Iron withholding: a defense against infection and neoplasia.

Weinberg, Eugene D.

doi:10.1152/physrev.1984.64.1.65

Cited by 807 publications

(428 citation statements)

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“…Lactoferrin possesses multiple biological functions, including bactericidal and bacteriostatic activities [11][12][13][14][15], anti-and pro-inflammatory responses [16], promotion of B-and T-cell maturation [17,18], and enhancement of the delayed type hypersensitivity (DTH) to defined antigens [19][20][21]. Mice immunized with BCG in the presence of bovine lactoferrin demonstrated increased host protection post-challenge with virulent MTB, as observed by decreasing organ bacterial load and pulmonary disease granulomatous pathology.…”

Section: Introductionmentioning

confidence: 99%

Influence of bovine lactoferrin on expression of presentation molecules on BCG-infected bone marrow derived macrophages

Hwang¹,

Kruzel

Actor³

2009

Biochimie

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The current vaccine for tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is an attenuated strain of Mycobacterium bovis bacillus Calmette-Guerin (BCG). BCG has proven to be effective in children, however, efficacy wanes in adulthood. Lactoferrin, a natural protein with immunomodulatory properties, is a potential adjuvant candidate to enhance efficacy of BCG. These studies define bovine lactoferrin as an enhancer of the BCG vaccine, functioning in part by modulating macrophage ability to present antigen and stimulate T-cells. BCG-infected bone marrow derived macrophages (BMMs) cultured with bovine lactoferrin increased the number of MHC II + expressing cells. Addition of IFN-γ and lactoferrin to BCG-infected BMMs enhanced MHC II expressiona dna increased the ratio of CD86/CD80. Lactoferrin treated BCG-infected BMMs were able to stimulate an increase in IFN-γ production from presensitized CD3 + splenocytes. Together, these results demonstrate that bovine lactoferrin is capable of modulating BCG-infected macrophages to enhance T-cell stimulation through increased surface expression of antigen presentation and costimulatory molecules, which potentially explains the observed in vivo bovine lactoferrin enhancement of BCG vaccine efficacy to protect against virulent MTB infection.

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Section: Introductionmentioning

confidence: 99%

Influence of bovine lactoferrin on expression of presentation molecules on BCG-infected bone marrow derived macrophages

Hwang¹,

Kruzel

Actor³

2009

Biochimie

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“…This system effectively maintains the free iron concentration in body fluid at an extremely low level insufficient for microbial growth. However, microbial pathogens have collectively evolved a diverse repertoire of highly effective iron acquisition mechanisms, some of which appear to be specifically "designed" to defeat the ironwithholding system or to target iron-rich niches of the host (3)(4)(5)(6). For example, pathogenic Neisseria species have surface receptors specific for the host extracellular iron-binding proteins transferrin and lactoferrin, turning the two major components of the host iron-withholding system into their iron sources (7,8).…”

mentioning

confidence: 99%

Characterization and Functional Analysis of the Siderophore-Iron Transporter CaArn1p in Candida albicans

Bai

Zheng

et al. 2002

Journal of Biological Chemistry

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Siderophores are small organic compounds with high affinity for ferric iron. Microorganisms commonly acquire iron via siderophore secretion and uptake. Here we report the characterization of the siderophore transporter CaArn1p in the fungal pathogen Candida albicans. Deletion of CaARN1 reduced the ability of C. albicans to use iron bound to the hydroxamate-type siderophore ferrichrome and abolished it when two high-affinity iron permease genes (CaFTR1 and CaFTR2) were also deleted, indicating a role of CaArn1p as well as the permeases in ferrichrome-iron uptake. Caarn1⌬ (but not Caftr1⌬Caftr2⌬) assimilated iron from another hydroxamate-type siderophore, ferrioxamine B, suggesting that iron uptake from this compound depends on the permeases, but not on CaArn1p. Northern blot analysis revealed that the transcription repressor CaTup1p repressed CaARN1 expression under iron-replete conditions via the DNA-binding protein Rfg1p. Green fluorescent protein-tagged CaArn1p was observed predominantly in the plasma membrane, with some in the cytoplasm as distinct spots. The number of these spots increased with the increase in ferrichrome concentration, suggesting that CaArn1p internalization might be a mechanism for ferrichrome-iron uptake or for recycling the transporter. Caarn1⌬ did not show reduced virulence when injected into the blood stream of mice, implying that CaArn1p is not required for iron uptake along this route of infection.

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“…Iron is easily cycled between two redox states, ferrous ions (Fe 2+ ) and ferric ions (Fe 3+ ), which provide electrons for enzymatic and free radical reactions [20,21]. Although iron deficiency can cause anemia leading to decreased oxygen transport [22], its excess can also cause damage leading to adverse health effects, such as inflammation and cancer [23][24][25][26][27][28][29][30][31][32]. The damage caused by excess iron is thought to be mediated by redox cycling between ferrous and ferric states, via Haber-Weiss, Fenton, or autoxidation reactions, producing powerful oxygen free radicals [33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Altered iron homeostasis involvement in arsenite-mediated cell transformation

Eckard

Chen

et al. 2006

Free Radical Biology and Medicine

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Chronic exposure to low doses of arsenite causes transformation of human osteogenic sarcoma (HOS) cells. Although oxidative stress is considered important in arsenite-induced cell transformation, the molecular and cellular mechanisms by which arsenite transforms human cells are still unknown. In the present study, we investigated whether altered iron homeostasis, known to affect cellular oxidative stress, can contribute to the arsenite-mediated cell transformation. Using arsenite-induced HOS cell transformation as a model, it was found that total iron levels are significantly higher in transformed HOS cells in comparison to parental control HOS cells. Under normal iron metabolism conditions, iron homeostasis is tightly controlled by inverse regulation of ferritin and transferrin receptor (TfR) through iron regulatory proteins (IRP). Increased iron levels in arsenite transformed cells should theoretically lead to higher ferritin and lower TfR in these cells than in controls. However, the results showed that both ferritin and TfR are decreased, apparently through two different mechanisms. A lower ferritin level in cytoplasm was due to the decreased mRNA in the arsenitetransformed HOS cells, while the decline in TfR was due to a lowered IRP-binding activity. By challenging cells with iron, it was further established that arsenite-transformed HOS cells are less responsive to iron treatment than control HOS cells, which allows accumulation of iron in the transformed cells, as exemplified by significantly lower ferritin induction. On the other hand, caffeic acid phenethyl ester (CAPE), an antioxidant previously shown to suppress As-mediated cell transformation, prevents As-mediated ferritin depletion. In conclusion, our results suggest that altered iron homeostasis contributes to arsenite-induced oxidative stress and, thus, may be involved in arsenite-mediated cell transformation.

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Iron withholding: a defense against infection and neoplasia.

Cited by 807 publications

References 0 publications

Influence of bovine lactoferrin on expression of presentation molecules on BCG-infected bone marrow derived macrophages

Influence of bovine lactoferrin on expression of presentation molecules on BCG-infected bone marrow derived macrophages

Characterization and Functional Analysis of the Siderophore-Iron Transporter CaArn1p in Candida albicans

Altered iron homeostasis involvement in arsenite-mediated cell transformation

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