Mechanism of Glutamine Action

There has been much speculation about the mechanism by which glutamine acts to preserve, or even improve, immune function. Similar metabolic characteristics apply to various cells of the immune system, despite the fact that their cell biology is different. Hence any hypothesis must explain high rates of gluta-mine utilization in cells with widely different cell-biological characteristics. As indicated earlier, glutamine makes a significant contribution to energy generation in cells of the immune system. However, oxidation of glutamine is only partial and immune cells can, and do, generate energy from other substrates (see Calder, 1995a). These observations suggest that the importance of gluta-mine to immune function is not simply through its action as an energy-yielding substrate. Another suggestion is that glutamine metabolism can generate intermediates for the synthesis of purines and pyrimidines and so provides the building blocks for mRNA and DNA. However, the rate of synthesis of nucleotides in lymphocytes is reported to be much less than the rate of gluta-mine utilization (Szondy and Newsholme, 1989). On the basis of 'metabolic control logic', it was suggested that the importance of a high rate of glutamine utilization in immune cells relates to maintenance of a high flux through the pathway of glutaminolysis (i.e. the pathway of partial glutamine oxidation (Fig. 6.4)), which would allow high sensitivity to regulatory molecules controlling biosynthetic pathways (Newsholme et al., 1989). This hypothesis has proved difficult to test. While the capacity for rapid cell division is retained by isolated lymphocytes, this does not apply to isolated neutrophils or macrophages, which are terminally differentiated cells with little capacity for cell division. However, neutrophils and macrophages have a large phagocytic capacity (requiring a high rate of lipid turnover and synthesis) and a high secretory activity. The mechanism by which glutamine can act to allow high rates of secretory-product formation and release and sustain cell proliferation must account for the diverse nature of these secretory products and the requirements for cell division and should include at least one common metabolic product.

NADPH is required by the enzymes responsible for the formation of the reactive species nitric oxide and superoxide, inducible nitric oxide synthase (iNOS) and NADPH oxidase, respectively. NADPH is also required for the formation of reduced glutathione (see below) and for de novo synthesis of DNA, RNA and fatty acids. Glutamine, via metabolism involving NADP+-dependent malate dehydrogenase (malic enzyme (enzyme 5 in Fig. 6.4)), can generate considerable NADPH for cell requirements. The NADP+-dependent malate dehydrogenase step will result in the formation of pyruvate, which can either be converted to lactate (ending the pathway of glutaminolysis) or be converted to acetyl-coenzyme A (CoA) and on to CO2. Thus, depending upon the energy demands placed on the cell, glutamine may be partially oxidized in the pathway of glutaminolysis or may be fully oxidized, but the outcome of metabolism in either case is NADPH production. Glucose may also, via metabolism through the pentose-phosphate pathway, generate NADPH. However, during periods of active pinocytosis and phagocytosis, glucose carbon may be diverted towards lipid synthesis and therefore the pentose-phosphate pathway may be compromised (Newsholme et al., 1996). Additionally, glutamine carbon may be used for new amino acid synthesis in periods of active synthesis and secretion. It is possible that NADPH is the 'common factor' that links the diverse effects that glutamine has in cells of the immune system (Newsholme, 2001). Evidence in support of this hypothesis is provided by the enhancing effect of glutamine on superoxide generation in neutrophils and monocytes (Garcia et al., 1999; Saito et al., 1999; Furukawa et al., 2000a, b) and recent in vitro data that cell prolifer ation in response to growth factors is positively related to the level of superoxide produced intracellularly (Suh et al., 1999). Superoxide generation in cells requires the electron-donating ability of NADPH if generated via the enzyme NADPH oxidase, which directly reduces molecular oxygen. The latter enzyme is quantitatively the most significant source of superoxide in immune cells.

It is also possible that the importance of glutamine relates to its many roles as a biosynthetic precursor. Of particular importance may be its role as the precursor of glutamate for the synthesis of glutathione. Glutathione is a tripeptide antioxidant composed of glutamate, cysteine and glycine (see also Grimble, Chapter 7, this volume). Glutathione concentrations in the liver, lung, small intestine and immune cells fall in response to infection, inflammatory stimuli and trauma. The fall in hepatic glutathione concentration and in the export of glutathione from the liver can be prevented by provision of oral glutamine for rats (Hong et al., 1992; Welbourne et al., 1993). Glutamine-enriched par-enteral nutrition elevated plasma glutathione concentration in rats (Denno et al., 1996; Cao et al., 1998) and promoted the release of glutathione from the rat gut into the bloodstream (Cao et al., 1998).

Culture of human lymphocytes in the presence of glutathione enhances cytotoxic T-cell activity (Droge et al., 1994) and depletion of intracellular glutathione diminishes lymphocyte proliferation (Chang et al., 1999a) and the generation of cytotoxic T lymphocytes (Droge et al., 1994). Depletion of glutathione through an exercise regimen decreased the number of CD4+ cells by 30% in a subset of individuals (Kinscherf et al., 1994). Treatment with N-acetyl-cysteine (400 mg day-1 for 4 weeks) prevented the exercise-induced fall in intracellular glutathione concentrations and increased the number of CD4+ cells by 25%. Glutathione depletion is associated with diminished IFN-7, but not IL-2 or IL-4, production by antigen-stimulated murine lymph-node cells (Peterson et al., 1998); this effect was mediated by antigen-presenting cells and the authors suggest that glutathione acts via inducing IL-12 production by these cells to alter the T-helper (Th)1/Th2 balance in favour of a Th1 response. Thus, glutathione appears to promote a range of cell-mediated immune responses. Although glutamine is able to preserve glutathione concentrations in the liver, gut, kidney and bloodstream (see above and also Welbourne and Dass, 1982; Harward et al., 1994), it is not clear whether it also preserves glutathione concentrations within immune cells. However, it was recently reported that incubation of human blood mononuclear cells with increasing concentrations of glutamine resulted in higher intracellular glutathione concentrations in both CD4+ and CD8+ cells (Chang et al., 1999a). Thus, one means by which glut-amine might exert its immunological effects is through maintenance of glu-tathione status. However, this hypothesis requires further investigation.

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