Mechanism of the Effect of Oxidants and Antioxidants on Inflammation and Immune Function

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There is a growing body of evidence that antioxidants suppress inflammatory components of the response to infection and trauma and enhance components related to cell-mediated immunity (see Hughes, Chapter 9, Prasad, Chapter 10, and McKenzie et al., Chapter 12, this volume). The reverse situation applies when antioxidant defences become depleted.

The oxidant molecules produced by the immune system to kill invading organisms may activate at least two important families of proteins that are sensitive to changes in cellular redox state. The families are nuclear transcription factor kappa B (NFkB) and activator protein 1 (API). These transcription factors act as 'control switches' for biological processes, not all of which are of advantage to the individual. NFkB is present in the cytosol in an inactive form, by virtue of being bound to IkB. Phosphorylation and dissociation of IkB renders the remaining NFkB dimer active. Activation of NFkB can be brought about by a wide range of stimuli, including pro-inflammatory cytokines, hydrogen peroxide, mitogens, bacteria and viruses and their related products, and UV and ionizing radiations. The dissociated IkB is degraded and the active NFkB is translocated to the nucleus, where it binds to response elements in the promoter regions of genes. A similar translocation of AP1, a transcription factor composed of the proto-oncogenes c-fos and c-jun, from cytosol to nucleus also occurs in the presence of oxidant stress. Binding of the transcription factors is implicated in the activation of a wide range of genes associated with inflammation and the immune response, including those encoding cytokines, cytokine receptors, cell-adhesion molecules, acute-phase proteins and growth factors (Schreck et al., 1991).

Unfortunately, NFkB also activates transcription of the genes of some viruses, such as HIV. This sequence of events in the case of HIV accounts for the ability of minor infections to speed the progression of individuals who are infected with HIV towards AIDS, since, if antioxidant defences are poor, each encounter with general infections results in cytokine and oxidant production, NFkB activation and an increase in viral replication. It is thus unfortunate that reduced cellular concentrations of GSH are a common feature of asymptomatic HIV infection (Staal et al., 1992).

Oxidant damage to cells will indirectly create a pro-inflammatory effect by the production of lipid peroxides. This situation may lead to up-regulation of NFkB activity, since the transcription factor has been shown to be activated in endothelial cells cultured with linoleic acid, the main dietary n-6 polyunsaturated fatty acid, an effect inhibited by vitamin E and NAC (Hennig et al., 1996). The interaction between oxidant stress and an impaired ability to synthesize glutathione, which results in enhanced inflammation, is clearly seen in cirrhosis, a disease that results in high levels of oxidative stress and an impaired ability to synthesize GSH (Pena et al., 1999). In this study, an inverse relationship between glutathione concentration and the ability of monocytes to produce IL-1, IL-8 and TNF-a was observed. Furthermore, treatment of the patients with the GSH pro-drug oxothiazalidine-4-carboxylate (procysteine) (Fig. 7.7) increased monocyte GSH content and reduced IL-1, IL-8 and TNF-a production. Thus, antioxidants might act to prevent NFkB activation by quenching oxidants. However, not all transcription factors respond to changes in cell redox state in the same way. When rats were subjected to depletion of effective tissue GSH pools by administration of diethyl maleate, there was a significant reduction in lymphocyte proliferation in spleen and mesenteric lymph nodes (Robinson et al., 1993). In an in vitro study using HeLa cells and cells from human embryonic kidney, both TNF and hydrogen peroxide resulted in




Otz Glutathione

Glutamic acid

Glutathione synthesis

Fig. 7.7. Nutrients and drugs that are important for enhancing glutathione synthesis. NAC, W-acetyl cysteine; OTZ, l-2-oxothiazolidine-4-carboxylate.


Glutamic acid

Glutathione synthesis


Fig. 7.7. Nutrients and drugs that are important for enhancing glutathione synthesis. NAC, W-acetyl cysteine; OTZ, l-2-oxothiazolidine-4-carboxylate.

activation of NFkB and AP1 (Wesselborg et al., 1997). Addition of the antioxidant sorbitol to the medium suppressed NFkB activation (as expected) but (unexpectedly) activated AP1. Thus, the antioxidant environment of the cell might exert opposite effects upon transcription factors closely associated with inflammation (e.g. NFkB) and cellular proliferation (e.g. AP1). Evidence for this biphasic effect was seen when glutathione was incubated with immune cells from young adults (Wu et al., 1994). A rise in cellular glutathione content was accompanied by an increase in IL-2 production and lymphocyte proliferation and a decrease in production of the inflammatory mediators prostaglandin E2 (PGE2) and leucotriene B4 (LTB4) Modification of the glutathione content of liver, lung, spleen and thymus in young rats, by feeding diets containing a range of casein (a protein with a low sulphur amino acid content) concentrations, changed immune cell numbers in the lung (Hunter and Grimble, 1994). It was found that, in unstressed animals, the number of lung neutrophils decreased as dietary protein intake and tissue glutathione content fell. However, in animals given an inflammatory challenge (endotoxin), liver and lung GSH concentrations increased directly in relation to dietary protein intake. Lung neutrophils, however, became related inversely with tissue glutathione content. Addition of methionine to the protein-deficient diets normalized tissue glutathione content and restored lung neutrophil numbers to those seen in unstressed animals fed a diet of adequate protein content.

Thus it can be hypothesized that antioxidants exert an immunoenhancing effect, by activating transcription factors that are strongly associated with cell proliferation (e.g. AP1), and an anti-inflammatory effect, by preventing activation of NFkB by oxidants produced during the inflammatory response.

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