Arginase II Restricts Host Defense to <i>Helicobacter pylori</i> by Attenuating Inducible Nitric Oxide Synthase Translation in Macrophages

Lewis, Nuruddeen D.; Asim, Mohammad; Barry, Daniel P.; Singh, Kshipra; Sablet, Thibaut de; Boucher, Jean‐Luc; Gobert, Alain P.; Chaturvedi, Rupesh; Wilson, Keith T.

doi:10.4049/jimmunol.0902436

Cited by 84 publications

(109 citation statements)

References 58 publications

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“…In H. pylori-stimulated macrophages, iNOS protein translation is dependent on the level of L-Arg in culture medium and bacterial killing requires high levels of L-Arg (46). Consistent with this, increased iNOS translation and NO production occurred with inhibition of arginase or siRNA knockdown of Arg2 or in primary macrophages from Arg2 Ϫ/Ϫ mice, while oral administration of an arginase inhibitor to H. pylori-infected mice increased iNOS protein expression and NO production by gastric macrophages (174). Second, Arg2 has a central role in inducing apoptosis of macrophages, which is dependent on the metabolism of its product, L-ornithine, into polyamines (116).…”

Section: General Considerations For Innate and Adaptive Immunitysupporting

confidence: 53%

Helicobacter pyloriand Gastric Cancer: Factors That Modulate Disease Risk

Wroblewski¹,

2010

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SUMMARY Helicobacter pylori is a gastric pathogen that colonizes approximately 50% of the world's population. Infection with H. pylori causes chronic inflammation and significantly increases the risk of developing duodenal and gastric ulcer disease and gastric cancer. Infection with H. pylori is the strongest known risk factor for gastric cancer, which is the second leading cause of cancer-related deaths worldwide. Once H. pylori colonizes the gastric environment, it persists for the lifetime of the host, suggesting that the host immune response is ineffective in clearing this bacterium. In this review, we discuss the host immune response and examine other host factors that increase the pathogenic potential of this bacterium, including host polymorphisms, alterations to the apical-junctional complex, and the effects of environmental factors. In addition to host effects and responses, H. pylori strains are genetically diverse. We discuss the main virulence determinants in H. pylori strains and the correlation between these and the diverse clinical outcomes following H. pylori infection. Since H. pylori inhibits the gastric epithelium of half of the world, it is crucial that we continue to gain understanding of host and microbial factors that increase the risk of developing more severe clinical outcomes.

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Section: General Considerations For Innate and Adaptive Immunitysupporting

confidence: 53%

Helicobacter pyloriand Gastric Cancer: Factors That Modulate Disease Risk

Wroblewski¹,

2010

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“…In the present study, increased arginase activity in VL was found to be associated with upregulation of arginase 1 enzyme at both the mRNA and protein level. Though mitochondrial arginase 2 expression could restrict macrophage NO production in Helicobacter pylori infection [30], we have excluded the role of arginase 2 in increasing arginase activity as arginase 2 was not induced in L. donovani-infected mice.…”

