Effects of ornithine 2-oxoglutarate on neutrophils in stressed rats: evidence for the involvement of nitric oxide and polyamines.
Diets enriched in ornithine 2-oxoglutarate (ornithine alpha-ketoglutarate; OKG) improve immune status during stress. We described previously the ability of OKG to increase the respiratory burst in polymorphonuclear neutrophils (PMNs), but the underlying mechanisms remain unclear. OKG is usually recognized as generating glutamine, arginine and polyamines. The aim of the present study was first to determine the effects of OKG on PMN bactericidal functions (chemotaxis and respiratory burst) in stressed rats, and whether these effects could be reproduced by glutamine- or arginine-enriched diets. Secondly, we investigated the metabolic pathway involved in these actions, using three metabolic inhibitors: methionine sulphoximine (an inhibitor of glutamine synthetase), S-methylthiourea (an inhibitor of inducible nitric oxide synthase) and difluoromethylornithine (an inhibitor of ornithine decarboxylase). OKG, arginine and glutamine all increased the production of reactive oxygen species (evaluated by chemiluminescence, ferricytochrome c reduction and flow cytometry). Only OKG markedly enhanced the chemotaxis index (5-fold). Inhibition of glutamine synthetase showed that glutamine production was not involved in the action of OKG. The use of S-methylthiourea and difluoromethylornithine demonstrated that OKG modulated the respiratory burst via nitric oxide (NO*) and polyamine generation. Moreover, OKG stimulated PMN migration via NO*, but arginine administration failed to reproduce this effect. These data suggest that OKG (or its metabolites) and arginine are channelled differently in PMNs. This hypothesis deserves further study.
Moinard
Christophe
C
Laboratoire de Biochimie, Biologie Moléculaire et Nutrition EA 2416 and Centre de Recherche en Nutrition Humaine, Faculté de Pharmacie, 63001 Clermont-Ferrand, France. C.moinard@netcourrier.com
Caldefie
Florence
F
Walrand
Stephane
S
Tridon
Arlette
A
Chassagne
Jacques
J
Vasson
Marie-Paule
MP
Cynober
Luc
L
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors; D005973:Glutamine / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008717:Methionine Sulfoximine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016897:Respiratory Burst / Q000187:drug effects; D013315:Stress, Psychological / Q000276:immunology*
D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D005973:Glutamine; D008717:Methionine Sulfoximine; D007550:Isothiuronium; D009569:Nitric Oxide; C002118:ornithine alpha-ketoglutarate; D003907:Dexamethasone; D001120:Arginine; D006861:Hydrogen Peroxide; D009952:Ornithine; D019001:Nitric Oxide Synthase; D005974:Glutamate-Ammonia Ligase; C027744:S-methylisothiopseudouronium; D000518:Eflornithine