Modulation of the nuclear factor-kappa B (NF-κB) signalling pathway by glutamine in peritoneal macrophages of a murine model of protein malnutrition
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Background and aims
Protein malnutrition affects resistance to infection by impairing the inflammatory response, modifying the function of effector cells, such as macrophages. Recent studies have revealed that glutamine—a non-essential amino acid, which could become conditionally essential in some situations like trauma, infection, post-surgery and sepsis—is able to modulate the synthesis of cytokines. The aim of this study was to evaluate the effect of glutamine on the expression of proteins involved in the nuclear factor-kappa B (NF-κB) signalling pathway of peritoneal macrophages from malnourished mice.
Two-month-old male Balb/c mice were submitted to protein-energy malnutrition (n = 10) with a low-protein diet containing 2 % protein, whereas control mice (n = 10) were fed a 12 % protein-containing diet. The haemogram and analysis of plasma glutamine and corticosterone were evaluated. Peritoneal macrophages were pre-treated in vitro with glutamine (0, 0.6, 2 and 10 mmol/L) for 24 h and then stimulated with 1.25 μg LPS for 30 min, and the synthesis of TNF-α and IL-1α and the expression of proteins related to the NF-κB pathway were evaluated.
Malnourished animals had anaemia, leucopoenia, lower plasma glutamine and increased corticosterone levels. TNF-α production of macrophages stimulated with LPS was significantly lower in cells from malnourished animals when cultivated in supraphysiological (2 and 10 mmol/L) concentrations of glutamine. Further, glutamine has a dose-dependent effect on the activation of macrophages, in both groups, when stimulated with LPS, inducing a decrease in TNF-α and IL-1α production and negatively modulating the NF-κB signalling pathway.
These data lead us to infer that the protein malnutrition state interferes with the activation of macrophages and that higher glutamine concentrations, in vitro, have the capacity to act negatively in the NF-κB signalling pathway.
KeywordsProtein malnutrition Macrophages Glutamine NF-κB TNF-α IL-1α
This investigation was supported by grants from the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP).
- 1.Akner G, Cederholm T (2001) Treatment of protein-energy malnutrition in chronic nonmalignant disorders. Am J Clin Nutr 74:6–24Google Scholar
- 4.Gadducci A, Cosio S, Fanucchi A et al (2001) Malnutrition and caquexia in ovarian cancer patients: pathophysiology and management. Anticancer Res 21:2941–2947Google Scholar
- 6.Keusch GT (2003) History of nutrition: malnutrition, infection and immunity. J Nutr 133:S336–S340Google Scholar
- 9.Newsholme P (2001) Why is l-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? J Nutr 131:S2515–S2522Google Scholar
- 10.Newsholme P, Gordon S, Newsholme EA (1987) Rates of utilization and fates of glucose, glutamine, pyruvate, fatty acids and ketone bodies by mouse macrophages. Biochem J 15:631–636Google Scholar
- 15.Nova E, Samartín S, Gómez S et al (2003) The adaptive response of the immune system to the particular malnutrition of eating disorders. Eur J Clin Nutr 56(Suppl. 3):S34–S37Google Scholar
- 16.Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition Ad Hoc Writing Committee on the Reformulation of the Ain-76a Rodent Diet. J Nutr 123:1939–1951Google Scholar
- 17.Ward PG (1963) A micro-Kjeldahl procedure for field use. J Med Lab Technol 20:191–195Google Scholar
- 18.Gornall AG, Bardawill CJ, David MM (1949) Determination of serum proteins by means of the biuret reactions. J Biol Chem 177:751–766Google Scholar
- 20.Lund P, Williamson DH (1985) Inter-tissue nitrogen fluxes. Br Med Bull 41:251–256Google Scholar
- 21.Eagle H (1955) The growth requirements of two mammalian cell lines in tissue culture. Trans Assoc Am Physicians 68:78–81Google Scholar
- 22.Eagle H, Oyama VI, Levy M, Horton CL, Fleischman R (1956) The growth response of mammalian cells in tissue culture to l-glutamine and l-glutamic acid. J Biol Chem 218:607–616Google Scholar
- 23.Hubert-Buron A, Leblond J, Jacquot A (2006) Glutamine pretreatment reduces IL-8 production in human intestinal epithelial cells by limiting IkappaB-alpha ubiquitination. J Nutr 136:1461–1465Google Scholar
- 32.Rogero MM, Tirapegui J, Vinolo MA et al (2008) Dietary glutamine supplementation increases the activity of peritoneal macrophages and hemopoiesis in early-weaned mice inoculated with Mycobacterium bovis bacillus Calmette-Guérin. J Nutr 138:1343–1348Google Scholar
- 36.Wischmeyer PE, Kahana M, Wolfson R et al (2001) Glutamine induces heat shock protein and protects against endotoxin shock in the rat. J Appl Physiol 90:2403–2410Google Scholar