Disease relevance of Arg1

• Using cytokine-deficient mice and two granuloma models, we show that induction of Arg-1 is type 2 cytokine dependent [1].
• Protective role of arginase in a mouse model of colitis [2].
• Arginase I is hypothesized to play a regulatory and potentially pathogenic role in diseases such as asthma, parasitic, bacterial, and worm infections by modulating NO levels and promoting fibrosis [3].
• Schistosome eggs induce Arg-1, while Mycobacterium avium-infected mice develop a dominant NOS-2 response [1].
• Here, we demonstrate the differential regulation of NOS-2 and arginase type 1 (Arg-1) by type 1/type 2 cytokines in vivo and for the first time show a critical role for arginase in the pathogenesis of schistosomiasis [1].

High impact information on Arg1

• To determine whether these two HDL populations have different effects on atherogenesis, human apoA-I (AI) and human apoA-I and apoA-II (AI/AII) transgenic mice were produced in an atherosclerosis-susceptible strain [4].
• These studies show that the protein composition of HDL significantly affects its role in atherogenesis and that AI-HDL is more antiatherogenic than AI/AII-HDL [4].
• Activated macrophages kill tumour cells by releasing arginase [5].
• In particular, sildenafil, down-regulates arginase 1 and nitric oxide synthase-2 expression, thereby reducing the suppressive machinery of CD11b(+)/Gr-1(+) myeloid-derived suppressor cells (MDSCs) recruited by growing tumors [6].
• Signaling through the PGE2 receptor E-prostanoid 4 expressed in MSCs induced arginase I [7].

Chemical compound and disease context of Arg1

• Induction of arginase I and II in bleomycin-induced fibrosis of mouse lung [8].
• Hyperargininemia is a urea cycle disorder caused by mutations in the gene for arginase I (AI) resulting in elevated blood arginine and ammonia levels [9].
• This is the first demonstration that the fatal hyperammonemia in the AI knockout mouse is almost certainly due to ornithine deficiency, the amino acid needed to drive the urea cycle [10].
• These results identify a mechanism of immune dysregulation induced by H. pylori in which stimulated spermine synthesis by the arginase-ODC pathway inhibits iNOS translation and NO production, leading to persistence of the bacterium and risk for peptic ulcer disease and gastric cancer [11].
• 8-Bromo-cyclic adenosine monophosphate (8-Br-cAMP, 0.5 mM), recombinant murine interleukin 4 (rmIL-4, 20 U/mL), Escherichia coli lipopolysaccharide (100 ng/mL), and hypoxia (1% O2) induced arginase activity in C/EBPbeta+/+ macrophages, where enzyme activity correlated with arginase I protein [12].

Biological context of Arg1

• Ab blocking experiments revealed the critical importance of IL-4 and IL-10 for arginase up-regulation [13].
• Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype [13].
• We show that Th2-inducible arginase I expression in mouse macrophages is controlled by an enhancer that lies -3 kb from the basal promoter [3].
• Therefore, we describe arginase- and ODC-dependent macrophage apoptosis, which implicates polyamines in the pathophysiology of H. pylori infection [14].
• Arginase expression in mouse embryonic development [15].

Anatomical context of Arg1

• We show that Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function [16].
• Because Arg1 and iNOS share L-arginine as a common substrate, our results indicate that L-arginine metabolism in myeloid cells is a potential target for selective intervention in reversing myeloid-induced dysfunction in tumor-bearing hosts [16].
• The activation status of macrophages was analyzed in this model of helminth infection by evaluating the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arg1 [17].
• The strong AI expression in the peripheral nervous system suggests that the pathogenesis of the neurological retardation in AI deficiency may be conditioned by AI deficiency in the nervous system during embryonic development [15].
• Arginase induction by sodium phenylbutyrate in mouse tissues and human cell lines [9].

Associations of Arg1 with chemical compounds

• Arginase activity was increased in allergen-challenged lungs, as demonstrated by increased enzyme activity, and increased levels of putrescine, a downstream product [18].
• Importantly, arginase synthesizes ornithine, which is metabolized by the enzyme ornithine decarboxylase (ODC) to produce polyamines [2].
• Arginase I expression in the liver must remain constant throughout life to eliminate excess nitrogen via the urea cycle [3].
• Furthermore, we show that type 2 cytokine-stimulated macrophages produce proline under strict arginase control [1].
• Moreover, inhibition of arginase reduces the number of parasites and delays disease outcome in BALB/c mice, while treatment with l-ornithine increases the susceptibility of C57BL/6 mice [19].
• We found that expression of arginase I and II, as well as that of ornithine decarboxylase, was much higher in BALB/c mice than in C57BL/6 mice and that it was associated with the parasite burden in heart tissue. iNOS and arginase II were expressed by cardiomyocytes [20].

Regulatory relationships of Arg1

• IL-4 alters macrophage arginine metabolism by inducing arginase I expression and inhibiting nitric oxide production [21].
• Lung arginase activity and mRNA expression were strongly induced by IL-4 and IL-13, and were differentially dependent on signal transducer and activator of transcription 6 [18].
• Similarly, high arginase levels could be induced by supernatants of Th2 cells stimulated in various ways [13].
• These data indicate that NO and arginase do not participate in the anti-MHV3 state induced by IFN gamma in macrophages [22].
• Peritonitis increased messenger RNA levels of arginase I and arginase II in controls and SAD mice but with a greater increase in arginase I in SAD than in control mice [23].

Other interactions of Arg1

• Arginase is the endogenous inhibitor of inducible NO synthase (iNOS), because both enzymes use the same substrate, l-arginine (Arg) [2].
• In the AI knockout mouse embryo, no AII overexpression was found [15].
• Others have shown that the expression of ornithine aminotransferase (OAT) rapidly decreases in the intestine at the same age when the AI-deficient animals die, indicating that this enzyme is critical to the maintenance of ornithine homeostasis, at least at this early stage of mouse development [10].
• The induction of the host arginase in both strains is mediated by the balance between interleukin-4 (IL-4) and IL-12 and opposite to nitric oxide synthase II expression [19].
• We found that, outside of liver, AI was expressed in many tissues and cells such as the salivary gland, esophagus, stomach, pancreas, thymus, leukocytes, skin, preputial gland, uterus and sympathetic ganglia [24].

Analytical, diagnostic and therapeutic context of Arg1

• In situ hybridization demonstrated marked staining of arginase I, predominantly in submucosal inflammatory lesions [18].
• Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis [18].
• In this study we undertook an extensive analysis of arginase expression in postnatal mouse tissues by in situ hybridization (ISH) and RT-PCR [24].
• Furthermore, an addition of arginase I represents a clinical approach to enhance the therapeutic potential of cancer immunotherapies [7].
• Microarray analysis of the expression profiles of lung tissue in two murine models of asthma revealed high levels of arginase I and arginase II activity, in association with IL-4 and IL-13 overexpression, suggesting that arginine pathways are critical in the pathogenesis of asthma [25].

References