Macrophage-mediated lysis of a beta-cell line, tumour necrosis factor-alpha release from Bacillus Calmette-Guerin (BCG)-activated murine macrophages and interleukin-8 release from human monocytes are dependent on extracellular glutamine concentration and glutamine metabolism

Macrophages and monocytes are cells with a large capacity for cytokine prod uction. Cytokines produced by these cells are not preformed and released up on stimulation, but must be transcribed and translated. Although much is kn own concerning the regulation of the latter processes at the molecular leve l, the role of exogenous amino acids in the secretory process has not been actively investigated. Glutamine is utilized by macrophages at a much faste r rate than any other amino acid. The role for high rates of glutamine util ization in macrophages or monocytes is not fully understood. We demonstrate here that the rates of lipopolysaccharide-stimulated tumour necrosis facto r-alpha secretion from bacillus Calmette-Guerin (BCG)-activated murine peri toneal macrophages and lipopolysaccharide-stimulated interleukin-8 producti on from human monocytes are dependent upon extracellular glutamine concentr ation. We also demonstrate that potent inhibition of cytokine production ca n be achieved by incubating macrophages or monocytes in the presence of the glutaminase inhibitor 6-diazo-5-oxo-norleucine. On co-culture of BCG-activ ated macrophages and the clonal pancreatic beta-cell line BRIN-BD11, macrop hage-specific beta-cell death was significantly reduced on prior exposure o f macrophages to 6-diazo-5-oxo-norleucine. Thus glutamine metabolism may be essential for generation of cytotoxic products from macrophages, including tumour necrosis factor-alpha.