MECHANISM OF ACTION OF GLUTAMINE IN THE IMMUNE SYSTEM AND IN EXERCISE-INDUCED IMMUNODEPRESSION
Glutamine is synthesized, stored, and released predominantly by skeletal muscle and, to a lesser extent, by adipocytes, liver, and lung: it is taken up by intestinal cells, such as enterocytes and colonocytes, by the kidney, liver, pancreatic islet cells, and immune cells such as lymphocytes, macrophages, and neutrophils (see also Chapter 21).
Glutamine is required by rapidly dividing cells (Krebs, 1980) and provides nitrogen for the synthesis of purine and pyrimidine nucleotides, enabling synthesis of new DNA and RNA, for mRNA synthesis and DNA repair. Ardawi and Newsholme (1983, 1985) observed a surprisingly high utilization of glutamine by resting, unstimulated human lymphocytes. Subsequent in vitro work (Parry- Billings et al., 1992) showed that, despite the presence of all other nutrients, only when glutamine was reduced in the culture medium did a decrease occur in the proliferative ability of human lymphocytes. In addition, the response time to mitogenic stimulation of the lymphocytes was slowed in vitro. When it was established that plasma glutamine decreased by approximately 25% after prolonged, exhaustive exercise, it was decided to investigate whether or not this might have ramifications for immune function in athletes.
During physiological stress such as exercise, an increase in the concentration of cortisol in the blood can initiate proteolysis of muscle proteins, transamination of amino acids to glutamate, and the synthesis and increased release of glutamine. About 8-9 g of glutamine per day is released from the entire human musculature (see Elia et al., 1990). Muscle glutamine in humans is ca. 20 mM, which is approximately 60% of the intramuscular pool (Bergstrom et al., 1974). The rate of release across the plasma membrane occurs via a specific transporter. It is controlled by factors such as the hormonal milieu and cytokines. The release of cytokines from cells of the immune system leads to communication with skeletal muscle (Newsholme and Parry-Billings, 1990). It has been demonstrated that the secretion of cytokines or cell surface activation markers is glutamine dependent (Horig et al., 1993; Murphy and Newsholme, 1999).
Glutaminase is the major degradation enzyme of glutamine. The presence of glutaminase in human neutrophils was established in 2004 by Castell et al., who also observed increased oxidative burst in human neutrophils after adding glutamine in vitro. Neutrophil function decreases in cyclists undertaking prolonged exercise (Robson et al., 1999) and in cross-country runners immediately after VO2max tests (Castell et al., 1999). The major chemoattractant for neutrophils is the chemokine interleukin-8 (IL-8), and there appears to be a link between its production and the concentration of glutamine. The provision of glutamine as a supplement to athletes has regularly resulted in a decrease in IL-8 production after mitogenic stimulation in vitro (Castell, 2003). IL-8 was also observed to be similarly reduced in clinical studies, for example, in patients with acute pancreatitis (De Beaux et al., 1998). It is, therefore, suggested that provision of exogenous glutamine might lead to enhanced function of neutrophils and to a decrease in the requirement for IL-8 secretion to attract more neutrophils to the site of tissue damage.