Fluozin‐3, a zinc ion‐specific probe, is increased 10‐fold by addition of 45 μ m zinc compared with the induction when no zinc was added . Furthermore, several studies have suggested that elevated cytoplasmic zinc in T cells has an influence on cytokine‐mediated signalling . Although no significant effects on the expression of Th17‐promoting cytokine receptors, including IL‐1RI, by the addition of zinc, using 45 μ m ZnCl 2 (Fig.…”

“…13 Furthermore, several studies have suggested that elevated cytoplasmic zinc in T cells has an influence on cytokine-mediated signalling. 20,38 Although no significant effects on the expression of Th17-promoting cytokine receptors, including IL-1RI, by the addition of zinc, using 45 lM ZnCl 2 (Fig. 5), IL-1b-induced phosphorylation of IRAK4 was significantly inhibited in CD4 + T cells under the same zinc conditions (Fig.…”