Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lactoferrin (LF) is a member of the transferrin family of iron-binding glycoproteins to which several anti-inflammatory functions have been ascribed. LF has been shown to down-regulate expression of the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha), although the possibility has been raised that the activity of LF in this regard was indirect and secondary to its ability to bind to and inactivate the bacterial lipopolysaccharide (LPS) used to induce cytokine production. However, the identification of putative membrane receptors for LF raises the possibility that the interaction of LF with its receptor may be one important route through which this protein exerts anti-inflammatory activity. In the present investigations the biological properties of LF have been examined in a model of cutaneous immune function where the allergen-induced migration of epidermal Langerhans cells (LC) from the skin and their subsequent accumulation as dendritic cells (DC) in skin-draining lymph nodes are known to be dependent upon the de novo synthesis of TNF-alpha, but independent of exogenous LPS. Consistent with the protein having direct anti-inflammatory properties, it was found that the intradermal injection of recombinant murine LF (either iron-saturated or iron-depleted LF) inhibited significantly allergen (oxazolone) -induced LC migration and DC accumulation. That these inhibitory effects were secondary to the inhibition of local TNF-alpha synthesis was suggested by the findings that first, LF was unable to inhibit LC migration induced by intradermal injection of TNF-alpha itself, and second, that migration stimulated by local administration of another epidermal cytokine, interleukin 1beta, which is also dependent upon TNF-alpha production, was impaired significantly by prior treatment with LF. Finally, immunohistochemical analyses demonstrated the presence of LF in skin, associated primarily with keratinocytes. Collectively these data support the possession by LF of direct immunomodulatory and/or anti-inflammatory activity, probably associated in this case with inhibition of cytokine production. Furthermore, the results suggest that as a constituent of normal skin, LF may play a role in homeostatic regulation of cutaneous immune function.
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PMID:Regulation of epidermal Langerhans cell migration by lactoferrin. 1080 55

Ingestion of thalidomide was associated with a reduction in the upregulation of the granulocyte activation marker CD11b and a reduced capacity to release elastase and lactoferrin after stimulation with lipopolysaccharide or lipoteichoic acid. A single oral dose of thalidomide attenuates neutrophil activation upon ex vivo stimulation with bacterial antigens.
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PMID:Thalidomide inhibits granulocyte responses in healthy humans after ex vivo stimulation with bacterial antigens. 1130 25

BALB/c mice were intravenously injected with lipopolysaccharide (LPS) (0.05 microg/g of body weight) 7 days after being primed with zymosan. Recombinant human lactoferrin (250 microg/g of body weight), intravenously administered 1 day before the injection of LPS, significantly lessened the severity of hepatitis, as assessed by levels of serum alanine transaminase compared to those seen when casein was administered. The transient rise of serum tumor necrosis factor alpha (TNF-alpha) after LPS treatment was also significantly lowered by the intravenous administration of lactoferrin, suggesting that the effect of lactoferrin was due to the suppression of TNF-alpha production. The following results indicate that the sites of action of lactoferrin for the suppression of the development of this type of hepatitis are Kupffer cells. Gadolinium chloride, a substance known to eliminate Kupffer cells, administered 1 day before LPS, inhibited the transient rise of TNF-alpha and protected against the development of hepatitis. Kupffer cells isolated from mice intraperitoneally injected with recombinant human lactoferrin became refractory to LPS. The specific interaction of recombinant human lactoferrin with the Kupffer cells was shown by a binding assay, which revealed two types of binding sites on mouse Kupffer cells. Of the two dissociation constants determined in this way, the lower dissociation constant, 0.47 x 10(-6) M, was within the range of the 50% effective doses for the suppression of TNF-alpha production. These results suggest that recombinant human lactoferrin administered to mice suppresses the production of TNF-alpha by Kupffer cells by directly associating with the binding sites on these cells.
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PMID:Lactoferrin protects against development of hepatitis caused by sensitization of Kupffer cells by lipopolysaccharide. 1168 69

