Membrane-bound lactoferrin alters the surface properties of polymorphonuclear leukocytes.

Boxer, Laurence A.; Haak, Richard A.; Yang, Hsin-Hsin; Wolach, JB; Whitcomb, James; Butterick, Charles J.; Baehner, Robert L.

doi:10.1172/jci110692

Cited by 91 publications

(37 citation statements)

References 44 publications

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“…Lactoferrin receptors have been described previously for a variety of cells, including various leukocytes (34 -39) and epithelial cells (40). The binding affinities reported for the different cells vary widely, with the dissociation constants ranging from nanomolar to micromolar concentrations (34,35,(37)(38)(39)41). The results presented here for binding of 125 I-labeled lactoferrin by the eosinophils indicate that the affinity of the lactoferrin receptor on eosinophils also falls within this range.…”

Section: Discussionsupporting

confidence: 52%

“…It is likely that the apparent two classes of lactoferrin receptors reflect at least in part the relative structural complexity of the 78-kDa lactoferrin molecule (24 -26). Of note, the apparent number of lactoferrin receptor molecules expressed by eosinophils is less than that reported for other cells (34,35,(37)(38)(39)41). Although complete saturation was not achieved in the binding experiments using 125 I-labeled lactoferrin, the results of the flow cytometric analysis indicate that binding of the lactoferrin by eosinophils is saturated following incubation with 30 g/ml (ϳ0.4 M) lactoferrin.…”

Section: Discussionmentioning

confidence: 62%

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Immobilized Lactoferrin Is a Stimulus for Eosinophil Activation

Thomas

Ardon

2002

The Journal of Immunology

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Eosinophils are strongly implicated in the pathogenesis of asthma, particularly in damage to the airway epithelial lining. We examined the potential for lactoferrin, a multifunctional glycoprotein present in the airway surface liquid, to activate eosinophils. Incubating eosinophils in tissue culture wells pretreated with 1–100 μg/ml human lactoferrin stimulated concentration-dependent superoxide production by eosinophils. The same concentrations of immobilized transferrin were without effect. The potency of immobilized lactoferrin was approximately one-third that of immobilized secretory IgA in the same experiments. In contrast, immobilized lactoferrin did not stimulate neutrophil superoxide production. Eosinophils bound lactoferrin as determined by flow cytometry and by binding of 125I-labeled lactoferrin. Transferrin did not block binding of 125I-labeled lactoferrin. Soluble lactoferrin, however, did not activate the eosinophils and did not block superoxide production stimulated by immobilized lactoferrin. Immobilized lactoferrin also stimulated release of eosinophil-derived neurotoxin and low levels of leukotriene C4 production; the latter was significantly enhanced in the presence of 100 pg/ml GM-CSF. GM-CSF also enhanced superoxide production and eosinophil-derived neurotoxin release stimulated by the lower concentrations of immobilized lactoferrin. Pretreatment of the lactoferrin with peptide N-glycosidase F or addition of heparin or chondroitin sulfate to the incubation contents had no or only a minimal effect on the activity of immobilized lactoferrin. These results demonstrate that lactoferrin adherent to the surface epithelium may contribute to the activation of eosinophils that infiltrate the airway lumen in eosinophil-associated disorders such as asthma.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 62%

Immobilized Lactoferrin Is a Stimulus for Eosinophil Activation

Thomas

Ardon

2002

The Journal of Immunology

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“…However, our results do not rule out that the DNA-binding protein whose expression is increased upon neutrophil activation is not a DNA receptor responsible for activation but a protein able to bind DNA and consequently cooperate in DNA binding to a transducing receptor. In fact, previous studies demonstrated that lactoferrin, a cationic protein contained in specific granules, is mobilized to plasma membrane upon neutrophil activation 48 and exhibits DNA-binding properties. 49 Moreover, we have also determined that myeloperoxidase and catepsin G, two cationic proteins contained in azurophilic granules, are able to bind DNA (JI Fuxman Bass, unpublished results).…”

