Effect of adrenaline and phorbol myristate acetate or bacterial lipopolysaccharide on stimulation of pathways of macrophage glucose, glutamine and O2 metabolism. Evidence for cyclic AMP-dependent protein kinase mediated inhibition of glucose-6-phosphate dehydrogenase and activation of NADP+-dependent 'malic' enzyme.
Adrenaline has recently been shown to stimulate both glucose metabolism and H2O2 release by macrophages but the activity of the key pentose phosphate pathway enzyme, glucose-6-phosphate dehydrogenase (which generates the NADPH crucial for the reduction of molecular oxygen), was reduced under these conditions [Costa Rosa, Safi, Cury and Curi (1992) Biochem. Pharmacol. 44, 2235-2241]. We report here that adrenaline activates another NADPH-producing enzyme, NADP(+)-dependent 'malic' enzyme, while also inhibiting glucose-6-phosphate dehydrogenase, via cyclic AMP-dependent protein kinase (PKA) activation. Regulation of glucose-6-phosphate dehydrogenase activity by PKA has not been reported elsewhere. The sparing of some glucose from pentose phosphate pathway consumption may be important in the provision of glycerol 3-phosphate which in the macrophage may be required for new phospholipid synthesis. Glutamine oxidation was also stimulated by adrenaline thus providing increased substrate (malate) for NADP(+)-dependent 'malic' enzyme and therefore shifting some of the burden of NADPH production from glucose to glutamine metabolism. We also report a novel synergistic effect of adrenaline and some bacterial products and/or gamma-interferon in stimulating secretory and metabolic pathways in macrophages which may be a part of a larger network of signals that lead to enhanced macrophage activity.
Costa Rosa
L F
LF
Department of Physiology and Biophysics, University of Sao Paulo, Brazil.
Curi
R
R
Murphy
C
C
Newsholme
P
P
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002463:Cell Membrane Permeability; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004072:Digitonin; D004837:Epinephrine / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D005990:Glycerol / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D008291:Malate Dehydrogenase / Q000378:metabolism; D008297:Male; D009163:Mycobacterium bovis; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009249:NADP / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D008070:Lipopolysaccharides; D005973:Glutamine; D009249:NADP; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003994:Bucladesine; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D008291:Malate Dehydrogenase; C030574:malate dehydrogenase (decarboxylating); D005954:Glucosephosphate Dehydrogenase; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D004072:Digitonin; D013755:Tetradecanoylphorbol Acetate; D005990:Glycerol; D004837:Epinephrine