The effect of oral administration of lactoferrin (LF) was studied to determine if it could modify post-surgical immune response. The action of LF was evaluated in 18 LF-treated patients vs 28 placebo counterparts. Patients (women and men, mean age 50 years) were given daily oral doses (20 mg each) of LF for 5 consecutive days prior to thyroid surgery. The following immune response parameters were determined in blood samples taken from the patients day before, day after, and 5-7 days following surgery: cell morphology, the proliferative response of peripheral blood mononuclear cells to phytohemagglutinin, and the spontaneous and lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). As a consequence of the thyroid surgery, the total leukocyte count increased on the post-operative day by about 50% in all patients and the percentage of lymphocytes fell by 26 and 35% in the control vs LF-treated group. The content of neutrophils, on the other hand, elevated on day 1 post-operation by 51 and 68%, respectively. The percent of neutrophil precursors was markedly higher in LF-treated patients, particularly on the day before and the day after surgery (4.1 and 4.8 vs 2.5 and 3.7%, respectively). The post-surgical values were, however, comparable in both groups for neutrophils. The proliferative response of lymphocytes showed a slight decrease in the control group and an increase in the LF-treated patients on day 5 post-operation (20% over control group). LPS-induced TNF-alpha production was higher in LF-treated patients both one day before and one day following surgery (28 and 24%, respectively). LPS-induced IL-6 production was comparable in both placebo and LF-treated patients before surgery, however, on day 1 and 5 following surgery, the production of IL-6 was higher in LF-treated patients by 65 and 27%, respectively. Taken together, the data presented in this study revealed an increased immune responsiveness in all patients treated with LF and subjected to thyroid surgery. This suggests that treatment with LF could constitute an effective protective measure against post-surgical complications.
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PMID:Lactoferrin regulates the immune responses in post-surgical patients. 1172 36

Interleukin-8 (IL-8), a C-X-C chemokine bound to endothelium proteoglycans, initiates the activation and selective recruitment of leukocytes at inflammatory foci. We demonstrate that human lactoferrin, an antimicrobial lipopolysaccharide (LPS)-binding protein, decreases both IL-8 mRNA and protein expression induced by the complex Escherichia coli 055:B5 LPS/sCD14 in human umbilical vein endothelial cells. The use of recombinant lactoferrins mutated in the LPS-binding sites indicates that this inhibitory effect is mediated by an interaction of lactoferrin with LPS and CD14s that suppresses the endotoxin biological activity. Furthermore, since dimeric IL-8 and lactoferrin are both proteoglycan-binding molecules, the competition between these proteins for heparin binding was investigated. Lactoferrin strongly inhibited the interaction of radiolabeled IL-8 to immobilized heparin, whereas a lactoferrin variant lacking the amino acid residues essential for heparin binding was not inhibitory. Moreover, this process is specific, since serum transferrin, a glycoprotein whose structure is close to that of lactoferrin, did not prevent the interaction of IL-8 with heparin. These results suggest that the anti-inflammatory properties of lactoferrin during septicemia are related, at least in part, to the regulation of IL-8 production and also to the ability of lactoferrin to compete with chemokines for their binding to proteoglycans.
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PMID:Lactoferrin inhibits the lipopolysaccharide-induced expression and proteoglycan-binding ability of interleukin-8 in human endothelial cells. 1189 48

We have previously shown that iron-containing human lactoferrin (LF) purified from breast milk is able to form both in vitro and in vivo a complex with ceruloplasmin (CP), the copper-containing protein of human plasma. Here we present evidence that the CP-LF complex is dissociated by high concentrations of NaCl, CaCl2, or EDTA, or by decreasing the pH to 4.7. In addition, DNA, bacterial lipopolysaccharide, and heparin can displace CP from its complex with LF. Antibodies to either of the two proteins also cause dissociation of the complex.
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PMID:Studies of the ceruloplasmin-lactoferrin complex. 1190 41