Section: Discussionmentioning

confidence: 99%

Characterization of bacterial DNA binding to human neutrophil surface

Bass

Gabelloni

Álvarez

et al. 2008

Laboratory Investigation

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Bacterial DNA activates neutrophils through a CpG-and TLR9-independent mechanism. Neutrophil activation does not require DNA internalization, suggesting that it results from the interaction of bacterial DNA with a neutrophil surface receptor. The aim of this study was to characterize the interaction of bacterial DNA with the neutrophil surface. Bacterial DNA binding showed saturation and was inhibited by unlabeled DNA but not by other polyanions like yeast tRNA and poly-A. Resembling the conditions under which bacterial DNA triggers neutrophil activation, binding was not modified in the presence or absence of calcium, magnesium or serum. Treatment of neutrophils with proteases not only dramatically reduced bacterial DNA binding but also inhibited neutrophil activation induced by bacterial DNA. Experiments performed with DNA samples of different lengths obtained after digestion of bacterial DNA with DNase showed that only DNA fragments greater than E170-180 nucleotides competed bacterial DNA binding and retained the ability to trigger cell activation. Treatment of neutrophils with chemoattractants or conventional agonists significantly increased bacterial DNA binding. Moreover, neutrophils that underwent transmigration through human endothelial cell monolayers even in the absence of chemoattractants, exhibited higher binding levels of bacterial DNA. Together, our findings provide evidence that binding of bacterial DNA to neutrophils is a receptor-mediated process that conditions the ability of DNA to trigger cell activation. We speculate that neutrophil recognition of bacterial DNA might be modulated by the balance of agonists present at inflammatory foci. This effect might be relevant in bacterial infections with a biofilm etiology, in which extracellular DNA could function as a potent neutrophil agonist.

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“…Various reports indicate that LF may influence neutrophil recruitment to sites of infection by altering aggregation, adhesion, attachment, and/or motility of this cell type. [35][36][37][38] In addition, it has been shown that LF stimulates phagocytosis. 39,40 Finally, an enhancement of superoxide production by neutrophils was demonstrated in the presence of LF 37 whereas contradictory reports in neutrophils and cell-free systems support either an enhancement [41][42][43] or no effect 44,45 of LF on hydroxyl radical formation.…”

mentioning

confidence: 99%

Stimulus-Dependent Impairment of the Neutrophil Oxidative Burst Response in Lactoferrin-Deficient Mice

Ward

Mendoza-Meneses

Park

et al. 2008

The American Journal of Pathology

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Lactoferrin (LF) is an iron-binding protein found in milk, mucosal secretions, and the secondary granules of neutrophils in which it is considered to be an important factor in the innate immune response against microbial infections. Moreover, LF deficiency in the secondary granules of neutrophils has long been speculated to contribute directly to the hypersusceptibility of specific granule deficiency (SGD) patients to severe, life-threatening bacterial infections. However, the exact physiological significance of LF in neutrophil-mediated host defense mechanisms remains controversial and has not yet been clearly established in vivo using relevant animal models. In this study, we used lactoferrin knockout (LFKO) mice to directly address the selective role of LF in the host defense response of neutrophils and to determine its contribution, if any, to the phenotype of SGD. Neutrophil maturation, migration, phagocytosis, granule release, and antimicrobial response to bacterial challenge were unaffected in LFKO mice. Interestingly, a stimulus-dependent defect in the oxidative burst response of LFKO neutrophils was observed in that normal activation was seen in response to opsonized bacteria whereas an impaired response was evident after phorbol myristate-13-acetate stimulation. Taken together, these results indicate that although LF deficiency alone is not a primary cause of the defects associated with SGD, this protein does play an immunomodulatory role in the oxidative burst response of neutrophils.

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Membrane-bound lactoferrin alters the surface properties of polymorphonuclear leukocytes.

Cited by 91 publications

References 44 publications

Immobilized Lactoferrin Is a Stimulus for Eosinophil Activation

Immobilized Lactoferrin Is a Stimulus for Eosinophil Activation

Characterization of bacterial DNA binding to human neutrophil surface

Stimulus-Dependent Impairment of the Neutrophil Oxidative Burst Response in Lactoferrin-Deficient Mice

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