Antioxidant and anti-inflammatory effects of zinc. Zinc-dependent NF-κB signaling

Abstract

Zinc is a nutritionally fundamental trace element, essential to the structure and function of numerous macromolecules, including enzymes regulating cellular processes and cellular signaling pathways. The mineral modulates immune response and exhibits antioxidant and anti-inflammatory activity. Zinc retards oxidative processes on a long-term basis by inducing the expression of metallothioneins. These metal-binding cysteine-rich proteins are responsible for maintaining zinc-related cell homeostasis and act as potent electrophilic scavengers and cytoprotective agents. Furthermore, zinc increases the activation of antioxidant proteins and enzymes, such as glutathione and catalase. On the other hand, zinc exerts its antioxidant effect via two acute mechanisms, one of which is the stabilization of protein sulfhydryls against oxidation. The second mechanism consists in antagonizing transition metal-catalyzed reactions. Zinc can exchange redox active metals, such as copper and iron, in certain binding sites and attenuate cellular site-specific oxidative injury. Studies have demonstrated that physiological reconstitution of zinc restrains immune activation, whereas zinc deficiency, in the setting of severe infection, provokes a systemic increase in NF-κB activation. In vitro studies have shown that zinc decreases NF-κB activation and its target genes, such as TNF-α and IL-1β, and increases the gene expression of A20 and PPAR-α, the two zinc finger proteins with anti-inflammatory properties. Alternative NF-κB inhibitory mechanism is initiated by the inhibition of cyclic nucleotide phosphodiesterase, whereas another presumed mechanism consists in inhibition of IκB kinase in response to infection by zinc ions that have been imported into cells by ZIP8.

Keywords: Inflammation; NF-κB signaling; Oxidative stress; Protein A20; ZIP8; Zinc.

Fig. 1

Canonical and alternative pathways for NF-κB activation. The canonical pathway is dependent on activation of IKKβ and is triggered mainly by proinflammatory cytokines, such as tumor necrosis factor-α (TNFα) and interleukin-1 (IL-1), bacterial lipopolysaccharides (LPS), growth factors, and antigens. Activation of this pathway regulates expression of proinflammatory and cell survival genes. The alternative NF-κB pathway is activated by lymphotoxin β (LTβ), CD40 ligand, and B-cell activating factor (BAFF) and results in the activation of IKKα by the NF-κB-inducing kinase (NIK), followed by phosphorylation of the p100 NF-κB subunit by IKKα. Activation of the alternative pathway regulates genes required for lymphoid organogenesis and B-cell activation

Fig. 2

Domain structure of A20. A20 consists of an N-terminal ovarian tumor (OTU) domain and 7C-terminal domain built up by seven zinc fingers (ZF1–ZF7), mediating, respectively, the deubiquitylating (DUB) activity of A20 and its ubiquitin ligase and ubiquitin-binding activity. A20 interacts with substrates, such as receptor-interacting protein 2 (RIP2), and enzymes, such as TNFR-associated factor 6 (TRAF6) via the OTU domain, and with ubiquitin-binding proteins, such as TAX1-binding protein 1 (TAX1BP1), RING-finger protein 11 (RNF11), IκB kinase-γ (IKKγ), A20-binding inhibitor of NF-κB activation 1 (ABIN1), and ABIN2 via the ZF domain

Fig. 3

Nuclear factor (NF)-κB regulatory activities of A20. A20 deubiquitinates receptor interacting protein 1 (RIP1), preventing its interaction with NF-κB essential modulator (IKK-γ and NEMO) during TNFR signaling. Moreover, A20 inhibits NF-κB signaling by removing polyubiquitin chains form TNF receptor associated factor 6 (TRAF6) and receptor interacting protein 2 (RIP2) during TLR/IL-1R and NOD signaling, respectively. A20 may interact also with other proteins that bind to ubiquitin