Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway.

Weiss, Günter; Goossen, B; Doppler, Wolfgang; Fuchs, Dietmar; Pantopoulos, Kostas; Werner-Felmayer, Gabriele; Wächter, Helmut; Hentze, Matthias W.

doi:10.1002/j.1460-2075.1993.tb06039.x

Cited by 374 publications

(246 citation statements)

References 62 publications

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“…2) and this increase is prevented by SnPP. Interestingly, in the presence of SnPP the levels of ferritin decrease substantially, perhaps indicative of nitrogen oxide-mediated downregulation of ferritin expression via activation of the iron-responsive element mechanism, as documented previously [18,19]. This result suggests that in hepatocytes iron liberation from heme by the action of heme oxygenase indeed upregulates ferritin expression.…”

Section: Resultssupporting

confidence: 69%

“…1, except that the duration of the second SNAP treatment was 4 h instead of 12 h. During this abbreviated time there was insignificant cell lysis (not shown), but significant decrease in activities of aconitase and upstream segments of mitochondrial electron transfer. As shown in regulatory mechanisms [18,19]. A similar protective effect is observed on inhibition of mitochondrial electron transfer through complexes I+III+IV and II+III+IV (3B).…”

Section: Resultsmentioning

confidence: 55%

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Nitrogen oxide‐induced autoprotection in isolated rat hepatocytes

Kim

Bergonia

Lancaster³

1995

FEBS Letters

197

110

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Pretreatment of rat hepatocytes with low-dose nitrogen oxide (addition of SNAP in vitro or induction of nitric oxide synthase in vitro or in vivo) imparts resistance to killing and decrease in aconitase and mitochondrial electron transfer from a second exposure to a higher dose of SNAP. Induction of this resistance is prevented by cycloheximide, indicating upregulation of protective protein(s). Ferritin levels are increased as are nonheme iron-NO EPR signals. Tin-protoporphyrin (SnPP) prevents protection, suggesting involvement of hsp32 (heme oxygenase) and/or guanylyl cyclase (GC). Cross-resistance to H2Oz killing is also observed, which is also prevented by cycloheximide and SnPP. Thus, hepatocytes possess inducible protective mechanisms against nitrogen oxide and reactive oxygen toxicity.

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Section: Resultssupporting

confidence: 69%

Section: Resultsmentioning

confidence: 55%

Nitrogen oxide‐induced autoprotection in isolated rat hepatocytes

Kim

Bergonia

Lancaster³

1995

FEBS Letters

197

110

View full text Add to dashboard Cite

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“…Recent evidence from this group and others indicates, however, that nitric oxide can induce IRE-binding activity in macrophages and other cells (Drapier et al, 1993;Weiss et al, 1993) and the possibility that small mediators might be capable of disrupting the cluster remains open. Another possible mechanism to control IRE binding in vivo might take advantage of the oxidation-reduction state of the sensitive cysteine 437 in the apo-IRF.…”

Section: Discussionmentioning

confidence: 99%

Mutational analysis of the [4Fe-4S]-cluster converting iron regulatory factor from its RNA-binding form to cytoplasmic aconitase.

1994

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“…For investigation of IRP binding activity, a 32 P-labeled IRE probe was prepared by an in vitro transcription procedure exactly as described [63] and the analysis of RNA/protein complexes was carried out by nondenaturing gel electrophoresis. The 2-mercaptoethanol (2%) was used for in vitro stimulation of IRP1-binding activity to ensure for equal loading of protein extracts [64].…”

Section: Gel-retardation Assaymentioning

confidence: 99%

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

et al. 2008

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In stimulating effector functions of mononuclear phagocytes, IFN-c is of pivotal importance in host defense against intramacrophage pathogens including salmonellae. As the activity of IFN-c is modulated by iron and since a sufficient availability of iron is essential for the growth of pathogens, we investigated the regulatory effects of IFN-c on iron homeostasis and immune function in murine macrophages infected with Salmonella typhimurium. In Salmonella-infected phagocytes, IFN-c caused a significant reduction of iron uptake via transferrin receptor 1 and resulted in an increased iron efflux caused by an enhanced expression of the iron exporter ferroportin 1. Moreover, the expression of haem oxygenase 1 and of the siderophore-capturing antimicrobial peptide lipocalin 2 was markedly elevated following bacterial invasion, with IFN-c exerting a super-inducing effect. This observed regulatory impact of IFN-c reduced the intracellular iron pools within infected phagocytes, thus restricting the acquisition of iron by engulfed Salmonella typhimurium while concomitantly promoting NO and TNF-a production. Our data suggest that the modulation of crucial pathways of macrophage iron metabolism in response to IFN-c concordantly aims at withdrawing iron from intracellular Salmonella and at strengthening macrophage immune response functions. These regulations are thus consistent with the principles of nutritional immunity. IntroductionHost defense against intracellular microbes such as salmonellae or mycobacteria strongly depends on cell-mediated immunity, a major component of which is characterized by interactions between Th1 cells and macrophages [1]. By secreting Th1 cytokines, particularly IFN-c, antigen-specific Th1 cells activate a plethora of microbicidal mechanisms in infected macrophages. Specifically, in mononuclear phagocytes infected with Salmonella enterica serovar typhimurium (S. typhimurium), IFN-c promotes the internalization of bacteria and stimulates their elimination by various mechanisms including reactive oxygen and nitrogen species (ROS and RNS), generated via NADPH phagocyte oxidase and iNOS, respectively [2][3][4][5]. In Salmonella-infected mice, treatment with recombinant IFN-c increases host survival and decreases bacterial numbers in liver and spleen [6]. Conversely, neutralization of murine IFN-c functions with specific antibodies results in reduced host survival and increased bacterial counts [7]. Eur. J. Immunol. 2008. 38: 1923-1936 Immunity to infection In humans, the central importance of IFN-c for immune response against salmonellae is highlighted by the fact that patients with genetic defects in the IL-12-induced production of IFN-c or in the IFN-c receptor 1 selectively suffer from infections with salmonellae and otherwise weakly pathogenic mycobacteria since their phagocytes fail to eliminate these microbes [8,9]. Iron serves as an essential nutrient for nearly all pathogenic microorganisms, and the expression of iron acquisition systems by infectious agents is associated with their virule...

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Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway.

Cited by 374 publications

References 62 publications

Nitrogen oxide‐induced autoprotection in isolated rat hepatocytes

Nitrogen oxide‐induced autoprotection in isolated rat hepatocytes

Mutational analysis of the [4Fe-4S]-cluster converting iron regulatory factor from its RNA-binding form to cytoplasmic aconitase.

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

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