Protective role of arginase in a mouse model of colitis.

Abstract

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.

• Authors: Alain P Gobert, Yulan Cheng, Mahmood Akhtar, Benjamin D Mersey, Darren R Blumberg, Raymond K Cross, Rupesh Chaturvedi, Cinthia B Drachenberg, Jean-Luc Boucher, Amy Hacker, Robert A Casero Jr, Keith T Wilson
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 173 Issue 3 Pg. 2109-17 (Aug 01 2004) ISSN: 0022-1767 [Print] United States
• PMID: 15265947 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• (2-boronoethyl)-cysteine
• Boronic Acids
• Enzyme Inhibitors
• Polyamines
• Arginine
• Ornithine
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Arginase
• Ornithine Decarboxylase
• Eflornithine

Topics

• Animals
• Arginase (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Arginine (metabolism, therapeutic use)
• Boronic Acids (pharmacology, toxicity)
• Citrobacter rodentium
• Colitis (drug therapy, enzymology, microbiology, pathology)
• Eflornithine (pharmacology, toxicity)
• Enterobacteriaceae Infections (enzymology, microbiology, pathology)
• Enzyme Induction
• Enzyme Inhibitors (pharmacology, toxicity)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase (antagonists & inhibitors, biosynthesis, genetics)
• Nitric Oxide Synthase Type II
• Ornithine (metabolism)
• Ornithine Decarboxylase (biosynthesis, genetics, physiology)
• Polyamines (metabolism)