The Roles ofNramp1andTnfaGenes in Nitric Oxide Production and Their Effect on the Growth ofSalmonella typhimuriumin Macrophages fromNramp1Congenic and Tumor Necrosis Factor-α-/-Mice

Ables, Gene P.; Takamatsu, Daisuke; Noma, Hiroko; El-Shazly, Samir Ahmed; Jin, Hee Kyung; Taniguchi, Takahide; Sekikawa, Kenji; Watanabe, Tomomasa

doi:10.1089/107999001459169

Cited by 30 publications

(24 citation statements)

References 47 publications

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“…Being aware of the central role of NO for host resistance against invading microbes (22,41) and the inability of Nramp1-resistant cells to exert antimicrobial effects after pharmacological blockage of NO formation (27), it is suggestive that part of the protective function of Nramp1 to control infections with intracellular pathogens such as Mycobacterium, Salmonella, or Leishmania species (27,29) can be related to its stimulatory effect toward increased and prolonged NO formation.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of NO generation and its modulation by Nramp1 for host defense against intracellular pathogens has been demonstrated by the observation that growth inhibition of mycobacteria by Nramp-resistant cells can be abrogated by the addition of iNOS inhibitors (27). Nramp1 was supposed to stabilize the mRNA of several IFN-␥-inducible genes, such as TNF-␣ (28), and TNF-␣ seems to be an important costimulus for NO production, as TNF-␣ knockout macrophages infected with S. typhimurium show no iNOS expression (29). Thus, the aim of our study was to examine the effect of Nramp1-functionality on iNOS expression and to elucidate the underlying molecular mechanism.…”

Section: N Mice Resistance To Infection With Various Intramacrophamentioning

confidence: 99%

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Nramp1 Functionality Increases Inducible Nitric Oxide Synthase Transcription Via Stimulation of IFN Regulatory Factor 1 Expression

Fritsche

Dlaska

Barton

et al. 2003

The Journal of Immunology

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Natural-resistance associated macrophage protein 1 (Nramp1) encodes a transmembrane phagolysosomal protein exerting resistance toward infections with intracellular pathogens by a mechanism not fully elucidated so far. We used the murine macrophage cell line RAW264.7, stably transfected with functional (RAW-37) or nonfunctional (RAW-21) Nramp1, to study for differences in the expression of NO, a central antimicrobial effector molecule of macrophages. Following stimulation with IFN-γ and LPS, Nramp1-expressing cells exhibit higher enzymatic activity of inducible NO synthase (iNOS) and increased cytoplasmic iNOS mRNA levels than RAW-21 cells. Time-course experiments showed that iNOS-mRNA levels remain increased in RAW-37 cells after prolonged cytokine stimulation while they decrease in RAW-21 cells. Reporter gene assays with iNOS-promoter luciferase constructs demonstrated an increased and prolonged promoter activity in Nramp1-resistant vs susceptible cells. This was paralleled by increased IFN regulatory factor 1 (IRF-1) expression and binding affinity to the iNOS promoter in RAW-37 cells, which may be related to enhanced STAT-1 binding affinity in these cells. A point mutation within the IRF-1 binding site of the iNOS promoter abolished the differences in iNOS transcription between RAW-21 and RAW-37 cells. Cells carrying functional Nramp1 express increased amounts of NO, which may be related to STAT-1-mediated stimulation of IRF-1 expression with subsequent prolonged activation of iNOS transcription. Enhanced NO expression may partly underlie the protection against infection with intracellular pathogens by Nramp1 functionality.

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Section: Discussionmentioning

confidence: 99%

Section: N Mice Resistance To Infection With Various Intramacrophamentioning

confidence: 99%

Nramp1 Functionality Increases Inducible Nitric Oxide Synthase Transcription Via Stimulation of IFN Regulatory Factor 1 Expression

Fritsche

Dlaska

Barton

et al. 2003

The Journal of Immunology

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“…Past studies have shown that Salmonella stimulates the rapid onset of tumor necrosis factor alpha (TNF-␣) following in vivo infection (15,26,39) or in vitro infection (1,11) of macrophages. TNF-␣ together with IFN-␥ activates macrophages for the enhanced killing of Salmonella (31,35).…”

mentioning

confidence: 99%

“…TNF-␣ together with IFN-␥ activates macrophages for the enhanced killing of Salmonella (31,35). Consequently, anti-TNF-␣ treatment exacerbates salmonellosis (28), resulting in diminished nitric oxide (NO) production (1). TNF-␣ has also been shown to be linked to Nramp1 gene expression (1,7).…”

mentioning

confidence: 99%

FimbriatedSalmonella entericaSerovar Typhimurium Abates Initial Inflammatory Responses by Macrophages

2002

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Oral immunization of mice with a Salmonella vaccine expressing colonization factor antigen I (CFA/I) from enterotoxigenic Escherichia coli results in the rapid onset of interleukin-4 (IL-4) and IL-5 production, which explains the observed elevations in mucosal immunoglobulin A (IgA) and serum IgG1 antibodies. In contrast, oral immunization with the Salmonella vector does not result in the production of Th2-type cytokines. To begin to assess why such differences exist between the two strains, it should be noted that in vitro infection of RAW 264.7 macrophages resulted in the absence of nitric oxide (NO) production in cells infected with the Salmonella-CFA/I vaccine. This observation suggests differential proinflammatory cytokine production by these isogenic Salmonella strains. Upon measurement of proinflammatory cytokines, minimal to no tumor necrosis factor alpha (TNF-␣), IL-1␣, IL-1␤, or IL-6 was produced by Salmonella-CFA/I-infected RAW 264.7 or peritoneal macrophages, but production was greatly induced in Salmonella vector-infected macrophages. Only minute levels of IL-12 p70 were induced by Salmonella vector-infected macrophages, and none was induced by Salmonella-CFA/I-infected macrophages. The absence of IL-12 was not due to overt increases in production of either IL-12 p40 or IL-10. CFU measurements taken at 8 h postinfection showed no differences in colonization in RAW 264.7 cells infected with either Salmonella construct, but there were differences in peritoneal macrophages. However, after 24 h, the Salmonella vector strain colonized to a greater extent in RAW 264.7 cells than in peritoneal macrophages. Infection of RAW 264.7 cells or peritoneal macrophages with either Salmonella construct showed no difference in macrophage viabilities. This evidence shows that the expression of CFA/I fimbriae alters how macrophages recognize or process salmonellae and prevents the rapid onset of proinflammatory cytokines which is typical during Salmonella infections.

