Protective role of arginase in a mouse model of colitis

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, Keith T. Wilson

Research output: Contribution to journalArticle

Abstract

Arginase is the endogenous inhibitor of inducible NO synfliase (iNOS), because both enzymes use the same substrate, L-arginase (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-γ, IL-1, and TNF-α 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 α-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.

Original languageEnglish (US)
Pages (from-to)2109-2117
Number of pages9
JournalJournal of Immunology
Volume173
Issue number3
DOIs
StatePublished - Aug 1 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Gobert, A. P., Cheng, Y., Akhtar, M., Mersey, B. D., Blumberg, D. R., Cross, R. K., Chaturvedi, R., Drachenberg, C. B., Boucher, J. L., Hacker, A., Casero, R. A., & Wilson, K. T. (2004). Protective role of arginase in a mouse model of colitis. Journal of Immunology, 173(3), 2109-2117. https://doi.org/10.4049/jimmunol.173.3.2109