Section: Discussionmentioning

confidence: 99%

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

et al. 2011

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Although enhanced macrophage-specific arginase activity is directly related to increased parasite burden in cutaneous leishmaniasis (CL), the regulation and precise role of arginase in the disease outcome of visceral leishmaniasis (VL) has yet to be explored. As in CL, BALB/c mice infected with Leishmania donovani showed increased levels of arginase in acute infection. Arginase 1 is the major isoform associated with infection and while the IL-4-induced arginase pathway is operative in CL, IL-10 plays a crucial role in modulating arginase activity in VL, although a synergism with IL-4 is required. IL-10, in combination with IL-4, regulated both in vivo and ex vivo arginase 1 induction in a STAT6 and C/EBPbdependent fashion. Further investigation toward the cause of such synergism suggests that induction of a STAT3-dependent IL-10-mediated cascade in VL triggers the expression and surface localization of the IL-4 receptor alpha (IL-4Ra) which, in turn, enhances IL-4 responsiveness toward STAT6 and C/EBPb-dependent signaling for arginase 1. This could also offer a mechanistic explanation for the fact that, in spite of the low level of IL-4 in VL, enhanced IL-4-Ra expression by IL-10 might markedly amplify IL-4-mediated arginase 1 signaling and provide a possible mechanism for synergistic induction of arginase 1.Keywords: Arginase 1 . IL-4 . IL-10 . IL-4 receptor a . Visceral leishmaniasis IntroductionArginase is classically considered as a rate-limiting enzyme of the urea cycle in liver, but has been found to be present in a number of organs and tissues where the urea cycle is not operative. To date, two distinct isoforms of arginase have been identified in mammals. They are encoded by different genes differing in their cellular localization as well as their mode of regulation: type 1 arginase, a cytosolic enzyme expressed at high levels in liver, and type 2 arginase, a mitochondrial enzyme found in several tissues in addition to liver [1]. A growing body of evidence suggests that arginase induction is correlated with parasite-specific immunosuppression of host, thereby facilitating pathogen survival and growth inside the hostile environment of phagocytic cells. Macrophages were found to upregulate arginase 1 expression upon activation by Th2 cytokines and shown to have a detrimental role in parasite infection by limiting the Th1-dependent parasite clearance [2]. Interestingly, cAMP and TGFb are known to induce arginase 1 induction in macrophages [3]. In Chagas disease, induction of the arginase pathway could be used by Trypanosoma cruzi to spread inside host [4]. Arginase activity was triggered in macrophages from mice infected with the helminth Schistosoma mansoni and was associated with an increase in concentration of circulating L-ornithine-derived polyamines [5]. Intracellular pathogens like Salmonella enterica and Mycobacterium tuberculosis also utilize host arginase for their own 992survival within the macrophages [6,7]. Moreover, in bacteria like Helicobacter pyroli, arginase plays a major role in its surv...

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“…In some studies macrophages were also activated with live H. pylori SS1 at an MOI of 10 (2, 34). C. rodentium was grown, and lysates were prepared as described (35). C. jejuni was obtained from ATCC, and lysates were prepared as for H. pylori.…”

Section: Methodsmentioning

confidence: 99%

“…C57BL/6 mice were inoculated by oral gavage with 5 ϫ 10 8 colony-forming units of H. pylori in 0.1 ml of Brucella broth or broth vehicle control. For the colonization time points of 14, 60, and 120 days, the mice were gavaged every other day three times (7,36), whereas for the time points of 1-7 days, the mice were inoculated once (35). In some studies, the mice were treated with PD98059 (5 mg/kg) or vehicle control (2% dimethyl sulfoxide) by intraperitoneal injection just prior to inoculation.…”

Section: Methodsmentioning

confidence: 99%

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Helicobacter pylori Induces ERK-dependent Formation of a Phospho-c-Fos·c-Jun Activator Protein-1 Complex That Causes Apoptosis in Macrophages

Asim

Chaturvedi

Hoge

et al. 2010

Journal of Biological Chemistry

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Macrophages are essential components of innate immunity, and apoptosis of these cells impairs mucosal defense to microbes. Helicobacter pylori is a gastric pathogen that infects half of the world population and causes peptic ulcer disease and gastric cancer. The host inflammatory response fails to eradicate the organism. We have reported that H. pylori induces apoptosis of macrophages by generation of polyamines from ornithine decarboxylase (

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Arginase II Restricts Host Defense to Helicobacter pylori by Attenuating Inducible Nitric Oxide Synthase Translation in Macrophages

Cited by 84 publications

References 58 publications

Helicobacter pyloriand Gastric Cancer: Factors That Modulate Disease Risk

Helicobacter pyloriand Gastric Cancer: Factors That Modulate Disease Risk

Expression of IL‐10‐triggered STAT3‐dependent IL‐4Rα is required for induction of arginase 1 in visceral leishmaniasis

Helicobacter pylori Induces ERK-dependent Formation of a Phospho-c-Fos·c-Jun Activator Protein-1 Complex That Causes Apoptosis in Macrophages

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