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“…Con base en las características de esta familia de proteínas, se ha propuesto que el gen Nramp1 afectaría la replicación intrafagosomal de la bacteria alterando el contenido de cationes divalentes y el pH del fagosoma (Grunenheid et al, 1997). En estudios funcionales se ha demostrado que el gen Nramp1 regula la actividad antimicrobial en macrófagos de ratón, a través de la expresión de citoquinas como el factor de necrosis tumoral (TNFα) e interferón gama (IFN-γ) (Ables et al, 2001). También se ha reportado que los macrófagos de bovinos genéticamente resistentes a un desafío infeccioso in vivo con Brucella abortus (cepa 2308) son superiores en su capacidad para controlar su multiplicación bacterial intracelular, al igual que de Salmonella dublin y Mycobacterium bovis; este mecanismo es mediado también por el gen Nramp1 (Barthel et al, 2001).…”

Section: N T R O D U C C I ó Nunclassified

Frecuencias alélicas para variantes SNP en el gen Nramp1 en bovinos infectados con Brucella abortus o clasificados por resistencia al patógeno

Cerquera¹,

Martínez

Toro³

et al. 2009

CTA

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La resistencia natural a la brucelosis en bovinos ha sido asociada a factores genéticos, principalmente a algunos polimorfismos de nucleótido simple ubicados dentro del gen Nramp1. La presente investigación evalúa el efecto de variantes tipo polimorfismos de nucleótido simple presentes en regiones codificantes y en la región 3’UTR del gen Nramp1, en la clasificación de los animales como resistentes o susceptibles; además se determinan los genotipos predominantes en animales naturalmente infectados y comprobados como positivos por la presencia de anticuerpos anti Brucella abortus. Se establecieron las frecuencias genotípicas y alélicas para cinco polimorfismos de nucleótido simple identificados dentro del gen Nramp1 en animales de las razas blanco orejinegro (Bos taurus taurus) y cebú (Bos taurus indicus) y en muestras serológicamente positivas provenientes de animales cruzados (Bos taurus x Bos indicus). La determinación de genotipos se realizó mediante la metodología polimorfismo conformacional de cadena sencilla. Se realizó un ensayo de desafío infeccioso in vitro, para estimar la capacidad de los macrófagos bovinos para controlar la sobrevivencia bacterial, lo que permitió definir los individuos como resistentes o susceptibles. Los resultados sugieren una asociación significativa del SNP4 (p = 0,0506) con la variación para el fenotipo de susceptibilidad, pues se encontró el genotipo homocigoto (BB) en alta frecuencia en animales catalogados como resistentes y el genotipo heterocigoto (AB) en alta frecuencia en animales catalogados como susceptibles y en animales con títulos de anticuerpos anti Brucella abortus. Allelic frequencies for SNP variants in the gene Nramp1 in bovine infected with Brucella abortus or classified by resistance to the pathogen The natural resistance to brucellosis in cattle has been associated to genetic factors mainly to some single nucleotide polymorphism (SNP), located within Nramp1 gen. The current research has studied the effect of nucleotide variants to be found in coding regions and other one located in 3 non translated region of Nramp1 gene, on the animal classification as resistant or susceptible, moreover was identified the main genotypes to be found on the infected animals, confirmed as positives by antibody antibrucella titles. Was established the genotypic and allelic frequencies for five single nucleotide polymorphism in animals from blanco orejinegro (Bos taurus taurus) and zebu breeds (Bos taurus indicus) and serum samples belonging to positive crossbred animals (Bos taurus x Bos indicus). The genotype was defined by the methodology known as “single strand conformational polymorphism”. To estimate the macrophage capacity to control the bacterial survival, an in vitro assay was performed, which allowed define the phenotype as resistant or susceptible. The results suggest a significant association for SNP4 (p = 0.0506) with the phenotypic variation for resistant or susceptibility, because was found the genotype (BB) at higher frequency in susceptible animals and naturally infected animals, than those resistant animals.

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The Roles ofNramp1andTnfaGenes in Nitric Oxide Production and Their Effect on the Growth ofSalmonella typhimuriumin Macrophages fromNramp1Congenic and Tumor Necrosis Factor-α^-/-Mice

Cited by 30 publications

References 47 publications

Nramp1 Functionality Increases Inducible Nitric Oxide Synthase Transcription Via Stimulation of IFN Regulatory Factor 1 Expression

Nramp1 Functionality Increases Inducible Nitric Oxide Synthase Transcription Via Stimulation of IFN Regulatory Factor 1 Expression

FimbriatedSalmonella entericaSerovar Typhimurium Abates Initial Inflammatory Responses by Macrophages

Frecuencias alélicas para variantes SNP en el gen Nramp1 en bovinos infectados con Brucella abortus o clasificados por resistencia al patógeno

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