Antiinflammatory effects of selenium

Effects on cell signalling and gene transcription

Se compounds have anti-inflammatory properties, probably resulting from their ability to influence the redox state of the cell and to remove ROS (Parnham and Graf, 1987). Recently, it has been realized that ROS serve as secondary messengers within cells, conveying signals of oxidative damage from the plasma membrane through the cellular signalling cascades by influencing kinase activity and by regulating the induction of transcription factors and their DNA-binding ability in the nucleus (Lander, 1997; McKenzie et al., 2002). Many protein-protein and protein-DNA interactions require thiol groups or cysteine residues on the proteins to be in a reduced state. This can be regulated by the thioredoxin reductase/thioredoxin system. The complexities of these interactions are still being unravelled. However, two key anti-inflammatory targets of Se are the transcription factors, activated protein 1 (AP-1) and nuclear factor kappa B (NFkB). These factors and the genes encoding them are activated by changes in the redox state of the cell and oxidative stress, such as may be caused by chemicals or radiation. For example, ROS activate a protease, which cleaves the inhibitory subunit from the inactive NFkB in the cytoplasm, allowing the activated NFkB to move to the nucleus, where it activates gene transcription. Many pro-inflammatory cytokine genes have binding sites for these factors in their promoter regions. Se prevents gene induction by metabolizing ROS to prevent transcription-factor activation and possibly by inhibiting binding of the transcription factor to its response element on the DNA (reviewed in McKenzie et al., 2002).

Effects of selenium on cytokines and adhesion molecules

Se compounds block the constitutive expression of IL-1, IL-6, tumour necrosis factor alpha (TNF-a) and IL-8 in skin cells (see Figs 12.4 and 12.6). Induction of these pro-inflammatory cytokines leads to up-regulation of adhesion molecules on endothelial cells and binding and recruitment of leucocytes to damaged tissue (Fig. 12.4). These cytokines also activate leucocytes, increasing their release of inflammatory mediators. IL-8 acts as a potent chemoattractant for neutrophils and T-cells. Endothelial cells grown under Se-deficient conditions and stimulated with TNF-a bind more neutrophils than endothelial cells from Se-replete controls and have higher levels of E-selectin, P-selectin and intercellular adhesion molecule-1 expression (see Maddox et al., 1999; McKenzie et al., 2002).

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Fig. 12.6. Inhibition of cytokine release from normal human keratinocytes in culture by selenium. Primary keratinocytes were supplemented with either sodium selenite or selenomethionine for 24 h prior to the media being collected and the protein levels measured by ELISA. Control cells had no selenium added. Results are expressed as the mean ± standard error of the mean, n = 3. Significant difference from the control cells, * P < 0.05. IL-8, interleukin-8.

Conversely, Beck and Levander have shown that Se deficiency down-regulates the production of certain cytokines in the hearts of mice infected with a cardiotoxic virus. Mice fed Se-deficient diets did not differ in the production of IL-1 from the Se-replete controls, but mRNA for IL-6, a co-stimulant for IL-2 production, was decreased in Se deficiency. A decrease in the production of mRNA for TNF-a was also observed and the authors suggest that the decrease in the availability of these cytokines could radically disrupt anti-viral immunity (Beck and Levander, 1998).

Cytokines can also be induced by non-specific damage to DNA. When skin cells (keratinocytes) are irradiated with ultraviolet B radiation (UVB), thymidine dimer formation (cross-linking of adjacent pyrimidines), single-strand breaks in DNA and oxidative damage to DNA occur. Two cytokines induced by DNA damage are TNF-a and IL-10. In the skin, TNF-a causes emigration of the Langerhans cells, the principal dendritic antigen-presenting cells in the skin. Without these antigen-presenting cells, local immune suppression occurs and neoplastic cells cannot be readily detected. Release of IL-10 potentiates this situation by inhibiting the release of pro-inflammatory cytokines and by inhibiting antigen presentation and cell-mediated immune responses. Se, as selenite or selenomethionine, protects keratinocytes from oxidative DNA damage and the UVB-induced release of IL-10 and TNF-a proteins, as well as inhibiting UVB induction of the pro-inflammatory cytokines, IL-6 and IL-8. Peroxynitrite can cause DNA single-strand breaks; strand breakage is prevented by GPX and thioredoxin reductase. Overall, Se can prevent cytokine release in response to DNA damage, preventing inflammation and helping to prevent immune suppression following UVB irradiation (reviewed in McKenzie, 2000).

Cytokines can also influence the expression of selenoproteins. The immunosuppressive cytokine transforming growth factor (3 inhibits GPX gene transcription (Mostert ei al., 1999). Also, activation of a plasmid construct consisting of the selenoprotein P promoter linked to a reporter gene was suppressed by treatment of cells harbouring the construct with IL-1p, interferon-7 or TNF-a (Dreher ei al., 1997).

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