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Top: Zinc interacts with a multitude of signaling pathways in different leukocyte subsets. During the activation of the adaptive immune system, the central interaction (depicted) takes place between antigen-presenting cells (APC) and T cells. Zinc, however, influences the same (as well as some other) pathways in different leukocyte subsets. APCs are activated by pattern recognition receptors, e.g., Toll-like receptors (TLRs). All TLRs, with the exception of TLR-3, generate a Zn signal after stimulation with their specific ligand.
For example, the activation of TLR-4 by lipopolysaccharide (LPS) from Gram-negative bacteria is shown to induce a fast Zn release (dotted arrows) from zincosomes. This fast Zn signal (in green) is physiologically required for nuclear factor kappa B (NFκB) activation (solid arrows) as well as for the mitogen-activated protein kinase (MAPK) signaling, both resulting in translocation of the appropriate transcription factors into the nucleus (dashed arrows). However, increasing Zn concentration for a time (e.g., after use of ionophores, highlighted in red) inhibits even TLR-4 signaling (). This effect appears to be mediated by direct inhibition of the IL-1 receptor-associated kinase (IRAK), a de-ubiquitination of the tumor necrosis factor receptor-associated factor 6 (TRAF-6) by upregulation of A20, a cyclic nucleotide phosphodiesterase (PDE) inhibition or an inhibition of TIR-domain-containing adapter-inducing interferon-β (TRIF). PDE inhibition results in an increase of cyclic guanosine monophosphate (cGMP). cGMP activates protein kinase A which inhibits RAF directly and NFκB indirectly. Lastly, increased intracellular Zn concentrations persisting for a longer time have the opposite effect due to an inhibition of adenylate cyclase (AC) transcription.
Bottom: On the T cell side, zinc influences the signaling of the T cell receptor (TCR), as well as the signaling pathways of at least IL-1, IL-2, and IL-4. A Zn signal is directly induced by ZIP 6 due to an APC-mediated activation (green) of TCR. This results in augmented ZAP phosphorylation, sustained Ca²⁺ influx, and downstream TCR signaling by binding of the lymphocyte-specific protein tyrosine kinase (LCK). The binding of IL-2 to its receptor (IL-2R) induces a Zn release from zincosomes (dotted arrow). The increased intracellular Zn concentration (red) mediates IRAK inhibition (), as described for APCs, and mediates c-Src tyrosine kinase (Csk)/protein kinase A (PKA) inhibition of LCK in TCR signaling. It also induces (solid arrows) a zeta-chain (TCR)-associated protein kinase (ZAP), and protein kinase C (PKC) activity, MAPK signaling, and NF-κB phosphorylation. Lastly, calcineurin (CN) is inhibited by increased intracellular Zn concentrations, avoiding translocation into the nucleus (dashed arrows) of the nuclear factor of activated T cells (NFAT). However, Zn deficiency also influences cytokine signaling in T cells. As an example, phosphorylation of the signal transducer and activator of transcription 6 (STAT6) in IL-4R signaling is decreased during Zn deficiency. Additional abbreviations: IKK, I kappa B kinase; IRF3, interferon regulatory factor 3; MKK, MAPK kinase; PKA, protein kinase A; PTP, protein tyrosine phosphatases; AP-1 activator protein 1; GMP, guanosine monophosphate; GTP, guanosine triphosphate; MKP, MAP-kinase phosphatase; CREB, cyclic adenosine monophosphate response element-binding protein.