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-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.

Nitric oxide inhibits Shiga-toxin synthesis by enterohemorrhagic Escherichia coli

“…We establish that the host innate immune response represses EHEC virulence, with this particular insight that NO does not directly kill the pathogen but decreases the production of a toxin. Thus, increasing NO production in infected patients, by using NO donor or L-arginine treatment (39), might represent an alternative strategy to limit the development of HUS. Moreover, we propose that differential NO production in infected patients could represent a marker of host susceptibility for EHEC infection.…”

Re-thinking the functions of IgA+plasma cells

“…123 In addition, infection with Citrobacter rodentium was shown to cause a significant decrease in serum LArg concentration with associated infection-induced immunopathology that was partially reversed after L-Arg supplementation. 124 Although, their distinct contribution remains to be explored, it is likely that altered activities of L-Arg catabolizing enzyme families, Arg as well as NOS all contribute to the observed intestinal immunopathologies. It therefore can be postulated that Arg activity through conversion of L-Arg into L-Orn enhances intestinal epithelial barrier function, 125 while iNOS activity confers an antiinflammatory state through regulation of energy metabolism.…”

Helicobacter pylori-induced Macrophage Apoptosis Requires Activation of Ornithine Decarboxylase by c-Myc

“…3 A further issue for consideration is what is the specificity of the c-Myc and ODC response to H. pylori in macrophages? For comparison, we have studied the Gram-negative enteric pathogen Citrobacter rodentium, which causes colitis in mice (22), and the effect of the chemical inducer of apoptosis, staurosporine, and found that both agents cause apoptosis in macrophages without inducing ODC or c-Myc (data not shown). Additionally, inhibition of H. pylori-induced apoptosis with catalase or cyclosporine A did not prevent induction of ODC or c-Myc (data not shown), indicating that the process of apoptosis itself is not required to stimulate this pathway of polyamine generation.…”