The Cell Biology of Zinc with Relevance to the Immune System

Zinc and the cell cycle

Treatment of lymphocytes with mitogens results in a fairly rapid increase in cellular Zn (see Zalewski, 1996; Shankar and Prasad, 1998; Prasad, 2000a). These findings are consistent with studies indicating a requirement for Zn during the mid to late G1 phase of the cell cycle in promotion of thymidine kinase expression (Chesters et al., 1993) and in another less well-defined step involved in cell transition to S phase. Activated lymphocytes take up Zn via multiple mechanisms, including receptors for Zn-transferrin, metallothionein, albumin and c^-macroglobulin (see Walsh et al., 1994; Shankar and Prasad, 1998; Prasad, 2000a) and also by other less well-characterized mechanisms, such as anionic channels or transporters. The Zn-dependent activity of DNA polymerase may account, in part, for the influence of Zn during the S phase of the cell cycle. Zn may also play a role in transition to the G2 and M phases. A greater proportion of S- compared with G2-phase cells was observed among mitogen-stimulated lymphocytes from mildly Zn-deficient patients suffering from sickle-cell anaemia (Prasad, 2000a). The ratio returned to normal following a period of Zn supplementation. The M phase of the cell cycle may also be affected by Zn deficiency, since defective tubulin polymerization is seen in tissues from Zn-deficient animals (see Shankar and Prasad, 1998), and Zn is known to bind the N-terminal of tubulin, thereby stabilizing microtubule formation.

Zinc and cell replication

Zn influences the activity of multiple enzymes, which act at the very basic levels of replication and transcription. These include DNA polymerase, thymidine kinase, DNA-dependent RNA polymerase, terminal deoxyribonucleotidyl trans-

ferase and aminoacyl tRNA synthetase (Walsh et al., 1994; Zalewski, 1996; Shankar and Prasad, 1998), and the family of transcriptional regulators known as Zn-finger DNA-binding proteins. In addition, Zn forms the active enzymatic sites of many metalloproteases. The activity of the major enzyme regulating DNA replication, DNA polymerase, is Zn-dependent. It is inhibited by Zn deficiency and Zn chelators and is enhanced by addition of low concentrations of Zn in vitro. Thymidine kinase, crucial for the synthesis of phosphorylated pyrim-idines, is also very sensitive to dietary Zn depletion. Zn is, in fact, required for expression of multiple genes regulating mitosis, including thymidine kinase, ornithine decarboxylase and c-myc. Several transcription factors, such as nuclear factor kappa B (NFkB), metallothionein transcription factor 1 (MTF-1) and really interesting new gene (RING), contain Zn-finger-like domains, which may be influenced by changes in intracellular pools of Zn. In addition, Zn deprivation affects the activity of RNA polymerase, needed for transcription.

Zinc and lymphocyte activation

Zn plays a role in multiple aspects of T lymphocyte activation and signal trans-duction. Zn has been implicated in the non-covalent interaction of the cytoplas-mic tails of CD4 and CD8 with the tyrosine kinase p56lck, an essential protein in the early steps of T-cell activation (Turner et al., 1990). Through this and possibly other pathways, Zn stimulates autophosphorylation of tyrosine residues by p56lck and subsequent phosphorylation of the T-cell-receptor complex involving CD45. Zn is also involved in the activity of phospholipase C to give rise to inositol trisphosphate and diacylglycerol (see Zalewski, 1996). In addition, Zn affects the phosphorylation of proteins mediated by protein kinase C. Subsequent changes through protein phosphorylation regulate activation and cell proliferation.

Zinc and apoptosis

The major mechanism of cell death in the body and in cell culture is apoptosis, a form of cell suicide characterized by a decrease in cell volume, dramatic condensation of the chromatin and cytoplasm and fragmentation of nuclear DNA. Apoptosis is a normal physiological process, enabling a variety of important processes, from epithelial turnover to T- and B-cell development. The dysregulation of such a basic process would, therefore, have important health consequences.

Zn-deficient animals exhibit enhanced spontaneous and toxin-induced apop-tosis in multiple cell types (see Zalewski and Forbes, 1993; Shankar and Prasad, 1998). Thymic atrophy is a central feature of Zn deficiency (see later). It is now known that this atrophy is accompanied by apoptotic cell death of thymocytes. Several studies have demonstrated that Zn is a regulator of lymphocyte apoptosis in vivo and in vitro (see Zalewski and Forbes, 1993; Shankar and Prasad, 1998; Prasad, 2000a). Zn supplementation decreased mycotoxin-induced apoptosis of macrophages and T-cells in mice. In addition, Zn administration to mice 48 h prior to intraperitoneal injection of endotoxin (lipopolysaccharide (LPS)) greatly abrogated subsequent apoptotic DNA cleavage in thymocytes and loss in thymic weight. In vitro, greater numbers of lymphocytes and thymocytes undergo apop-tosis when cultured with Zn-free medium or with Zn chelators. Conversely, apop-tosis of T lymphocytes induced by in vitro exposure to toxins and other agents is prevented by the addition of high concentrations of Zn salts. Cells could also be rescued from apoptosis with physiological levels (5-25 ^M) of Zn salts if uptake was facilitated by the Zn ionophore pyrithione. It has been suggested that Zn is a major intracellular regulator of apoptosis, since lymphocytes maintain intracellular Zn at levels slightly above those needed to suppress apoptosis. In addition, a dose-response relationship exists between intracellular Zn levels and the degree of susceptibility to apoptosis.

The mechanisms whereby Zn affects apoptosis are not well understood, but it is likely that Zn acts at multiple levels. There is a good correlation between inhibition of Ca2+/Mg2+ DNA endonuclease activity and inhibition of apoptotic DNA fragmentation (see Shankar and Prasad, 1998). Although in vivo data are lacking, the Ca/Zn balance may regulate endonuclease activity. Nucleoside phosphorylase, another Zn-dependent enzyme, may inhibit apoptosis by preventing the accumulation of toxic nucleotides (Prasad, 1993). Likewise, poly (ADP-ribose) polymerase, the Zn-dependent nuclear enzyme, interacts with and inhibits the Ca2+/Mg2+ DNA endonuclease. In lymphocytes undergoing apoptosis, there is a large increase in cytoplasmic Zn, possibly originating from release of Zn from nuclear proteins.

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