Protective role of arginase in a mouse model of colitis.
Arginase is the endogenous inhibitor of inducible NO synthase (iNOS), because both enzymes use the same substrate, l-arginine (Arg). Importantly, arginase synthesizes ornithine, which is metabolized by the enzyme ornithine decarboxylase (ODC) to produce polyamines. We investigated the role of these enzymes in the Citrobacter rodentium model of colitis. Arginase I, iNOS, and ODC were induced in the colon during the infection, while arginase II was not up-regulated. l-Arg supplementation of wild-type mice or iNOS deletion significantly improved colitis, and l-Arg treatment of iNOS(-/-) mice led to an additive improvement. There was a significant induction of IFN-gamma, IL-1, and TNF-alpha mRNA expression in colitis tissues that was markedly attenuated with l-Arg treatment or iNOS deletion. Treatment with the arginase inhibitor S-(2-boronoethyl)-l-cysteine worsened colitis in both wild-type and iNOS(-/-) mice. Polyamine levels were increased in colitis tissues, and were further increased by l-Arg. In addition, in vivo inhibition of ODC with alpha-difluoromethylornithine also exacerbated the colitis. Taken together, these data indicate that arginase is protective in C. rodentium colitis by enhancing the generation of polyamines in addition to competitive inhibition of iNOS. Modulation of the balance of iNOS and arginase, and of the arginase-ODC metabolic pathway may represent a new strategy for regulating intestinal inflammation.
Gobert
Alain P
AP
Department of Medicine, Division of Gastroenterology, School of Medicine, University of Maryland, and Veterans Affairs Maryland Health Care System, Baltimore, MD 21201, USA.
Cheng
Yulan
Y
Akhtar
Mahmood
M
Mersey
Benjamin D
BD
Blumberg
Darren R
DR
Cross
Raymond K
RK
Chaturvedi
Rupesh
R
Drachenberg
Cinthia B
CB
Boucher
Jean-Luc
JL
Hacker
Amy
A
Casero
Robert A
RA
Wilson
Keith T
KT
D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001120:Arginine / Q000378:metabolism / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology / Q000633:toxicity; D044082:Citrobacter rodentium; D003092:Colitis / Q000188:drug therapy / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D000518:Eflornithine / Q000494:pharmacology / Q000633:toxicity; D004756:Enterobacteriaceae Infections / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009952:Ornithine / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011073:Polyamines / Q000378:metabolism
C425062:(2-boronoethyl)-cysteine; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D011073:Polyamines; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001119:Arginase; D009955:Ornithine Decarboxylase; D000518:Eflornithine