Metabolism of agmatine in macrophages: modulation by lipopolysaccharide and inhibitory cytokines.
Agmatine is an amine derived from the decarboxylation of arginine by arginine decarboxylase (ADC) and metabolized to putrescine by agmatinase. While prevalent in bacteria and plants, agmatine and its metabolic enzymes have been recently identified in mammalian tissues. In the present study we sought to determine: (a) whether macrophages (cell line RAW 264.7) express ADC and agmatinase, and (b) if the enzymes are regulated by lipopolysaccharide (LPS), and/or by the inhibitory cytokines transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10) and interleukin-4 (IL-4). LPS induced a dose-dependent stimulation of agmatinase, while it decreased ADC, the effect in both cases being maximum at 20 h. As expected, LPS dose-dependently stimulated the inducible nitric oxide synthase activity (iNOS). A strong correlation was observed between the effects of LPS on the agmatine-related enzymes and iNOS. By contrast, exposure to IL-10 and TGF-beta caused a reduction in ADC and agmatinase, whereas IL-4 was ineffective on ADC, but reverted the LPS-induced increase of agmatinase. We conclude that the agmatine pathway may be an alternative metabolic route for arginine in macrophages, suggesting a regulatory role of agmatine during inflammation.
Sastre
M
M
Division of Neurobiology, Department of Neurology and Neuroscience, Cornell University Medical College, 411 East 69th Street, New York, NY 10021, USA.
Galea
E
E
Feinstein
D
D
Reis
D J
DJ
Regunathan
S
S
D000376:Agmatine / Q000378:metabolism*; D000818:Animals; D002262:Carboxy-Lyases / Q000096:biosynthesis*; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D016207:Cytokines / Q000494:pharmacology*; D004790:Enzyme Induction; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D012044:Regression Analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014512:Ureohydrolases / Q000096:biosynthesis*
D016207:Cytokines; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4; D000376:Agmatine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D014512:Ureohydrolases; C019625:agmatinase; D002262:Carboxy-Lyases; C019722:arginine decarboxylase