At the cellular level, a large body of data clearly demonstrated that ROS, when produced in low amounts and in a controlled manner, are physiological components of the signalling generated by cytokines, growth factors and neurotrophic peptides [17-22], although they may also activate apoptotic cell death [23]. Extracellularly generated ROS can diffuse through anion channels into the cytoplasm; the resulting variation in the cell redox state leads to modulation of an array of transcription factors (eg. NF-kB, AP-1), protein kinases (e.g. AKT, JNK, p38), and receptor activated MAP kinases involved in apoptosis [17,24-26]. Moreover, the proapoptotic molecules Fas and Fas ligand (FasL) undergo positive transcriptional regulation after exposure to oxidants [27]. Interestingly, Krammer and Colleagues demonstrated that in vitro administration of vitamin E suppresses FasL mRNA expression and protects T cells of HIV-1 infected individuals from Fas mediated apoptosis [28]. Moreover, it was demonstrated that administration of combinations of vitamin E and C to cultures of human umbilical vein endothelial cells (HUVEC) treated with lipopolysaccharide could prevent apoptosis by upregulation of Bcl-2 [29].
Antioxidants, The Immune System And Related Disorders
The protective function against external pathogens carried out by the immune system is by itself a source of ROS, since activated neutrophils, produce free radicals to a significant extent [30]. Moreover, during the inflammatory process, activation of phagocytes through the interaction of proinflammatory mediators, or bacterial products with specific receptors results in the assembly of the multicomponent flavoprotein NADPH oxidase which catalyzes the production of large quantities of the superoxide anion radical (O2 -) [31]. In addition to classical reactive oxygen metabolites, activated neutrophils and monocytes release the hemoprotein myeloperoxidase (MPO) into the extracellular space, where it catalyzes the oxidation of Cl- by H2O2 to yield hypochlorous acid (HClO) [32]. HClO is a non-specific oxidizing and chlorinating agent that reacts rapidly with a variety of biological compounds, such as sulphydryls, polyunsatured fatty acids, DNA, pyridine nucleotides, aliphatic and aromatic aminoacids and nitrogen-containing compounds [33-35]. Moreover, apart from their direct toxic effects, neutrophil-derived oxidants may promote tissue injury indirectly by altering the protease/antiprotease equilibrium that normally exists within the intestinal interstitium. The oxidative inactivation of important protease inhibitors, coupled to the oxidant-mediated activation of latent proteases, creates a favorable environment for neutrophils that allows degradation of the interstitial matrix through elastases, collagenases and gelatinases, as well as injury to epithelial cells [36,37]. However, not only immune cell produce ROS necessary for the microbicidal activity, but they are also sensitive to external ROS, due to their high polyunsaturated fatty acids (PUFA) content. Immune cells are atypical, as compared with other somatic cells, in that they contain high levels of antioxidant vitamins, presumably providing protection against lipid peroxidation and immunosuppression, both of which are well known risks posed by high PUFA content [38]. The reactivity of immune cells to exogenous ROS has been shown to be age-dependent. In fact, lymphocytes from elderly individuals appear to be more sensitive to exposure to hydrogen peroxide than those from young adults [39]. Moreover, it has been demonstrated that a micronutrient deficiency can be the cause of suppression of immune function affecting both innate T-cell-mediated immune response and adaptive antibody response, thus altering the balanced host response. Therefore, an adequate intake of vitamins and antioxidant elements seems to be essential for an efficient function of the immune system. Micronutrient deficiency occurs in various conditions, such as eating disorders, tobacco smokers, chronic diseases, aging. During aging, changes in the immune system are frequent and associated with increased susceptibility to infections. Antioxidant vitamins and trace elements contribute to maintain an effective immune response [40]. For example, administration of vitamin E supplement to healthy elderly patients produced an increased antibody titer to both hepatitis B and tetanus vaccine [41], thus enhancing T-cell mediated functions. In conclusion, maintaining adequate antioxidant status may provide a useful approach in attenuating cell injury and dysfunction observed in some inflammatory/autoimmune disorders [42,43].