Bovine lactoferrin (bLf) is known to damage the outer membrane of Gram-negative bacteria by binding to bacterial lipopolysaccharide (LPS). We report that LPS is released from bacterial outer membranes also when apo- or metal-saturated Lf is separated from bacterial cells by a dialysis membrane. This process occurs in phosphate-buffered saline with no added Ca2+ and Mg2+ and is hindered by addition of these cations. The effect of bLf is similar to that induced by EDTA and has been ascribed to chelation of Ca2+. In fact, it may be envisaged that Ca2+-binding sites on LPS have different affinities and that bLf can remove those ions that are more weakly bound. Ca2+ binding does not alter Lf iron-binding properties significantly or its UV and CD spectral features but brings about changes in the FT-IR bands due to carboxylate residues. Ca2+ binding is characterized by an apparent dissociation constant of 6 microM and a stoichiometry of 1.55 Ca2+ per Lf molecule; it enhances bLf stability towards chemical and thermal denaturation. The increase in stability takes place in both the apo- and iron-saturated forms but not in the desialilated protein, indicating that the carboxylate groups of the sialic acid residues present on two of the glycan chains are involved in Ca2+ binding.
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PMID:Ca2+ binding to bovine lactoferrin enhances protein stability and influences the release of bacterial lipopolysaccharide. 1190 42

A number of host and microbial factors have been shown to modulate HIV-1 infection. Their inhibitory effects are either HIV-specific or non-specific, and involve many different kinds of mechanisms. Among anti-HIV host factors are natural ligands or natural antibodies to HIV coreceptors, anti-inflammatory cytokines, interferons and several body fluid components (such as lactoferrin and prostaglandins). Microbial pathogens/factors that may suppress HIV-1 infection include lipopolysaccharide, scrub-typhus rickettsia, human herpesviruses-6 or -7, and GB virus C. While simple application of these HIV-suppressive factors for HIV-infected individuals is not realistic, investigation of mechanisms involved may lead to better understanding of HIV pathogenesis and help establish novel anti-HIV strategy.
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PMID:[HIV-suppressive factors]. 1196 71

beta-defensin 2 is produced by a variety of epithelial cell types in the body and exhibits potent antimicrobial activity against a variety of pathogens, including the bacteria that are most commonly associated with otitis media (OM). The human beta-defensin 2 (hBD-2) gene is an NF-kappa B regulated gene and a variety of proinflammatory stimuli can induce its expression. Although the presence of molecules of innate immunity such as lysozyme and lactoferrin has been demonstrated in the middle ear, to date there have been no reports on the expression of beta-defensin 2. In the present study, we demonstrate that beta-defensin 2 is expressed in the middle ear mucosa of humans and rats. We also show that it is expressed in a human middle ear epithelial cell line and that its expression is induced by proinflammatory stimuli such as interleukin 1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF-alpha), and lipopolysaccharide (LPS). Moreover, we demonstrate that the transcriptional activation of hBD-2 gene by IL-1 alpha is mediated through an Src-dependent Raf-MEK1/2-ERK signaling pathway.
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PMID:Activation of a Src-dependent Raf-MEK1/2-ERK signaling pathway is required for IL-1alpha-induced upregulation of beta-defensin 2 in human middle ear epithelial cells. 1206 67

The iron-binding glycoprotein human lactoferrin (hLF) is involved in the host defense against infection and is a modulator of inflammatory reactions. We generated monoclonal antibodies (mAbs) to hLF as tools to assist both structure-function studies and the development of recombinant human lactoferrin for applications in human health care. Binding experiments with ten distinct anti-hLF mAbs to tryptic and recombinant hLF fragments in ELISA and/or on immunoblots revealed that five mAbs bound to conformational epitopes residing in the N-lobe (residues 1 to 334), whereas the other five bound to C-lobe conformational epitopes (residues 335 to 692). None of the mAbs bound to hLF denatured upon reduction. Monoclonal antibody E11 appeared to bind to the arginine-rich N-terminus of hLF, which is the binding site for heparin, bacterial lipopolysaccharide, human lysozyme, DNA and receptors. The dissociation constant of the distinct mAbs for hLF ranged from 0.5 to 18 nM, without differences in affinity for unsaturated or iron-saturated hLF, indicating that the conformational changes subject to incorporation of iron do not seem to affect the exposure and/or conformation of the antibody epitopes. The mAbs did not bind to human transferrin, a protein closely related to hLF in size, primary amino acid sequence and structure. Two C-lobe specific mAbs, E2 and E8, cross-reacted with bovine and/or porcine lactoferrin, indicating that human, bovine and porcine lactoferrin share antigenic determinants. This panel of mAbs will be used to develop quantitative and qualitative immunoassays for hLF and to delineate which regions of hLF are relevant to its anti-infective and anti-inflammatory properties.
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PMID:Characterization of monoclonal antibodies against human lactoferrin. 1216 35


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